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Clinical Trial of Lurbinectedin (PM01183)/Doxorubicin Versus CAV or Topotecan as Treatment in Patients With Small-Cell Lung Cancer (ATLANTIS)

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ClinicalTrials.gov Identifier: NCT02566993
Recruitment Status : Completed
First Posted : October 2, 2015
Results First Posted : October 28, 2021
Last Update Posted : October 28, 2021
Sponsor:
Information provided by (Responsible Party):
PharmaMar

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Small-cell Lung Cancer
Interventions Drug: Lurbinectedin (PM01183)
Drug: Doxorubicin (DOX)
Drug: Cyclophosphamide (CTX)
Drug: Vincristine (VCR)
Drug: Topotecan
Enrollment 613
Recruitment Details

The first randomization took place on 30 August 2016 and the first study treatment was administered on 25 October 2016. The cutoff date for results presented in this Clinical Study Report was 24 February 2020.

A total of 919 patients were screened; 613 of these 919 patients were randomized at a 1:1 ratio to receive any of the study treatments at 135 investigational sites from 20 countries.
Pre-assignment Details  
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and Cyclophosphamide, Doxorubicin and Vincristine (CAV), until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated Creatinine Clearance (CrCL) ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg flat dose. The triple combination was to be administered for up to a maximum of ten cycles
Period Title: Overall Study
Started 307 306
Completed 0 0
Not Completed 307 306
Reason Not Completed
Randomized but not treated             5             16
Progressive disease             213             152
Withdrawal by Subject             12             28
Death             17             23
Physician Decision             10             17
Study drug-related adverse event             20             41
Non study drug-related adverse event             9             9
Symptomatic deterioration             9             16
End of study due to events required for OS analysis according to study protocol had been reached             9             1
Sponsor's decision after incorrect treatment at site             1             1
Screening failure             2             0
Lost to Follow-up             0             1
Symptomatic deterioration, progression disease, and a decision by the Investigator             0             1
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine Total
Hide Arm/Group Description

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg flat dose. The triple combination was to be administered for up to a maximum of ten cycles
 Total of all reporting groups
Overall Number of Baseline Participants 307 306 613
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 307 participants 306 participants 613 participants
63.0
(19 to 83)
63.0
(37 to 82)
63
(19 to 83)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
18-49 years
16
   5.2%
13
   4.2%
29
   4.7%
50-65 years
161
  52.4%
166
  54.2%
327
  53.3%
>65 years
130
  42.3%
127
  41.5%
257
  41.9%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
Female
131
  42.7%
133
  43.5%
264
  43.1%
Male
176
  57.3%
173
  56.5%
349
  56.9%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
White
266
  86.6%
265
  86.6%
531
  86.6%
Black or African American
1
   0.3%
1
   0.3%
2
   0.3%
Asian
0
   0.0%
1
   0.3%
1
   0.2%
Other
2
   0.7%
2
   0.7%
4
   0.7%
Not available
38
  12.4%
37
  12.1%
75
  12.2%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 307 participants 306 participants 613 participants
Argentina
3
   1.0%
4
   1.3%
7
   1.1%
Romania
20
   6.5%
19
   6.2%
39
   6.4%
Hungary
23
   7.5%
23
   7.5%
46
   7.5%
United States
32
  10.4%
30
   9.8%
62
  10.1%
Czechia
4
   1.3%
5
   1.6%
9
   1.5%
United Kingdom
10
   3.3%
11
   3.6%
21
   3.4%
Portugal
10
   3.3%
5
   1.6%
15
   2.4%
Spain
62
  20.2%
63
  20.6%
125
  20.4%
Greece
12
   3.9%
13
   4.2%
25
   4.1%
Lebanon
8
   2.6%
9
   2.9%
17
   2.8%
Canada
10
   3.3%
7
   2.3%
17
   2.8%
Austria
5
   1.6%
3
   1.0%
8
   1.3%
Netherlands
9
   2.9%
9
   2.9%
18
   2.9%
Belgium
9
   2.9%
12
   3.9%
21
   3.4%
Brazil
13
   4.2%
15
   4.9%
28
   4.6%
Poland
7
   2.3%
6
   2.0%
13
   2.1%
Italy
21
   6.8%
20
   6.5%
41
   6.7%
Bulgaria
5
   1.6%
6
   2.0%
11
   1.8%
France
11
   3.6%
12
   3.9%
23
   3.8%
Germany
33
  10.7%
34
  11.1%
67
  10.9%
Weight  
Median (Full Range)
Unit of measure:  Kg
Number Analyzed 307 participants 306 participants 613 participants
73.0
(40 to 143)
74.0
(38 to 158)
73.4
(37.9 to 158)
Height  
Median (Full Range)
Unit of measure:  Cm
Number Analyzed 307 participants 306 participants 613 participants
168
(145 to 196)
168
(146 to 191)
168
(145 to 196)
Body surface area  
Median (Full Range)
Unit of measure:  M^2
Number Analyzed 307 participants 306 participants 613 participants
1.8
(1.4 to 2.5)
1.8
(1.3 to 2.8)
1.8
(1.3 to 2.8)
Body mass index  
Median (Full Range)
Unit of measure:  Kg/m^2
Number Analyzed 307 participants 306 participants 613 participants
25.9
(15.3 to 51.2)
26.0
(14.8 to 43.8)
25.9
(14.8 to 51.2)
Eastern Cooperative Oncology Group Performance Status   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
PS 0
95
  30.9%
95
  31.0%
190
  31.0%
PS 1
197
  64.2%
204
  66.7%
401
  65.4%
PS 2
15
   4.9%
7
   2.3%
22
   3.6%
[1]
Measure Description: Eastern Cooperative Oncology Group Performance Status (ECOG PS) PS 0 Fully active able to carry on all pre-disease performance without restriction PS 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature PS 2 Ambulatory and capable of all selfcare but unable to carry out any work activities up and about more than 50% of waking hours PS 3 Capable of only limited selfcare confined to bed or chair more than 50% of waking hours PS 4 Completely disabled cannot carry on any selfcare; totally confined to bed or chair PS 5 Dead
Smoking status  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
Former
197
  64.2%
199
  65.0%
396
  64.6%
Current
91
  29.6%
89
  29.1%
180
  29.4%
Never
19
   6.2%
18
   5.9%
37
   6.0%
Time from first diagnosis to randomization  
Median (Full Range)
Unit of measure:  Months
Number Analyzed 307 participants 306 participants 613 participants
9.3
(2.5 to 55.5)
9.1
(2.3 to 42.3)
9.2
(2.5 to 55.5)
Disease stage   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
Limited
25
   8.1%
28
   9.2%
53
   8.6%
Extensive
282
  91.9%
278
  90.8%
560
  91.4%
[1]
Measure Description:

Limited stage. Limited stage means that the cancer is only in 1 part of the chest and radiation therapy could be a treatment option.

Extensive stage. Extensive stage is used to describe SCLC that has spread to other parts of the body such as the opposite lung, bone, brain, or bone marrow.
Number of sites involved  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
<3 sites
38
  12.4%
31
  10.1%
69
  11.3%
≥3 sites
269
  87.6%
275
  89.9%
544
  88.7%
Number of sites involved  
Median (Full Range)
Unit of measure:  Sites
Number Analyzed 307 participants 306 participants 613 participants
4.0
(1 to 10)
4.0
(2 to 11)
4.0
(1 to 11)
Bulky disease   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
144
  46.9%
127
  41.5%
271
  44.2%
[1]
Measure Description: Bulky disease defined as one lesion ≥50 mm
Central Nervous System involvement  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
46
  15.0%
49
  16.0%
95
  15.5%
Paraneoplastic syndrome  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
9
   2.9%
11
   3.6%
20
   3.3%
Prior radiotherapy  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
237
  77.2%
236
  77.1%
473
  77.2%
Prior surgery  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
27
   8.8%
39
  12.7%
66
  10.8%
Lines of anticancer therapy  
Median (Full Range)
Unit of measure:  Lines of therapies
Number Analyzed 307 participants 306 participants 613 participants
1.0
(1 to 2)
1.0
(1 to 2)
1.0
(1 to 2)
Best response to last prior chemotherapy   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
Complete response
17
   5.5%
15
   4.9%
32
   5.2%
Partial response
192
  62.5%
191
  62.4%
383
  62.5%
Stable disease
71
  23.1%
63
  20.6%
134
  21.9%
Progressive disease
17
   5.5%
21
   6.9%
38
   6.2%
Unknown
10
   3.3%
16
   5.2%
26
   4.2%
[1]
Measure Description: Complete response (CR): disappearance of all lesions; Partial response (PR): ≥10% decrease in target lesion size or ≥15% decrease in tumor density; Disease progression (PD): ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; Stable disease (SD): none of the CR, PR, or PD criteria met; Unknown (UK)
Prior immunotherapy against PD-1 or PD-L1   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
19
   6.2%
17
   5.6%
36
   5.9%
[1]
Measure Description: PD-1, programmed cell death protein-1; PD-L1, programmed death ligand-1
Time-to-progression to prior chemotherapy  
Median (Full Range)
Unit of measure:  Months
Number Analyzed 307 participants 306 participants 613 participants
7.4
(0.8 to 40.2)
7.4
(1.6 to 33.7)
7.4
(0.8 to 40.2)
Time from last prior progressive disease to randomization  
Median (Full Range)
Unit of measure:  Days
Number Analyzed 307 participants 306 participants 613 participants
25.0
(3 to 621)
25.5
(1 to 327)
25.0
(1.0 to 621)
Time from end date of last prior chemotherapy to randomization  
Median (Full Range)
Unit of measure:  Days
Number Analyzed 307 participants 306 participants 613 participants
157.0
(28.0 to 1545.0)
153.0
(29.0 to 1151.0)
155
(28 to 1545)
Chemotherapy-free interval  
Median (Full Range)
Unit of measure:  Days
Number Analyzed 307 participants 306 participants 613 participants
115.0
(0 to 1094)
120.5
(13 to 960)
120
(0 to 1094)
Chemotherapy-free interval  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 306 participants 613 participants
<90 days
99
  32.2%
101
  33.0%
200
  32.6%
90-179 days
115
  37.5%
116
  37.9%
231
  37.7%
≥180 days
93
  30.3%
89
  29.1%
182
  29.7%
1.Primary Outcome
Title Overall Survival (OS)
Hide Description Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg flat dose (FD). The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 307 306
Median (95% Confidence Interval)
Unit of Measure: months
8.6
(7.1 to 9.4)
7.6
(6.6 to 8.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9029
Comments [Not Specified]
Method Log Rank
Comments Stratified log-rank test
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.967
Confidence Interval (2-Sided) 95%
0.815 to 1.148
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Difference in Overall Survival Between Lurbinectedin/Doxorubicin (DOX) and CAV in Patients With CAV as Best Investigator's Choice: Overall Survival Rate at 12 Months
Hide Description Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).
Time Frame At 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
Patients with Cyclophosphamide, Doxorubicin and Vincristine (CAV) as best Investigator's choice
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 184 179
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
29.6
(22.8 to 36.3)
24.4
(17.9 to 31.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2826
Comments [Not Specified]
Method Normal test
Comments [Not Specified]
3.Secondary Outcome
Title Difference in Overall Survival Between Lurbinectedin/DOX and CAV in Patients With CAV as Best Investigator's Choice: Overall Survival Rate at 18 Months
Hide Description Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).
Time Frame At 18 months
Hide Outcome Measure Data
Hide Analysis Population Description
Patients with Cyclophosphamide, Doxorubicin and Vincristine (CAV) as best Investigator's choice
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 184 179
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
13.9
(8.8 to 19.1)
15.9
(10.3 to 21.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6216
Comments [Not Specified]
Method Normal test
Comments [Not Specified]
4.Secondary Outcome
Title Difference in Overall Survival Between Lurbinectedin/DOX and CAV in Patients With CAV as Best Investigator's Choice: Overall Survival Rate at 24 Months
Hide Description Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).
Time Frame At 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Patients with Cyclophosphamide, Doxorubicin and Vincristine (CAV) as best Investigator's choice
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 184 179
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
8.6
(4.1 to 13.1)
8.7
(4.1 to 13.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9708
Comments [Not Specified]
Method Normal test
Comments [Not Specified]
5.Secondary Outcome
Title Progression-free Survival (PFS) by Independent Review Committee
Hide Description Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.
Time Frame Every six weeks up to progression disease, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 307 306
Median (95% Confidence Interval)
Unit of Measure: months
4.0
(2.8 to 4.2)
4.0
(3.0 to 4.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3257
Comments [Not Specified]
Method Log Rank
Comments Stratified log-rank test
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.831
Confidence Interval (2-Sided) 95%
0.693 to 0.996
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Progression-free Survival Rate at 6 Months by Independent Review Committee
Hide Description Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.
Time Frame At 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 307 306
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
31.3
(25.7 to 36.8)
24.4
(18.9 to 29.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0851
Comments [Not Specified]
Method Normal test
Comments [Not Specified]
7.Secondary Outcome
Title Progression-free Survival Rate at 12 Months by Independent Review Committee
Hide Description Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.
Time Frame at 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 307 306
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
10.8
(6.7 to 14.9)
4.4
(1.4 to 7.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0129
Comments [Not Specified]
Method Normal test
Comments [Not Specified]
8.Secondary Outcome
Title Best Antitumor Response by Independent Review Committee
Hide Description

Best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 307 306
Measure Type: Count of Participants
Unit of Measure: Participants
Complete response
8
   2.6%
4
   1.3%
Partial response
89
  29.0%
87
  28.4%
Stable disease
111
  36.2%
116
  37.9%
Progressive disease
74
  24.1%
52
  17.0%
Unknown
25
   8.1%
47
  15.4%
9.Secondary Outcome
Title Overall Response Rate by Independent Review Committee
Hide Description

Overall response rate is defined as the proportion of patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 307 306
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
31.6
(26.4 to 37.1)
29.7
(24.7 to 35.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6616
Comments [Not Specified]
Method Binomial test
Comments [Not Specified]
10.Secondary Outcome
Title Duration of Response by Independent Review Committee
Hide Description

Duration of Response is defined as the time that patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who have a partial or complete response in the best antitumor response
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 97 91
Median (95% Confidence Interval)
Unit of Measure: months
5.7
(4.1 to 7.1)
3.8
(2.8 to 4.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0012
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.581
Confidence Interval (2-Sided) 95%
0.416 to 0.812
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Overall Survival in Patients With Chemotherapy-free Interval ≥ 90 Days
Hide Description Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval ≥90 days after first-line chemotherapy
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 208 205
Median (95% Confidence Interval)
Unit of Measure: months
10.3
(9.0 to 11.8)
8.7
(7.8 to 9.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.921
Confidence Interval (2-Sided) 95%
0.744 to 1.140
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Progression-free Survival in Patients With Chemotherapy-free Interval ≥90 Days
Hide Description Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.
Time Frame Every six weeks up to progression disease, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval ≥90 days after first-line chemotherapy
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 208 205
Median (95% Confidence Interval)
Unit of Measure: months
4.8
(4.1 to 5.6)
4.4
(4.0 to 5.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.688
Confidence Interval (2-Sided) 95%
0.549 to 0.863
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Best Antitumor Response in Patients With Chemotherapy-free Interval ≥ 90 Days
Hide Description

Best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval ≥90 days after first-line chemotherapy
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 208 205
Measure Type: Count of Participants
Unit of Measure: Participants
Complete response
8
   3.8%
4
   2.0%
Partial response
69
  33.2%
68
  33.2%
Stable disease
85
  40.9%
73
  35.6%
Progression disease
32
  15.4%
35
  17.1%
Unknown
14
   6.7%
25
  12.2%
14.Secondary Outcome
Title Overall Response Rate in Patients With Chemotherapy-free Interval ≥ 90 Days
Hide Description

Overall response rate is defined as the proportion of patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval ≥90 days after first-line chemotherapy
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 208 205
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
37.0
(30.4 to 44.0)
35.1
(28.6 to 42.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.921
Confidence Interval (2-Sided) 95%
0.616 to 1.376
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Duration of Response in Patients With Chemotherapy-free Interval ≥ 90 Days
Hide Description

Duration of Response is defined as the time that patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who have a partial or complete response in the best antitumor response. A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval ≥90 days after first-line chemotherapy.
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 77 72
Median (95% Confidence Interval)
Unit of Measure: months
6.9
(4.1 to 8.3)
4.0
(3.0 to 4.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.504
Confidence Interval (2-Sided) 95%
0.346 to 0.736
Estimation Comments [Not Specified]
16.Secondary Outcome
Title Overall Survival in Patients With Chemotherapy-free Interval < 90 Days
Hide Description Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval <90 days after first-line chemotherapy
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 99 101
Median (95% Confidence Interval)
Unit of Measure: months
5.7
(4.1 to 6.7)
5.3
(4.2 to 6.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.122
Confidence Interval (2-Sided) 95%
0.840 to 1.500
Estimation Comments [Not Specified]
17.Secondary Outcome
Title Progression-free Survival in Patients With Chemotherapy-free Interval <90 Days
Hide Description Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.
Time Frame Every six weeks up to progression disease, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval <90 days after first-line chemotherapy
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 99 101
Median (95% Confidence Interval)
Unit of Measure: months
1.6
(1.4 to 2.7)
2.8
(2.5 to 3.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.306
Confidence Interval (2-Sided) 95%
0.955 to 1.786
Estimation Comments [Not Specified]
18.Secondary Outcome
Title Best Antitumor Response in Patients With Chemotherapy-free Interval <90 Days
Hide Description

Best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval <90 days after first-line chemotherapy
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 99 101
Measure Type: Count of Participants
Unit of Measure: Participants
Partial response
20
  20.2%
19
  18.8%
Stable disease
26
  26.3%
43
  42.6%
Progression disease
42
  42.4%
17
  16.8%
Unknown
11
  11.1%
22
  21.8%
19.Secondary Outcome
Title Overall Response Rate in Patients With Chemotherapy-free Interval <90 Days
Hide Description

Overall response rate is defined as the proportion of patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval <90 days after first-line chemotherapy
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 99 101
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
20.2
(12.8 to 29.5)
18.8
(11.7 to 27.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.915
Confidence Interval (2-Sided) 95%
0.455 to 1.843
Estimation Comments [Not Specified]
20.Secondary Outcome
Title Duration of Response in Patients With Chemotherapy-free Interval <90 Days
Hide Description

Duration of Response is defined as the time that patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who have a partial or complete response in the best antitumor response. A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval <90 days after first-line chemotherapy.
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 20 19
Median (95% Confidence Interval)
Unit of Measure: months
3.0
(1.4 to 4.5)
2.8
(1.4 to 4.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.092
Confidence Interval (2-Sided) 95%
0.506 to 2.360
Estimation Comments [Not Specified]
21.Secondary Outcome
Title Overall Survival in Patients Without Central Nervous System Involvement at Baseline
Hide Description Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients without Central Nervous System Involvement at Baseline
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 261 257
Median (95% Confidence Interval)
Unit of Measure: months
9.1
(8.1 to 10.2)
7.7
(6.7 to 8.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.923
Confidence Interval (2-Sided) 95%
0.765 to 1.113
Estimation Comments [Not Specified]
22.Secondary Outcome
Title Progression-free Survival in Patients Without Central Nervous System Involvement at Baseline
Hide Description Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.
Time Frame Every six weeks up to progression disease, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients without Central Nervous System Involvement at Baseline
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 261 257
Median (95% Confidence Interval)
Unit of Measure: months
4.2
(3.7 to 4.8)
4.1
(3.1 to 4.3)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.788
Confidence Interval (2-Sided) 95%
0.645 to 0.961
Estimation Comments [Not Specified]
23.Secondary Outcome
Title Best Antitumor Response in Patients Without Central Nervous System Involvement at Baseline
Hide Description

Best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients without Central Nervous System Involvement at Baseline
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 261 257
Measure Type: Count of Participants
Unit of Measure: Participants
Complete response
7
   2.7%
3
   1.2%
Partial response
79
  30.3%
76
  29.6%
Stable disease
101
  38.7%
100
  38.9%
Progression disease
55
  21.1%
40
  15.6%
Unknown
19
   7.3%
38
  14.8%
24.Secondary Outcome
Title Overall Response Rate in Patients Without Central Nervous System Involvement at Baseline
Hide Description

Overall response rate is defined as the proportion of patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients without Central Nervous System Involvement at Baseline
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 261 257
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
33.0
(27.3 to 39.0)
30.7
(25.2 to 36.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.903
Confidence Interval (2-Sided) 95%
0.624 to 1.307
Estimation Comments [Not Specified]
25.Secondary Outcome
Title Duration of Response in Patients Without Central Nervous System Involvement at Baseline
Hide Description

Duration of Response is defined as the time that patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who have a partial or complete response in the best antitumor response. A preplanned exploratory efficacy subgroup analysis was focused on patients without Central Nervous System Involvement at Baseline
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 86 79
Median (95% Confidence Interval)
Unit of Measure: months
5.7
(4.1 to 7.3)
4.0
(3.0 to 4.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.560
Confidence Interval (2-Sided) 95%
0.392 to 0.799
Estimation Comments [Not Specified]
26.Secondary Outcome
Title Overall Survival in Patients With Central Nervous System Involvement at Baseline
Hide Description Overall survival (OS) will be calculated from the date of randomization to the date of death (death event) or last contact(in this case, survival will be censored on that date).
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients with Central Nervous System Involvement at Baseline
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 46 49
Median (95% Confidence Interval)
Unit of Measure: months
4.6
(3.1 to 6.1)
6.6
(4.0 to 8.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.291
Confidence Interval (2-Sided) 95%
0.838 to 1.990
Estimation Comments [Not Specified]
27.Secondary Outcome
Title Progression-free Survival in Patients With Central Nervous System Involvement at Baseline
Hide Description Progression-free survival (PFS) is defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent antitumor therapy.
Time Frame Every six weeks up to progression disease, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients with Central Nervous System Involvement at Baseline
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 46 49
Median (95% Confidence Interval)
Unit of Measure: months
1.9
(1.4 to 2.7)
2.8
(1.4 to 3.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.290
Confidence Interval (2-Sided) 95%
0.824 to 2.019
Estimation Comments [Not Specified]
28.Secondary Outcome
Title Best Antitumor Response in Patients With Central Nervous System Involvement at Baseline
Hide Description

Best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients with Central Nervous System Involvement at Baseline
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 46 49
Measure Type: Count of Participants
Unit of Measure: Participants
Complete response
1
   2.2%
1
   2.0%
Partial response
10
  21.7%
11
  22.4%
Stable disease
10
  21.7%
16
  32.7%
Progression disease
19
  41.3%
12
  24.5%
Unknown
6
  13.0%
9
  18.4%
29.Secondary Outcome
Title Overall Response Rate in Patients With Central Nervous System Involvement at Baseline
Hide Description

Overall response rate is defined as the proportion of patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
A preplanned exploratory efficacy subgroup analysis was focused on patients with Central Nervous System Involvement at Baseline
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 46 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
23.9
(12.6 to 38.8)
24.5
(13.3 to 38.9)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.032
Confidence Interval (2-Sided) 95%
0.403 to 2.641
Estimation Comments [Not Specified]
30.Secondary Outcome
Title Duration of Response in Patients With Central Nervous System Involvement at Baseline
Hide Description

Duration of Response is defined as the time that patients who have a partial or complete response in the best antitumor response. The best antitumor response will be the best response obtained in any evaluation according to RECIST v.1.1.

CR, complete response: disappearance of all lesions; PD, disease progression: ≥10% increase in target lesion size and does not meet tumor density criteria of PR density; PR, partial response: ≥10% decrease in target lesion size or ≥15% decrease in tumor density; SD, stable disease: none of the CR, PR, or PD criteria met; UK,unknown
Time Frame Every three months up to death or study termination, a period of approximately 3.5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Patients who have a partial or complete response in the best antitumor response. A preplanned exploratory efficacy subgroup analysis was focused on patients with Central Nervous System Involvement at Baseline
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description:

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

or

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
Overall Number of Participants Analyzed 11 12
Median (95% Confidence Interval)
Unit of Measure: months
1.5 [1] 
(0.1 to NA)
2.7
(1.3 to 4.0)
[1]
Not reached
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lurbinectedin/Doxorubicin, Topotecan or Cyclophosphamide/Doxorubicin/Vincristine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.013
Confidence Interval (2-Sided) 95%
0.373 to 2.750
Estimation Comments [Not Specified]
Time Frame Patients were assessed through study completion, approximately 2 years
Adverse Event Reporting Description 21 of 613 randomized patients did not receive the study treatment. Safety population consisted of 592 treated patients. 302 had been randomized to lurbinectedin/DOX and 290 to topotecan or CAV. However, one patient randomized to receive topotecan was treated with lurbinectedin/DOX instead. For safety data analysis, this patient has been moved to the lurbinectedin/DOX Arm, and the safety population thereby comprised 303 patients with lurbinectedin/DOX and 289 patients with topotecan or CAV.
 
Arm/Group Title Lurbinectedin/Doxorubicin Topotecan Cyclophosphamide/Doxorubicin/Vincristine
Hide Arm/Group Description

Doxorubicin: 40.0 mg/m2 i.v. on Day 1 through peripheral or central lines (according to local label), followed by, Lurbinectedin: 2.0 mg/m2 i.v. as a 1-hour infusion on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines. A minimum volume of 100 mL diluted in 5% glucose or 0.9% sodium chloride solution for infusion, had to be used for administration through a central venous catheter; if a peripheral venous catheter was used, the minimum volume was 250 mL.

The combination was to be administered for up to a maximum of ten cycles.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

Topotecan: i.v. daily on Days 1-5 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines (according to local label) at the following doses:

  • 1.50 mg/m2 daily, for patients with calculated CrCL ≥60 mL/min.
  • 1.25 mg/m2 daily, for patients with calculated CrCL between 40 and 59 mL/min.
  • 0.75 mg/m2 daily, for patients with calculated CrCL between 30 and 39 mL/min.

If the patient was randomized to the Control Arm, the assigned treatment was based on the reported Investigator's preference between topotecan and CAV, until the first of these options had reached 55% of the target patient enrollment in this arm. Once this had occurred, patients in the Control Arm were to receive the other option.

CAV: i.v. on Day 1 q3wk (three weeks ±48h = one treatment cycle) through peripheral or central lines at the following doses:

  • Cyclophosphamide: 1000 mg/m2,
  • Doxorubicin: 45.0 mg/m2,
  • Vincristine: 2.0 mg FD. The triple combination was to be administered for up to a maximum of ten cycles
All-Cause Mortality
Lurbinectedin/Doxorubicin Topotecan Cyclophosphamide/Doxorubicin/Vincristine
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   264/303 (87.13%)      100/121 (82.64%)      148/168 (88.10%)    
Hide Serious Adverse Events
Lurbinectedin/Doxorubicin Topotecan Cyclophosphamide/Doxorubicin/Vincristine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   126/303 (41.58%)      66/121 (54.55%)      75/168 (44.64%)    
Blood and lymphatic system disorders       
Anaemia * 1  10/303 (3.30%)  17 13/121 (10.74%)  16 9/168 (5.36%)  12
Febrile neutropenia * 1  12/303 (3.96%)  12 7/121 (5.79%)  8 17/168 (10.12%)  17
Leukopenia * 1  1/303 (0.33%)  1 2/121 (1.65%)  2 2/168 (1.19%)  3
Neutropenia * 1  4/303 (1.32%)  5 9/121 (7.44%)  10 12/168 (7.14%)  18
Thrombocytopenia * 1  9/303 (2.97%)  16 15/121 (12.40%)  33 4/168 (2.38%)  4
Pancytopenia * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Lymphopenia * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Cardiac disorders       
Angina pectoris * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Atrial fibrillation * 1  1/303 (0.33%)  2 1/121 (0.83%)  1 0/168 (0.00%)  0
Cardiac failure * 1  1/303 (0.33%)  1 1/121 (0.83%)  1 0/168 (0.00%)  0
Cardio-respiratory arrest * 1  1/303 (0.33%)  1 1/121 (0.83%)  1 2/168 (1.19%)  2
Coronary artery stenosis * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Left ventricular dysfunction * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Sinus tachycardia * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Acute coronary syndrome * 1  0/303 (0.00%)  0 2/121 (1.65%)  2 0/168 (0.00%)  0
Bradycardia * 1  0/303 (0.00%)  0 1/121 (0.83%)  1 0/168 (0.00%)  0
Myocardial infarction * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Pericarditis * 1  0/303 (0.00%)  0 1/121 (0.83%)  1 0/168 (0.00%)  0
Tachycardia * 1  0/303 (0.00%)  0 1/121 (0.83%)  1 0/168 (0.00%)  0
Endocrine disorders       
Inappropriate antidiuretic hormone secretion * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Eye disorders       
Vision blurred * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Optic atrophy * 1  0/303 (0.00%)  0 1/121 (0.83%)  1 0/168 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 2/168 (1.19%)  2
Constipation * 1  2/303 (0.66%)  2 0/121 (0.00%)  0 0/168 (0.00%)  0
Diarrhoea * 1  3/303 (0.99%)  3 2/121 (1.65%)  2 0/168 (0.00%)  0
Gastritis * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Gastrointestinal motility disorder * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Impaired gastric emptying * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Nausea * 1  3/303 (0.99%)  3 1/121 (0.83%)  1 2/168 (1.19%)  2
Vomiting * 1  2/303 (0.66%)  3 0/121 (0.00%)  0 1/168 (0.60%)  1
Gastric perforation * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Neutropenic colitis * 1  0/303 (0.00%)  0 1/121 (0.83%)  2 0/168 (0.00%)  0
Oesophagitis * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Stomatitis * 1  0/303 (0.00%)  0 1/121 (0.83%)  3 0/168 (0.00%)  0
General disorders       
Complication associated with device * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Face oedema * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Fatigue * 1  4/303 (1.32%)  4 5/121 (4.13%)  5 2/168 (1.19%)  2
General physical health deterioration * 1  7/303 (2.31%)  8 4/121 (3.31%)  5 5/168 (2.98%)  6
Infusion site extravasation * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Non-cardiac chest pain * 1  4/303 (1.32%)  4 1/121 (0.83%)  2 1/168 (0.60%)  1
Oedema * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Pain * 1  2/303 (0.66%)  2 1/121 (0.83%)  1 0/168 (0.00%)  0
Pyrexia * 1  1/303 (0.33%)  2 1/121 (0.83%)  1 2/168 (1.19%)  2
Multiple organ dysfunction syndrome * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 2/168 (1.19%)  3
Hepatobiliary disorders       
Cholecystitis * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Cholangitis * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 2/168 (1.19%)  2
Infections and infestations       
Bronchiolitis * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Bronchitis * 1  2/303 (0.66%)  2 0/121 (0.00%)  0 1/168 (0.60%)  1
Cellulitis * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Gastroenteritis * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 1/168 (0.60%)  1
Influenza * 1  2/303 (0.66%)  2 0/121 (0.00%)  0 0/168 (0.00%)  0
Lower respiratory tract infection * 1  5/303 (1.65%)  5 5/121 (4.13%)  6 6/168 (3.57%)  6
Pneumonia * 1  14/303 (4.62%)  18 5/121 (4.13%)  5 7/168 (4.17%)  7
Sepsis * 1  3/303 (0.99%)  3 4/121 (3.31%)  4 2/168 (1.19%)  2
Subcutaneous abscess * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Urinary tract infection * 1  1/303 (0.33%)  1 1/121 (0.83%)  1 1/168 (0.60%)  1
Clostridium difficile colitis * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Herpes zoster * 1  0/303 (0.00%)  0 1/121 (0.83%)  1 0/168 (0.00%)  0
Infection * 1  0/303 (0.00%)  0 1/121 (0.83%)  2 0/168 (0.00%)  0
Localised infection * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Neutropenic infection * 1  0/303 (0.00%)  0 1/121 (0.83%)  1 0/168 (0.00%)  0
Neutropenic sepsis * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 3/168 (1.79%)  3
Post procedural infection * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Septic shock * 1  0/303 (0.00%)  0 4/121 (3.31%)  4 4/168 (2.38%)  4
Upper respiratory tract infection * 1  0/303 (0.00%)  0 1/121 (0.83%)  1 0/168 (0.00%)  0
Urosepsis * 1  0/303 (0.00%)  0 1/121 (0.83%)  1 1/168 (0.60%)  1
Injury, poisoning and procedural complications       
Femur fracture * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Hip fracture * 1  1/303 (0.33%)  1 1/121 (0.83%)  1 0/168 (0.00%)  0
Humerus fracture * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Procedural pneumothorax * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Radiation pneumonitis * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Fall * 1  0/303 (0.00%)  0 2/121 (1.65%)  2 0/168 (0.00%)  0
Investigations       
Blood creatinine increased * 1  1/303 (0.33%)  1 1/121 (0.83%)  1 1/168 (0.60%)  1
C-reactive protein increased * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Alanine aminotransferase increased * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Aspartate aminotransferase increased * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Metabolism and nutrition disorders       
Decreased appetite * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Dehydration * 1  4/303 (1.32%)  4 1/121 (0.83%)  1 2/168 (1.19%)  2
Hypercalcaemia * 1  2/303 (0.66%)  2 0/121 (0.00%)  0 0/168 (0.00%)  0
Hyponatraemia * 1  7/303 (2.31%)  11 3/121 (2.48%)  5 3/168 (1.79%)  3
Hyperkalaemia * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Hypokalaemia * 1  0/303 (0.00%)  0 2/121 (1.65%)  2 0/168 (0.00%)  0
Hypomagnesaemia * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  1/303 (0.33%)  3 0/121 (0.00%)  0 0/168 (0.00%)  0
Back pain * 1  5/303 (1.65%)  5 1/121 (0.83%)  1 1/168 (0.60%)  1
Muscular weakness * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Pain in extremity * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Infected neoplasm * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Metastases to meninges * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Tumour pain * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Nervous system disorders       
Altered state of consciousness * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Depressed level of consciousness * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Ischaemic stroke * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 1/168 (0.60%)  1
Post herpetic neuralgia * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Sciatica * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Seizure * 1  2/303 (0.66%)  2 0/121 (0.00%)  0 0/168 (0.00%)  0
Spinal cord compression * 1  2/303 (0.66%)  2 0/121 (0.00%)  0 0/168 (0.00%)  0
Aphasia * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Central pain syndrome * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Cerebral haemorrhage * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Dizziness * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Epilepsy * 1  0/303 (0.00%)  0 1/121 (0.83%)  1 2/168 (1.19%)  2
Headache * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Hemiparesis * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Nervous system disorder * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 2/168 (1.19%)  2
Neurological decompensation * 1  0/303 (0.00%)  0 1/121 (0.83%)  1 0/168 (0.00%)  0
Psychiatric disorders       
Confusional state * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Agitation * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Delirium * 1  0/303 (0.00%)  0 1/121 (0.83%)  1 0/168 (0.00%)  0
Renal and urinary disorders       
Acute kidney injury * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 1/168 (0.60%)  1
Anuria * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Hydronephrosis * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Renal failure * 1  1/303 (0.33%)  1 1/121 (0.83%)  1 1/168 (0.60%)  1
Reproductive system and breast disorders       
Prostatitis * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Acute respiratory distress syndrome * 1  1/303 (0.33%)  1 1/121 (0.83%)  1 1/168 (0.60%)  1
Acute respiratory failure * 1  2/303 (0.66%)  2 1/121 (0.83%)  2 1/168 (0.60%)  1
Chronic obstructive pulmonary disease * 1  3/303 (0.99%)  3 0/121 (0.00%)  0 1/168 (0.60%)  1
Cough * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Dyspnoea * 1  10/303 (3.30%)  12 0/121 (0.00%)  0 4/168 (2.38%)  4
Haemoptysis * 1  1/303 (0.33%)  1 1/121 (0.83%)  1 0/168 (0.00%)  0
Hypoxia * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Mediastinal disorder * 1  1/303 (0.33%)  1 1/121 (0.83%)  1 0/168 (0.00%)  0
Pleural effusion * 1  4/303 (1.32%)  5 0/121 (0.00%)  0 0/168 (0.00%)  0
Pneumonitis * 1  2/303 (0.66%)  2 0/121 (0.00%)  0 0/168 (0.00%)  0
Pneumothorax * 1  2/303 (0.66%)  2 0/121 (0.00%)  0 1/168 (0.60%)  1
Pulmonary embolism * 1  5/303 (1.65%)  6 0/121 (0.00%)  0 0/168 (0.00%)  0
Asthma * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Interstitial lung disease * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  2
Lung infiltration * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Vascular disorders       
Peripheral artery thrombosis * 1  1/303 (0.33%)  1 0/121 (0.00%)  0 0/168 (0.00%)  0
Superior vena cava syndrome * 1  2/303 (0.66%)  5 1/121 (0.83%)  1 0/168 (0.00%)  0
Deep vein thrombosis * 1  0/303 (0.00%)  0 0/121 (0.00%)  0 1/168 (0.60%)  1
Hypotension * 1  0/303 (0.00%)  0 2/121 (1.65%)  2 0/168 (0.00%)  0
1
Term from vocabulary, MedDRA (19.0)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Lurbinectedin/Doxorubicin Topotecan Cyclophosphamide/Doxorubicin/Vincristine
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   292/303 (96.37%)      120/121 (99.17%)      148/168 (88.10%)    
Blood and lymphatic system disorders       
Anaemia * 1  121/303 (39.93%)  341 84/121 (69.42%)  283 89/168 (52.98%)  250
Leukopenia * 1  28/303 (9.24%)  106 32/121 (26.45%)  77 46/168 (27.38%)  123
Lymphopenia * 1  15/303 (4.95%)  51 10/121 (8.26%)  21 13/168 (7.74%)  61
Neutropenia * 1  101/303 (33.33%)  316 74/121 (61.16%)  173 107/168 (63.69%)  251
Thrombocytopenia * 1  70/303 (23.10%)  246 71/121 (58.68%)  251 61/168 (36.31%)  155
Gastrointestinal disorders       
Abdominal pain * 1  14/303 (4.62%)  17 12/121 (9.92%)  16 12/168 (7.14%)  13
Constipation * 1  59/303 (19.47%)  90 30/121 (24.79%)  45 25/168 (14.88%)  31
Diarrhoea * 1  43/303 (14.19%)  65 25/121 (20.66%)  30 23/168 (13.69%)  29
Nausea * 1  123/303 (40.59%)  219 33/121 (27.27%)  42 55/168 (32.74%)  76
Vomiting * 1  72/303 (23.76%)  125 15/121 (12.40%)  17 33/168 (19.64%)  36
General disorders       
Fatigue * 1  164/303 (54.13%)  365 64/121 (52.89%)  162 79/168 (47.02%)  152
Mucosal inflammation * 1  30/303 (9.90%)  50 5/121 (4.13%)  7 14/168 (8.33%)  24
Non-cardiac chest pain * 1  26/303 (8.58%)  27 7/121 (5.79%)  9 13/168 (7.74%)  16
Oedema * 1  21/303 (6.93%)  24 13/121 (10.74%)  14 7/168 (4.17%)  7
Pyrexia * 1  28/303 (9.24%)  32 12/121 (9.92%)  19 21/168 (12.50%)  28
General physical health deterioration * 1  6/303 (1.98%)  7 4/121 (3.31%)  4 9/168 (5.36%)  9
Infections and infestations       
Lower respiratory tract infection * 1  18/303 (5.94%)  24 10/121 (8.26%)  15 11/168 (6.55%)  14
Pharyngitis * 1  19/303 (6.27%)  26 7/121 (5.79%)  7 5/168 (2.98%)  6
Pneumonia * 1  10/303 (3.30%)  12 6/121 (4.96%)  6 9/168 (5.36%)  9
Candida infection * 1  10/303 (3.30%)  11 3/121 (2.48%)  3 11/168 (6.55%)  12
Urinary tract infection * 1  15/303 (4.95%)  17 3/121 (2.48%)  3 10/168 (5.95%)  11
Investigations       
Ejection fraction decreased * 1  16/303 (5.28%)  17 0/121 (0.00%)  0 9/168 (5.36%)  11
Weight decreased * 1  64/303 (21.12%)  79 14/121 (11.57%)  19 24/168 (14.29%)  25
Metabolism and nutrition disorders       
Decreased appetite * 1  85/303 (28.05%)  129 20/121 (16.53%)  27 40/168 (23.81%)  61
Hypokalaemia * 1  25/303 (8.25%)  41 13/121 (10.74%)  25 12/168 (7.14%)  13
Hyponatraemia * 1  18/303 (5.94%)  25 7/121 (5.79%)  12 14/168 (8.33%)  20
Hypoalbuminaemia * 1  10/303 (3.30%)  12 7/121 (5.79%)  12 6/168 (3.57%)  9
Musculoskeletal and connective tissue disorders       
Arthralgia * 1  24/303 (7.92%)  29 5/121 (4.13%)  6 10/168 (5.95%)  11
Back pain * 1  37/303 (12.21%)  49 13/121 (10.74%)  19 20/168 (11.90%)  24
Pain in extremity * 1  13/303 (4.29%)  14 5/121 (4.13%)  5 9/168 (5.36%)  12
Nervous system disorders       
Dizziness * 1  28/303 (9.24%)  31 10/121 (8.26%)  11 13/168 (7.74%)  15
Headache * 1  30/303 (9.90%)  33 13/121 (10.74%)  14 19/168 (11.31%)  19
Neuropathy peripheral * 1  9/303 (2.97%)  9 4/121 (3.31%)  4 10/168 (5.95%)  10
Psychiatric disorders       
Insomnia * 1  13/303 (4.29%)  13 8/121 (6.61%)  11 7/168 (4.17%)  8
Respiratory, thoracic and mediastinal disorders       
Cough * 1  60/303 (19.80%)  80 23/121 (19.01%)  28 26/168 (15.48%)  31
Dyspnoea * 1  52/303 (17.16%)  63 24/121 (19.83%)  26 24/168 (14.29%)  30
Epistaxis * 1  3/303 (0.99%)  3 8/121 (6.61%)  10 4/168 (2.38%)  4
Skin and subcutaneous tissue disorders       
Alopecia * 1  34/303 (11.22%)  40 9/121 (7.44%)  9 27/168 (16.07%)  36
Vascular disorders       
Hypotension * 1  19/303 (6.27%)  25 4/121 (3.31%)  4 13/168 (7.74%)  14
1
Term from vocabulary, MedDRA (19.0)
*
Indicates events were collected by non-systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review.
Results Point of Contact
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Name/Title: Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit.
Organization: Pharma Mar S.A.
Phone: 0034 918466000
EMail: clinicaltrials@pharmamar.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: PharmaMar
ClinicalTrials.gov Identifier: NCT02566993    
Other Study ID Numbers: PM1183-C-003-14
First Submitted: September 24, 2015
First Posted: October 2, 2015
Results First Submitted: August 6, 2021
Results First Posted: October 28, 2021
Last Update Posted: October 28, 2021