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

• 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: PharmaMar
• Information provided by (Responsible Party): PharmaMar

Tracking Information

• First Submitted Date: September 24, 2015
• First Posted Date: October 2, 2015
• Results First Submitted Date: August 6, 2021
• Results First Posted Date: October 28, 2021
• Last Update Posted Date: October 28, 2021
• Actual Study Start Date: August 30, 2016
• Actual Primary Completion Date: February 24, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 29, 2021)

Overall Survival (OS) [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]

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).

• Original Primary Outcome Measures (submitted: October 1, 2015): Progression-free survival (PFS) [ Time Frame: Every six weeks up to progression disease (aprox. 5 months) ]

Current Secondary Outcome Measures (submitted: September 29, 2021)

• 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 [ Time Frame: At 12 months ]
  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).
• Difference in Overall Survival Between Lurbinectedin/DOX and CAV in Patients With CAV as Best Investigator's Choice: Overall Survival Rate at 18 Months [ Time Frame: At 18 months ]
  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).
• Difference in Overall Survival Between Lurbinectedin/DOX and CAV in Patients With CAV as Best Investigator's Choice: Overall Survival Rate at 24 Months [ Time Frame: At 24 months ]
  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).
• Progression-free Survival (PFS) by Independent Review Committee [ Time Frame: Every six weeks up to progression disease, a period of approximately 3.5 years ]
  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.
• Progression-free Survival Rate at 6 Months by Independent Review Committee [ Time Frame: At 6 months ]
  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.
• Progression-free Survival Rate at 12 Months by Independent Review Committee [ Time Frame: at 12 months ]
  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.
• Best Antitumor Response by Independent Review Committee [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Overall Response Rate by Independent Review Committee [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Duration of Response by Independent Review Committee [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Overall Survival in Patients With Chemotherapy-free Interval ≥ 90 Days [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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).
• Progression-free Survival in Patients With Chemotherapy-free Interval ≥90 Days [ Time Frame: Every six weeks up to progression disease, a period of approximately 3.5 years ]
  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.
• Best Antitumor Response in Patients With Chemotherapy-free Interval ≥ 90 Days [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Overall Response Rate in Patients With Chemotherapy-free Interval ≥ 90 Days [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Duration of Response in Patients With Chemotherapy-free Interval ≥ 90 Days [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Overall Survival in Patients With Chemotherapy-free Interval < 90 Days [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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).
• Progression-free Survival in Patients With Chemotherapy-free Interval <90 Days [ Time Frame: Every six weeks up to progression disease, a period of approximately 3.5 years ]
  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.
• Best Antitumor Response in Patients With Chemotherapy-free Interval <90 Days [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Overall Response Rate in Patients With Chemotherapy-free Interval <90 Days [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Duration of Response in Patients With Chemotherapy-free Interval <90 Days [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Overall Survival in Patients Without Central Nervous System Involvement at Baseline [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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).
• Progression-free Survival in Patients Without Central Nervous System Involvement at Baseline [ Time Frame: Every six weeks up to progression disease, a period of approximately 3.5 years ]
  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.
• Best Antitumor Response in Patients Without Central Nervous System Involvement at Baseline [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Overall Response Rate in Patients Without Central Nervous System Involvement at Baseline [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Duration of Response in Patients Without Central Nervous System Involvement at Baseline [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Overall Survival in Patients With Central Nervous System Involvement at Baseline [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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).
• Progression-free Survival in Patients With Central Nervous System Involvement at Baseline [ Time Frame: Every six weeks up to progression disease, a period of approximately 3.5 years ]
  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.
• Best Antitumor Response in Patients With Central Nervous System Involvement at Baseline [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Overall Response Rate in Patients With Central Nervous System Involvement at Baseline [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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
• Duration of Response in Patients With Central Nervous System Involvement at Baseline [ Time Frame: Every three months up to death or study termination, a period of approximately 3.5 years ]
  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

Original Secondary Outcome Measures (submitted: October 1, 2015)

• Overall survival (OS) [ Time Frame: Every three months up to death or study termination (aprox. 10 months) ]
• Overall survival rate 12, 18 & 24 months [ Time Frame: Every three months up to death or study termination (aprox. 24 months) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Clinical Trial of Lurbinectedin (PM01183)/Doxorubicin Versus CAV or Topotecan as Treatment in Patients With Small-Cell Lung Cancer
• Official Title: Phase III Randomized Clinical Trial of Lurbinectedin (PM01183)/Doxorubicin Versus Cyclophosphamide, Doxorubicin and Vincristine (CAV) or Topotecan as Treatment in Patients With Small-Cell Lung Cancer (SCLC) Who Failed One Prior Platinum-containing Line (ATLANTIS)
• Brief Summary: Phase III randomized clinical trial of lurbinectedin (PM01183)/doxorubicin (DOX) versus cyclophosphamide (CTX), doxorubicin (DOX) and vincristine (VCR) (CAV) or topotecan as treatment in patients with small-cell lung cancer (SCLC) who failed one prior platinum-containing line.
• Detailed Description: Multicenter, open-label, randomized, controlled phase III clinical trial to evaluate and compare the activity and safety of an experimental arm consisting of PM01183/DOX combination followed by PM01183 alone, if applicable vs. best Investigator's choice between CAV or topotecan as a control arm, in SCLC patients who failed one prior platinum-containing line but no more than one prior chemotherapy-containing line.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Small-cell Lung Cancer

Intervention

• Drug: Lurbinectedin (PM01183)
• Drug: Doxorubicin (DOX)
• Drug: Cyclophosphamide (CTX)
• Drug: Vincristine (VCR)
• Drug: Topotecan

Study Arms

• Experimental: Experimental Arm
  Lurbinectedin (PM01183) / Doxorubicin
  Interventions:

  • Drug: Lurbinectedin (PM01183)
  • Drug: Doxorubicin (DOX)
• Active Comparator: Control Arm 1
  CAV (Cyclophosphamide (CTX), Doxorubicin (DOX) and Vincristine (VCR))
  Interventions:

  • Drug: Doxorubicin (DOX)
  • Drug: Cyclophosphamide (CTX)
  • Drug: Vincristine (VCR)
• Active Comparator: Control Arm 2
  Topotecan
  Intervention: Drug: Topotecan

• Publications *: Aix SP, Ciuleanu TE, Navarro A, Cousin S, Bonanno L, Smit EF, Chiappori A, Olmedo ME, Horvath I, Grohe C, Farago AF, Lopez-Vilarino JA, Cullell-Young M, Nieto A, Vasco N, Gomez J, Kahatt C, Zeaiter A, Carcereny E, Roubec J, Syrigos K, Lo G, Barneto I, Pope A, Sanchez A, Kattan J, Zarogoulidis K, Waller CF, Bischoff H, Juan-Vidal O, Reinmuth N, Domine M, Paz-Ares L. Combination lurbinectedin and doxorubicin versus physician's choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): a multicentre, randomised, open-label, phase 3 trial. Lancet Respir Med. 2023 Jan;11(1):74-86. doi: 10.1016/S2213-2600(22)00309-5. Epub 2022 Oct 14.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 10, 2018): 613
• Original Estimated Enrollment (submitted: October 1, 2015): 600
• Actual Study Completion Date: February 24, 2020
• Actual Primary Completion Date: February 24, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Voluntary written informed consent
2. Adult patients ≥ 18 years
3. Histologically or cytologically confirmed diagnosis of limited or extensive stage SCLC which failed one prior platinum-containing regimen and with a chemotherapy-free interval (CTFI, time from the last dose of first-line chemotherapy to the occurrence of progressive disease) ≥ 30 days. Small-cell carcinoma of unknown primary site with or without neuroendocrine features confirmed in histology test(s) performed on metastatic lesion(s) are eligible, if Ki-67/MIB-1 is expressed in >50% of tumor cells.
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2.
5. Adequate hematological, renal, metabolic and hepatic function within 7-10 days prior to randomization
6. At least three weeks since last prior anticancer treatment and adequate recovery from prior treatment toxicity
7. Prior radiotherapy (RT): At least four weeks since completion of whole-brain irradiation, at least two weeks since completion of prophylactic cranial irradiation, and to any other site.
8. Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to six weeks after treatment discontinuation. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product dose.

Exclusion Criteria:

1. More than one prior chemotherapy-containing line(re-challenge with the same initial regimen is not allowed)
2. Patients who never received platinum-containing regimen for Small-cell Lung Cancer (SCLC)
3. Prior treatment with PM01183, topotecan or anthracyclines.
4. Limited-stage patients who are candidates for local or regional therapy
5. Impending need for palliative RT or surgery for pathological fractures and/or for medullary compression within four weeks prior to randomization.
6. Symptomatic or progressing or steroid requiring Central Nervous System (CNS) involvement disease at least four weeks prior to randomization

7. Concomitant diseases/conditions:

   Angina, myocardial infarction, congestive heart failure or clinically significant valvular heart disease, arrhythmia, immunodeficiency (including known HIV seropositive), ongoing or treatment-requiring chronic liver disease, active infection, oxygen requirement within two weeks prior to randomization, diffuse interstitial lung disease (ILD) or pulmonary fibrosis, second invasive malignancy treated with chemotherapy and/or radiotherapy, invasive fungal infections requiring systemic treatment within 12 weeks of randomization.

8. Pregnant or breast feeding women

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Austria, Belgium, Brazil, Bulgaria, Canada, Czechia, France, Germany, Greece, Hungary, Italy, Lebanon, Netherlands, Poland, Portugal, Romania, Spain, United Kingdom, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT02566993
• Other Study ID Numbers: PM1183-C-003-14
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: PharmaMar
• Original Responsible Party: Same as current
• Current Study Sponsor: PharmaMar
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: PharmaMar
• Verification Date: August 2021