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Efficacy and Safety Doxorubicin Transdrug Study in Patients Suffering From Advanced Hepatocellular Carcinoma (ReLive)

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ClinicalTrials.gov Identifier: NCT01655693
Recruitment Status : Completed
First Posted : August 2, 2012
Results First Posted : June 2, 2021
Last Update Posted : June 2, 2021
Sponsor:
Information provided by (Responsible Party):
Valerio Therapeutics

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Carcinoma, Hepatocellular
Interventions Drug: Doxorubicin 20 mg/m2
Drug: Doxorubicin 30 mg/m2
Drug: Best Standard of Care
Enrollment 397
Recruitment Details

A total of 541 patients were screened, and 397 patients were randomized a 1:1:1 allocation at 69 sites in 11 countries worldwide. The randomization was performed using an interactive web response system (IWRS) with stratification based on region.

Enrollment of first patient was June 15, 2012. Data cutoff was May 28, 2017 (24 months) for initial study and May 10, 2019, for follow-up period (45 months).
Pre-assignment Details Of the 144 patients who failed screening, the most common reason for screen failure was meeting liver function exclusion criteria.
Arm/Group Title Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Best Standard of Care
Hide Arm/Group Description DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity. DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity. Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Period Title: Overall Study
Started 130 133 134
Completed 4 7 4
Not Completed 126 126 130
Reason Not Completed
Progression of Disease             92             76             58
Death             8             9             12
Serious Adverse Event             3             15             11
Withdrawal by Subject             3             2             20
Adverse Event             3             11             3
Aggravation of Liver Dysfunction             5             4             0
Non-Compliance             0             0             7
No Respect of Criteria for Continuing Treatment             1             3             0
Protocol Violation             1             0             3
Lost to Follow-up             1             0             1
Screening Failure             1             0             0
Other             8             6             15
Arm/Group Title Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Best Standard of Care Total
Hide Arm/Group Description DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity. DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity. Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity. Total of all reporting groups
Overall Number of Baseline Participants 130 133 134 397
Hide Baseline Analysis Population Description
Intent-to-Treat population: all randomized patients.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 130 participants 133 participants 134 participants 397 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
50
  38.5%
62
  46.6%
57
  42.5%
169
  42.6%
>=65 years
80
  61.5%
71
  53.4%
77
  57.5%
228
  57.4%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 130 participants 133 participants 134 participants 397 participants
Female
12
   9.2%
27
  20.3%
18
  13.4%
57
  14.4%
Male
118
  90.8%
106
  79.7%
116
  86.6%
340
  85.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
White
120
  92.3%
119
  89.5%
125
  93.3%
364
  91.7%
Black
1
   0.8%
3
   2.3%
2
   1.5%
6
   1.5%
Asian
1
   0.8%
3
   2.3%
2
   1.5%
6
   1.5%
Other
1
   0.8%
3
   2.3%
3
   2.2%
7
   1.8%
Hispanic or Latino
0
   0.0%
2
   1.5%
1
   0.7%
3
   0.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
North African
6
   4.6%
2
   1.5%
0
   0.0%
8
   2.0%
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown
1
   0.8%
1
   0.8%
1
   0.7%
3
   0.8%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
United States
2
   1.5%
2
   1.5%
3
   2.2%
7
   1.8%
Europe
118
  90.8%
120
  90.2%
119
  88.8%
357
  89.9%
Middle East
10
   7.7%
11
   8.3%
12
   9.0%
33
   8.3%
Alcohol Consumption  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
No Significant Alcohol Consumption
119
  91.5%
127
  95.5%
123
  91.8%
369
  92.9%
Active Alcohol Consumption
11
   8.5%
6
   4.5%
11
   8.2%
28
   7.1%
Child Pugh Class   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
Child Pugh A
114
  87.7%
109
  82.0%
113
  84.3%
336
  84.6%
Child Pugh B
15
  11.5%
24
  18.0%
21
  15.7%
60
  15.1%
Child Pugh C
1
   0.8%
0
   0.0%
0
   0.0%
1
   0.3%
[1]
Measure Description:

The Child-Pugh score is determined by scoring five clinical measures of liver disease: encephalopathy, ascites, albumin, total bilirubin, prothrombin time rate. A score of 1, 2, or 3 is given to each measure, with 3 being the most severe. The total score is used to assign the Child-Pugh class as follows:

Class A: 5-6 points (least severe liver disease) Class B: 7-9 points (moderately severe liver disease) Class C: 10-15 points (most severe liver disease)
Previous Hepatocellular Carcinoma (HCC) Treatments   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
Surgery/Resection
41
  31.5%
49
  36.8%
40
  29.9%
130
  32.7%
Loco-regional Treatment
84
  64.6%
84
  63.2%
84
  62.7%
252
  63.5%
Radiotherapy
14
  10.8%
14
  10.5%
9
   6.7%
37
   9.3%
Sorafenib
130
 100.0%
133
 100.0%
134
 100.0%
397
 100.0%
Other Systemic Anticancer Therapy
68
  52.3%
73
  54.9%
80
  59.7%
221
  55.7%
[1]
Measure Description: Prior treatment for HCC is collected at baseline as part of the medical history for surgery and the following drugs and therapy: sorafenib, hormone therapy, tyrosine kinase inhibitor, investigational drug, cytotoxic chemotherapy, and other anticancer therapy. Patients may have received treatment in more than one of these categories.
Medical History Active   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
Hypertension
73
  56.2%
82
  61.7%
84
  62.7%
239
  60.2%
Type 2 Diabetes Mellitus
28
  21.5%
15
  11.3%
35
  26.1%
78
  19.6%
Diabetes Mellitus
17
  13.1%
26
  19.5%
17
  12.7%
60
  15.1%
Hypercholestrolaemia
12
   9.2%
14
  10.5%
9
   6.7%
35
   8.8%
Varices Oesophageal
14
  10.8%
24
  18.0%
15
  11.2%
53
  13.4%
Chronic Obstructive Pulmonary Disease
13
  10.0%
8
   6.0%
9
   6.7%
30
   7.6%
Thrombocytopenia
7
   5.4%
15
  11.3%
8
   6.0%
30
   7.6%
[1]
Measure Description: Active medical history of patient at time of baseline assessment is collected. Presenting all active medical history that occurred at an incidence of >=10% of the patients in at least one of the treatment groups is presented for all groups. Patients may fall into more than one of these categories.
HCC History-Cirrhosis  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
Yes
93
  71.5%
96
  72.2%
101
  75.4%
290
  73.0%
No
36
  27.7%
35
  26.3%
31
  23.1%
102
  25.7%
Unknown
1
   0.8%
2
   1.5%
2
   1.5%
5
   1.3%
HCC History - Cyto Histology   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
Yes
80
  61.5%
87
  65.4%
92
  68.7%
259
  65.2%
No
50
  38.5%
46
  34.6%
42
  31.3%
138
  34.8%
[1]
Measure Description: Used American Association for the Study of Liver Diseases (AASLD)/European Association for the Study of the Liver (EASL) Criteria
HCC History - Macroscopic Vascular Invasion   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
Macroscopic Portal Vein or Portal Branch Vascular Invasion - Yes
48
  36.9%
41
  30.8%
39
  29.1%
128
  32.2%
Macroscopic Portal Vein or Portal Branch Vascular Invasion - No
82
  63.1%
92
  69.2%
95
  70.9%
269
  67.8%
Supra-hepatic Vascular Invasion Vein - Yes
9
   6.9%
8
   6.0%
10
   7.5%
27
   6.8%
Supra-hepatic Vascular Invasion Vein - No
121
  93.1%
125
  94.0%
124
  92.5%
370
  93.2%
Vascular Invasion (Portal and/or Supra Hepatic) - Yes
50
  38.5%
43
  32.3%
45
  33.6%
138
  34.8%
Vascular Invasion (Portal and/or Supra Hepatic) - No
80
  61.5%
90
  67.7%
89
  66.4%
259
  65.2%
[1]
Measure Description: Multiple selection possible for vascular invasion.
HCC History - Extra Hepatic Spread - Porta Hepatic Lymph Nodes  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
Yes
24
  18.5%
19
  14.3%
31
  23.1%
74
  18.6%
No
99
  76.2%
104
  78.2%
98
  73.1%
301
  75.8%
Unknown
7
   5.4%
10
   7.5%
5
   3.7%
22
   5.5%
HCC History - Extra Hepatic Spread - Distant Metastases  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
Yes
64
  49.2%
68
  51.1%
71
  53.0%
203
  51.1%
No
64
  49.2%
61
  45.9%
57
  42.5%
182
  45.8%
Unknown
2
   1.5%
4
   3.0%
6
   4.5%
12
   3.0%
HCC History - Aetiology of Underlying Liver Disease   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
Alcohol
64
  49.2%
60
  45.1%
68
  50.7%
192
  48.4%
Hepatitis C Virus
40
  30.8%
40
  30.1%
38
  28.4%
118
  29.7%
Nonalcoholic Steatohepatitis
14
  10.8%
21
  15.8%
23
  17.2%
58
  14.6%
Unknown
26
  20.0%
14
  10.5%
16
  11.9%
56
  14.1%
Hepatitis B Virus
7
   5.4%
16
  12.0%
14
  10.4%
37
   9.3%
Other
4
   3.1%
12
   9.0%
3
   2.2%
19
   4.8%
Hemochromatosis
3
   2.3%
6
   4.5%
4
   3.0%
13
   3.3%
Autoimmune
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Primary Biliary Cirrhosis
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: Percentages are based on the number of patients in the respective group. Patients could have more than one aetiology of underlying liver disease and may be counted in more than one category.
HCC History - Nodule in the Liver  
Measure Type: Count of Participants
Unit of measure:  Participants
 Number Analyzed 130 participants 133 participants 134 participants 397 participants
Single Nodule
15
  11.5%
5
   3.8%
8
   6.0%
28
   7.1%
Multiple Nodules
102
  78.5%
106
  79.7%
111
  82.8%
319
  80.4%
Infiltrate HCC
8
   6.2%
17
  12.8%
13
   9.7%
38
   9.6%
Unknown
5
   3.8%
5
   3.8%
2
   1.5%
12
   3.0%
HCC History - Disease Duration   [1] 
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 130 participants 133 participants 134 participants 397 participants
28.1  (24.04) 30.5  (35.86) 31.5  (28.38) 30.1  (29.83)
[1]
Measure Description: Disease duration is calculated at study entry in months as the screening visit date - cancer diagnosis date.
1.Primary Outcome
Title Overall Survival (OS)
Hide Description OS is defined as the time from date of randomization to the date of death from any cause.
Time Frame Time from date of randomization to the date of death from any cause with initial assessment up to 24 months and follow-up assessment up to 45 months.
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) Population: All randomized patients. The DT at 20 mg/m2 and 30 mg/m2 are combined into DT pooled experimental group for comparison with the BSC group. The primary analysis per protocol is DT pooled versus BSC and not individual DT groups.
Arm/Group Title Doxorubicin Transdrug (DT) 20 mg/m2 Group Doxorubicin Transdrug at 30 mg/m2 Doxorubicin Transdrug Pooled Best Standard of Care (BSC)
Hide Arm/Group Description:
DT was infused over 6 hours through the intravenous route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
The DT 20 mg/m2 and 30 mg/m2 treatment group were pooled together for OS comparison to Best Standard of Care (BCS) for initial study.
Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity in initial study.
Overall Number of Participants Analyzed 130 133 263 134
Median (95% Confidence Interval)
Unit of Measure: months
OS up to 24 Months
10.1
(7.3 to 11.4)
8.9
(7.0 to 10.3)
9.1
(8.1 to 10.4)
9.0
(7.1 to 11.8)
OS up to 45 Months
9.8
(7.4 to 11.2)
8.8
(7.1 to 10.3)
8.9
(8.1 to 10.3)
9.0
(7.2 to 11.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Doxorubicin Transdrug (DT) 20 mg/m2 Group, Doxorubicin Transdrug at 30 mg/m2, Doxorubicin Transdrug Pooled, Best Standard of Care (BSC)
Comments Initial 24 month assessment: the primary aim was to demonstrate the superiority of DT pooled (20 mg/m2 and 30 mg/m2) compared to BSC treatment and not individual DT groups per protocol. OS was estimated using the Kaplan-Meier method. The comparison of treatment groups (pooled DT groups versus BSC group) was performed using a non-stratified log-rank test as the primary analysis. The Cox model and Wilcoxon test was used for sensitivity analysis.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.991
Comments Treatment comparison of DT pooled with BCS used non-stratified Log-rank test at significance level p=0.05.
Method Log Rank
Comments Log rank test is used after checking the proportional hazards (PH) assumption is valid. The Wilcoxon test is used when the PH assumption fails.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.00
Estimation Comments The hazard ratio was controlled for the overall type I error rate at 5% (2-sided) corresponding to 95% confidence interval (CI) and type II error rate as 15%.
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Doxorubicin Transdrug (DT) 20 mg/m2 Group, Doxorubicin Transdrug at 30 mg/m2, Doxorubicin Transdrug Pooled, Best Standard of Care (BSC)
Comments Follow-up 45 month assessment: the primary aim was to demonstrate the superiority of DT pooled (20 mg/m2 and 30 mg/m2) compared to BSC treatment and not individual DT groups per protocol. OS was estimated using the Kaplan-Meier method. The comparison of treatment groups (pooled DT groups versus BSC group) was performed using a non-stratified log-rank test as the primary analysis. The Cox model and Wilcoxon test was used for sensitivity analysis.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.796
Comments Treatment comparison of DT pooled with BCS used non-stratified Log-rank test at significance level p=0.05.
Method Log Rank
Comments Log rank test is used after checking the proportional hazards (PH) assumption is valid. The Wilcoxon test is used when the PH assumption fails.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.00
Estimation Comments The hazard ratio was controlled for the overall type I error rate at 5% (2-sided) corresponding to 95% confidence interval (CI) and type II error rate as 15%.
2.Secondary Outcome
Title Progression-free Survival (PFS)
Hide Description PFS is defined as time from the date of randomisation to the date of the first documented progression or death from any cause. PFS determined by independent radiological review according to Response Evaluation Criteria In Solid Tumour (RECIST) 1.1 is determine by at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is considered progression.
Time Frame Time from date of randomization to date of first documented progression or death from any cause, which ever came first, assessed up to 20 months.
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population: All randomized patients. The DT at 20 mg/m2 and 30 mg/m2 are combined into DT pooled experimental group for comparison with the BSC group. The primary analysis is DT pooled versus BSC. This was only analyzed for the initial study.
Arm/Group Title Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Doxorubicin Transdrug Pooled Best Standard of Care
Hide Arm/Group Description:
DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
The DT 20 mg/m2 and 30 mg/m2 treatment group were pooled together for PFS comparison to BCS.
Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 130 133 263 134
Median (95% Confidence Interval)
Unit of Measure: months
2.3
(2.0 to 2.8)
2.3
(2.1 to 2.6)
2.3
(2.1 to 2.6)
2.3
(2.1 to 2.8)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Doxorubicin Transdrug (DT) at 20 mg/m2, Doxorubicin Transdrug at 30 mg/m2, Best Standard of Care
Comments PFS was estimated using Kaplan-Meier methods and plotted as curves by treatment group. For comparison between treatment groups (pooled DT 20 mg/m2 and 30 mg/m2 versus BSC) used Log-rank test as primary analysis. Hazard ratio, mean, and mean PFS rate were given with corresponding 95% CI.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7
Comments Treatment comparison with BCS using non-stratified Log-rank test at significance level p=0.05.
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.00
Estimation Comments Hazard ratio for treatment variable was determined by Cox model. The hazard ratio was controlled for the overall type I error rate at 5% (2-sided) and type II error rate as 15%.
3.Secondary Outcome
Title Objective Response Rate (ORR)
Hide Description ORR is defined as percent of patients whose best overall response is complete response (CR) or partial response (PR) during the study treatment period and based on the evaluation of independent radiological review according to RECIST 1.1 for target lesions and assessed by MRI: CR is disappearance of all targets extra nodal lesions and the regression of all nodal lesions to < 10 mm; PR is at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum of diameters while on study. PD is at least a 20% increase in the sum of diameters of target lesions, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is considered progression.
Time Frame Time from date of first treatment cycle to date of last cycle of treatment for the full duration of study treatment up to 24 months.
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Hide Analysis Population Description
ITT population: all randomized patients. The DT at 20 mg/m2 and 30 mg/m2 are combined into DT pooled experimental group for comparison with the BSC group. The primary analysis is the DT pooled versus BCS. This was only analyzed for the initial study.
Arm/Group Title Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Doxorubicin Transdrug Pooled Best Standard of Care
Hide Arm/Group Description:
DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.

DT will be infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and will be repeated every 4 weeks until disease progression or unacceptable toxicity

Doxorubicin
The DT 20 mg/m2 and 30 mg/m2 treatment group were pooled together for ORR comparison to BCS.

Patients randomized in the control group will receive treatment according to the investigator's choice, until disease progression or unacceptable toxicity

Best Standard of Care
Overall Number of Participants Analyzed 130 133 263 134
Measure Type: Count of Participants
Unit of Measure: Participants
Complete Response
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Partial Response
0
   0.0%
2
   1.5%
2
   0.8%
1
   0.7%
Stable Disease
39
  30.0%
41
  30.8%
80
  30.4%
31
  23.1%
Progressive Disease
58
  44.6%
63
  47.4%
121
  46.0%
40
  29.9%
Not Evaluable
33
  25.4%
27
  20.3%
60
  22.8%
62
  46.3%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Doxorubicin Transdrug (DT) at 20 mg/m2, Doxorubicin Transdrug at 30 mg/m2, Doxorubicin Transdrug Pooled, Best Standard of Care
Comments The comparisons between groups (pooled DT 20 mg/m2 and 30mg/m2 versus BSC) used Fisher's exact test.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0
Comments Treatment comparison with BCS using Fisher's exact test at significance level p=0.05.
Method Fisher Exact
Comments [Not Specified]
4.Other Pre-specified Outcome
Title Number of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) Considered Related to Treatment Categorized by Severity, Withdrawal From Study, or Death
Hide Description The number of participants experiencing TEAEs considered related to treatment and categorized by severity of all related TEAEs according to National Cancer Institute/Common Toxicity Criteria (NCI-CTCAE) v4.0 and resulting in patient withdrawal from study or death.
Time Frame Time from date of initial treatment to date of death, disease progression, or participant withdrawal from the study.
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Hide Analysis Population Description
Safety Population: All patients receiving at least one infusion for DT groups and all patients for BSC group whatever treatment they received.
Arm/Group Title Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Best Standard of Care (BSC)
Hide Arm/Group Description:
DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 122 120 134
Measure Type: Count of Participants
Unit of Measure: Participants
TEAEs
79
  64.8%
98
  81.7%
58
  43.3%
Severe TEAEs
26
  21.3%
46
  38.3%
31
  23.1%
Serious TEAEs
13
  10.7%
18
  15.0%
13
   9.7%
TEAEs Leading to Withdrawal
5
   4.1%
9
   7.5%
9
   6.7%
TEAEs Leading to Death
1
   0.8%
2
   1.7%
1
   0.7%
5.Other Pre-specified Outcome
Title Number of Participants With Cardiovascular and Respiratory Events Related to Study Drug
Hide Description The number of participants with cardiovascular and respiratory adverse events (AEs) were assessed according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) criteria version 4.0, using the Medical Dictionary for Regulatory Activities (MedDRA). The AE numbers reported are those considered related to treatment. Related AEs are those that are judged unlikely, possibly, probably or definitely related to the study or study drug by the investigator.
Time Frame Time from date of initial treatment to date of death, disease progression, or patient withdrawal from the study.
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Hide Analysis Population Description
Safety Population: All patients receiving at least one infusion for DT groups and all patients for BSC group whatever treatment they received.
Arm/Group Title Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Best Standard of Care (BSC)
Hide Arm/Group Description:
DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 122 120 134
Measure Type: Count of Participants
Unit of Measure: Participants
Cardiac Disorders
4
   3.3%
5
   4.2%
1
   0.7%
Vascular Disorders
8
   6.6%
8
   6.7%
6
   4.5%
Blood Pressure Increased
0
   0.0%
1
   0.8%
0
   0.0%
Respiratory, Thoracic, and Mediastinal Disorders
17
  13.9%
20
  16.7%
13
   9.7%
Oxygen Saturation Decreased
2
   1.6%
7
   5.8%
1
   0.7%
Respiratory Rate Increased
2
   1.6%
5
   4.2%
0
   0.0%
Respiratory Rate Decreased
1
   0.8%
1
   0.8%
0
   0.0%
Ejection Fraction Decreased
1
   0.8%
0
   0.0%
0
   0.0%
6.Other Pre-specified Outcome
Title Number of Participants Experiencing a Reduction of Oxygen Saturation (SaO2) During and After Doxorubicin Transdrug (DT) Infusion
Hide Description Number of participants experiencing an SaO2 reduction defined as a decrease =< 90% during or after DT infusion until resolution to =>93%. Participants had continuous monitoring of SaO2 saturation with pulse oximeter during 6 hour infusion and up to 24 hour after infusion start. SaO2 measures the amount of oxygen (in percent) bound to hemoglobin in red blood cells. SaO2 saturation was only monitored and reported in the DT infusion group. Reduction in SaO2 could result in modify DT dosing regimen. Decreases in SaO2 are a known and expected occurrence with DT infusions, and close monitoring of SaO2 was specified by the protocol to protect patients from potential respiratory distress during infusions.
Time Frame Time from start of infusion to resolution of reduction in oxygen saturation.
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Hide Analysis Population Description
Safety population: All patients receiving at least one infusion for DT groups.
Arm/Group Title Doxorubicin Transdrug (DT) 20 mg/m2 Doxorubicin Transdrug 30 mg/m2
Hide Arm/Group Description:
DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 122 120
Measure Type: Count of Participants
Unit of Measure: Participants
2
   1.6%
4
   3.3%
7.Other Pre-specified Outcome
Title Number of Participants With Clinically Significant Abnormal Change in Respiratory Function
Hide Description Number of participants with any clinically significant abnormal change in respiratory function test over the study to include carbon monoxide diffusing capacity to measure lung function, forced expiratory volume in 1 second to measure ability to expel air from your lungs, total lung capacity to measure total amount of air in the lungs after taking the deepest breath possible, and vital capacity to measure the greatest volume of air that can be expelled from the lungs after taking the deepest breath possible. Clinically significant abnormal changes in respiratory function was determined by the investigator.
Time Frame Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All patients receiving at least one infusion for DT groups and all patients for BSC group whatever treatment they received.
Arm/Group Title Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Best Standard of Care (BSC)
Hide Arm/Group Description:
DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 122 120 134
Measure Type: Count of Participants
Unit of Measure: Participants
13
  10.7%
8
   6.7%
0
   0.0%
8.Other Pre-specified Outcome
Title Number of Participants Experiencing Clinically Significant Abnormal Electrocardiogram (ECG) Changes From Baseline
Hide Description Number of participants experiencing clinically significant abnormal ECG changes from baseline over the course of the study. ECG were completed every month before each infusion. ECG will detect changes in heart rhythm. Clinically significant abnormal changes in ECG were determined by the investigator.
Time Frame Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.
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Hide Analysis Population Description
Safety Population: All patients receiving at least one infusion for DT groups and all patients for BSC group whatever treatment they received.
Arm/Group Title Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Best Standard of Care (BSC)
Hide Arm/Group Description:
DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 122 120 134
Measure Type: Count of Participants
Unit of Measure: Participants
4
   3.3%
6
   5.0%
5
   3.7%
9.Other Pre-specified Outcome
Title Number of Participants Experiencing Clinically Significant Changes in Left Ventricular Ejection Fraction (LVEF) and the Severity of the Event
Hide Description Number of participants that experienced a change from baseline in LVEF with severity of LVEF noted as follows: Normal: 100 - 50%, 0 - 9% drop from baseline resting ejection fraction (EF), Grade 2 = 50 - 40%, 10 - 19% drop from baseline resting EF; Grade 3 = 39 - 20%, >20% drop from baseline; Grade 4 = <20%. LVEF was monitored every other month. LVEF measures how much blood the left ventricle of the heart pumps out with each contraction and is used to assess the severity of left ventricle dysfunction in the heart. Clinical significance changes were determined by the investigator.
Time Frame Time from baseline assessment to time of death, disease progression, or withdrawal of patient from the study.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: All patients receiving at least one infusion for DT groups and all patients for BSC group whatever treatment they received.
Arm/Group Title Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Best Standard of Care (BSC)
Hide Arm/Group Description:
DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity.
Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
Overall Number of Participants Analyzed 122 120 134
Measure Type: Count of Participants
Unit of Measure: Participants
At Least One Abnormal Value
1
   0.8%
4
   3.3%
2
   1.5%
At Least One Grade 3-4 Value
1
   0.8%
1
   0.8%
1
   0.7%
Time Frame Adverse events (AEs) were collected until 1 month after last treatment. Treatment continued until patient experienced disease progression, aggravation of liver dysfunction, death, serious AE (SAE), or intolerable AE; or the patient withdrew consent or was withdrawn from study by investigator for reasons listed in the protocol. Median treatment durations were 1.9, 2.7, and 2.4 months in the Doxorubicin Transdrug (DT) 20 mg/m2, DT 30 mg/m2, and best standard of care (BSC) groups, respectively.
Adverse Event Reporting Description The incidence and severity of all AEs and SAEs were assessed according to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) criteria version 4.0, using the Medical Dictionary for Regulatory Activities (MedDRA). The cutoff for AE reporting was May 28, 2017.
 
Arm/Group Title Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Best Standard of Care
Hide Arm/Group Description DT was infused over 6 hours through the intravenous (IV) route at dose of 20 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity. DT was infused over 6 hours through the IV route at dose of 30 mg/m2 on Day 1 and was repeated every 4 weeks until disease progression or unacceptable toxicity. Patients randomized in the control group received treatment according to the investigator's choice, until disease progression or unacceptable toxicity.
All-Cause Mortality
Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Best Standard of Care
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   118/122 (96.72%)      119/120 (99.17%)      113/134 (84.33%)    
Hide Serious Adverse Events
Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Best Standard of Care
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   37/122 (30.33%)      37/120 (30.83%)      48/134 (35.82%)    
Blood and lymphatic system disorders       
Neutropenia * 1  0/122 (0.00%)  0 1/120 (0.83%)  2 1/134 (0.75%)  1
Leukopenia * 1  0/122 (0.00%)  0 2/120 (1.67%)  2 0/134 (0.00%)  0
Anaemia * 1  1/122 (0.82%)  1 1/120 (0.83%)  1 4/134 (2.99%)  4
Thrombocytopenia * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Cardiac disorders       
Atrial fibrillation * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Atrioventricular block complete * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Atrioventricular block second degree * 1  1/122 (0.82%)  1 1/120 (0.83%)  1 0/134 (0.00%)  0
Cardiac failure * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Ischaemic cardiomyopathy * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Supraventricular tachycardia * 1  1/122 (0.82%)  1 1/120 (0.83%)  1 0/134 (0.00%)  0
Atrial thrombosis * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Gastrointestinal disorders       
Ascites * 1  3/122 (2.46%)  3 1/120 (0.83%)  1 3/134 (2.24%)  3
Abdominal pain * 1  3/122 (2.46%)  4 0/120 (0.00%)  0 1/134 (0.75%)  1
Peritoneal haemorrhage * 1  1/122 (0.82%)  1 2/120 (1.67%)  2 0/134 (0.00%)  0
Dysphagia * 1  3/122 (2.46%)  3 0/120 (0.00%)  0 1/134 (0.75%)  1
Gastrooesophageal reflux disease * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Melaena * 1  2/122 (1.64%)  2 0/120 (0.00%)  0 1/134 (0.75%)  1
Oesophageal varices haemorrhage * 1  1/122 (0.82%)  1 3/120 (2.50%)  3 7/134 (5.22%)  7
Upper gastrointestinal haemorrhage * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 2/134 (1.49%)  2
Abdominal pain upper * 1  1/122 (0.82%)  1 1/120 (0.83%)  1 0/134 (0.00%)  0
Haematemesis * 1  1/122 (0.82%)  1 1/120 (0.83%)  1 0/134 (0.00%)  0
Vomiting * 1  1/122 (0.82%)  1 1/120 (0.83%)  1 0/134 (0.00%)  0
Peptic ulcer haemorrhage * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Retroperitoneal haematoma * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
General disorders       
Fatigue * 1  0/122 (0.00%)  0 3/120 (2.50%)  3 0/134 (0.00%)  0
General physical health deterioration * 1  3/122 (2.46%)  3 2/120 (1.67%)  2 8/134 (5.97%)  8
Pyrexia * 1  2/122 (1.64%)  2 0/120 (0.00%)  0 2/134 (1.49%)  2
Chills * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Mucosal inflammation * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Oedema * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Oedema peripheral * 1  0/122 (0.00%)  0 2/120 (1.67%)  2 0/134 (0.00%)  0
Asthenia * 1  1/122 (0.82%)  1 1/120 (0.83%)  1 2/134 (1.49%)  2
Pain * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 1/134 (0.75%)  1
Complications associated with device * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Generalised oedema * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Hypothermia * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Multiple organ dysfunction syndrome * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Hepatobiliary disorders       
Hepatic encephalopathy * 1  1/122 (0.82%)  1 5/120 (4.17%)  6 7/134 (5.22%)  9
Hepatic failure * 1  1/122 (0.82%)  1 2/120 (1.67%)  2 0/134 (0.00%)  0
Hepatorenal syndrome * 1  0/122 (0.00%)  0 2/120 (1.67%)  2 1/134 (0.75%)  1
Portal vein thrombosis * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 2/134 (1.49%)  2
Biliary dilatation * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Cholelithiasis * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Coma hepatic * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Jaundice * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Immune system disorders       
Drug hypersensitivity * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Infections and infestations       
Catheter site infection * 1  3/122 (2.46%)  3 0/120 (0.00%)  0 2/134 (1.49%)  2
Pneumonia * 1  0/122 (0.00%)  0 2/120 (1.67%)  2 2/134 (1.49%)  2
Sepsis * 1  2/122 (1.64%)  2 0/120 (0.00%)  0 2/134 (1.49%)  2
Endocarditis * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Escherichia sepsis * 1  1/122 (0.82%)  1 1/120 (0.83%)  1 0/134 (0.00%)  0
Liver abscess * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Lower respiratory tract infection * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Lung infection * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Septic shock * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Staphylococcal sepsis * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Subcutaneous abscess * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Peritonitis * 1  1/122 (0.82%)  1 1/120 (0.83%)  1 1/134 (0.75%)  1
Urinary tract infection * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 1/134 (0.75%)  1
Campylobacter infection * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Enterobacter pneumonia * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Erysipelas * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Peritonitis bacterial * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Injury, poisoning and procedural complications       
Femur fracture * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Lumbar vertebral fracture * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Post procedural bile leak * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Spinal fracture * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Investigations       
Oxygen saturation decreased * 1  0/122 (0.00%)  0 2/120 (1.67%)  2 0/134 (0.00%)  0
N-terminal prohormone brain natriuretic peptide increased * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Respiratory rate decreased * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Metabolism and nutrition disorders       
Hypokalaemia * 1  0/122 (0.00%)  0 1/120 (0.83%)  2 0/134 (0.00%)  0
Decreased appetite * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Dehydration * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Hypoglycaemia * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Osteitis * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Back pain * 1  0/122 (0.00%)  0 2/120 (1.67%)  2 0/134 (0.00%)  0
Bone pain * 1  2/122 (1.64%)  2 0/120 (0.00%)  0 0/134 (0.00%)  0
Pain in extremity * 1  1/122 (0.82%)  1 1/120 (0.83%)  1 0/134 (0.00%)  0
Flank pain * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Osteoarthritis * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Trismus * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Tumour haemorrhage * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 1/134 (0.75%)  1
Malignant neoplasm progression * 1  2/122 (1.64%)  2 0/120 (0.00%)  0 1/134 (0.75%)  1
Lung neoplasm malignant * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Metastases to adrenals * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Metastases to bone * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Metastases to central nervous system * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Neoplasm progression * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Peritumoural oedema * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Squamous cell carcinoma of lung * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Nervous system disorders       
Cerebral haematoma * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Neuralgia * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Psychiatric disorders       
Completed suicide * 1  1/122 (0.82%)  1 1/120 (0.83%)  1 0/134 (0.00%)  0
Depression * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Mental status changes * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Renal and urinary disorders       
Acute kidney injury * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 3/134 (2.24%)  3
Proteinuria * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Respiratory, thoracic and mediastinal disorders       
Acute pulmonary oedema * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 1/134 (0.75%)  1
Bronchopneumopathy * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Interstitial lung disease * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Pleural effusion * 1  1/122 (0.82%)  2 2/120 (1.67%)  2 0/134 (0.00%)  0
Pulmonary embolism * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Restrictive pulmonary disease * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Dyspnoea * 1  1/122 (0.82%)  2 1/120 (0.83%)  1 0/134 (0.00%)  0
Lung disorder * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Skin and subcutaneous tissue disorders       
Skin ulcer * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Venous ulcer pain * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 0/134 (0.00%)  0
Social circumstances       
Impaired quality of life * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Vascular disorders       
Hypotension * 1  0/122 (0.00%)  0 2/120 (1.67%)  2 0/134 (0.00%)  0
Arterial occlusive disease * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
Superior vena cava syndrome * 1  1/122 (0.82%)  1 0/120 (0.00%)  0 0/134 (0.00%)  0
Vena cava thrombosis * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 1/134 (0.75%)  1
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%
Doxorubicin Transdrug (DT) at 20 mg/m2 Doxorubicin Transdrug at 30 mg/m2 Best Standard of Care
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   110/122 (90.16%)      112/120 (93.33%)      97/134 (72.39%)    
Blood and lymphatic system disorders       
Thrombocytopenia * 1  2/122 (1.64%)  2 14/120 (11.67%)  26 24/134 (17.91%)  40
Anaemia * 1  15/122 (12.30%)  24 22/120 (18.33%)  30 22/134 (16.42%)  28
Neutropenia * 1  4/122 (3.28%)  16 18/120 (15.00%)  41 7/134 (5.22%)  9
Leukopenia * 1  1/122 (0.82%)  6 11/120 (9.17%)  23 3/134 (2.24%)  3
Lymphopenia * 1  5/122 (4.10%)  6 7/120 (5.83%)  16 3/134 (2.24%)  4
Gastrointestinal disorders       
Nausea * 1  26/122 (21.31%)  44 33/120 (27.50%)  62 24/134 (17.91%)  28
Diarrhoea * 1  21/122 (17.21%)  39 23/120 (19.17%)  31 20/134 (14.93%)  26
Vomiting * 1  15/122 (12.30%)  19 20/120 (16.67%)  28 10/134 (7.46%)  13
Constipation * 1  18/122 (14.75%)  22 15/120 (12.50%)  18 12/134 (8.96%)  14
Abdominal pain * 1  13/122 (10.66%)  15 15/120 (12.50%)  18 13/134 (9.70%)  17
Abdominal pain upper * 1  10/122 (8.20%)  13 12/120 (10.00%)  15 5/134 (3.73%)  5
General disorders       
Asthenia * 1  41/122 (33.61%)  65 57/120 (47.50%)  82 39/134 (29.10%)  48
Fatigue * 1  9/122 (7.38%)  11 14/120 (11.67%)  18 14/134 (10.45%)  15
Pyrexia * 1  9/122 (7.38%)  13 23/120 (19.17%)  32 8/134 (5.97%)  8
Oedema peripheral * 1  9/122 (7.38%)  10 25/120 (20.83%)  27 24/134 (17.91%)  26
Mucosal inflammation * 1  2/122 (1.64%)  2 6/120 (5.00%)  7 4/134 (2.99%)  4
Hepatobiliary disorders       
Hyperbilirubinaemia * 1  2/122 (1.64%)  2 7/120 (5.83%)  17 3/134 (2.24%)  3
Jaundice * 1  2/122 (1.64%)  2 8/120 (6.67%)  9 1/134 (0.75%)  1
Infections and infestations       
Bronchitis * 1  7/122 (5.74%)  10 7/120 (5.83%)  7 4/134 (2.99%)  4
Investigations       
Weight decreased * 1  5/122 (4.10%)  5 13/120 (10.83%)  13 5/134 (3.73%)  5
Blood bilirubin increased * 1  8/122 (6.56%)  9 2/120 (1.67%)  3 7/134 (5.22%)  12
Gamma-glutamyltransferase increased * 1  3/122 (2.46%)  3 6/120 (5.00%)  6 3/134 (2.24%)  5
Metabolism and nutrition disorders       
Decreased Appetite * 1  16/122 (13.11%)  16 19/120 (15.83%)  19 21/134 (15.67%)  23
Hypokalaemia * 1  4/122 (3.28%)  5 11/120 (9.17%)  13 5/134 (3.73%)  6
Hypoalbuminaemia * 1  3/122 (2.46%)  9 6/120 (5.00%)  13 6/134 (4.48%)  11
Musculoskeletal and connective tissue disorders       
Back pain * 1  11/122 (9.02%)  13 15/120 (12.50%)  23 6/134 (4.48%)  6
Muscle spasms * 1  0/122 (0.00%)  0 7/120 (5.83%)  7 5/134 (3.73%)  5
Nervous system disorders       
Paraesthesia * 1  4/122 (3.28%)  5 2/120 (1.67%)  2 20/134 (14.93%)  35
Headache * 1  11/122 (9.02%)  12 16/120 (13.33%)  23 6/134 (4.48%)  8
Neuropathy peripheral * 1  0/122 (0.00%)  0 0/120 (0.00%)  0 9/134 (6.72%)  9
Dizziness * 1  7/122 (5.74%)  8 1/120 (0.83%)  2 1/134 (0.75%)  1
Psychiatric disorders       
Anxiety * 1  3/122 (2.46%)  3 8/120 (6.67%)  8 5/134 (3.73%)  5
Respiratory, thoracic and mediastinal disorders       
Dyspnoea * 1  12/122 (9.84%)  20 12/120 (10.00%)  16 9/134 (6.72%)  9
Cough * 1  13/122 (10.66%)  19 9/120 (7.50%)  10 10/134 (7.46%)  12
Skin and subcutaneous tissue disorders       
Alopecia * 1  3/122 (2.46%)  3 7/120 (5.83%)  7 2/134 (1.49%)  2
Palmar-plantar erythrodysaesthesia syndrome * 1  0/122 (0.00%)  0 1/120 (0.83%)  1 7/134 (5.22%)  11
Pruritus * 1  7/122 (5.74%)  10 9/120 (7.50%)  10 7/134 (5.22%)  7
Dry skin * 1  3/122 (2.46%)  3 7/120 (5.83%)  7 3/134 (2.24%)  3
Vascular disorders       
Hypertension * 1  8/122 (6.56%)  10 5/120 (4.17%)  5 3/134 (2.24%)  5
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 NOT 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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Olivier De Beaumont; Chief Medical Officer
Organization: ONXEO
Phone: +33 (0) 1 45 58 95 33
EMail: o.debeaumont@onxeo.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Valerio Therapeutics
ClinicalTrials.gov Identifier: NCT01655693    
Other Study ID Numbers: BA2011/03/04
2011-002843-92 ( EudraCT Number )
First Submitted: July 26, 2012
First Posted: August 2, 2012
Results First Submitted: November 12, 2020
Results First Posted: June 2, 2021
Last Update Posted: June 2, 2021