Trial Outcomes & Findings for Clinical Trial of Lurbinectedin (PM01183)/Doxorubicin Versus CAV or Topotecan as Treatment in Patients With Small-Cell Lung Cancer (NCT NCT02566993)

Last Updated: 2021-10-28

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

613 participants

Primary outcome timeframe

Every three months up to death or study termination, a period of approximately 3.5 years

Results posted on

2021-10-28

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Lurbinectedin/Doxorubicin 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine 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
Overall Study STARTED	307	306
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	307	306

Reasons for withdrawal

Reasons for withdrawal
Measure	Lurbinectedin/Doxorubicin 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine 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
Overall Study Randomized but not treated	5	16
Overall Study Progressive disease	213	152
Overall Study Withdrawal by Subject	12	28
Overall Study Death	17	23
Overall Study Physician Decision	10	17
Overall Study Study drug-related adverse event	20	41
Overall Study Non study drug-related adverse event	9	9
Overall Study Symptomatic deterioration	9	16
Overall Study End of study due to events required for OS analysis according to study protocol had been reached	9	1
Overall Study Sponsor's decision after incorrect treatment at site	1	1
Overall Study Screening failure	2	0
Overall Study Lost to Follow-up	0	1
Overall Study Symptomatic deterioration, progression disease, and a decision by the Investigator	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lurbinectedin/Doxorubicin n=307 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=306 Participants 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 n=613 Participants Total of all reporting groups
Age, Continuous	63.0 years n=5 Participants	63.0 years n=7 Participants	63 years n=5 Participants
Age, Customized 18-49 years	16 Participants n=5 Participants	13 Participants n=7 Participants	29 Participants n=5 Participants
Age, Customized 50-65 years	161 Participants n=5 Participants	166 Participants n=7 Participants	327 Participants n=5 Participants
Age, Customized >65 years	130 Participants n=5 Participants	127 Participants n=7 Participants	257 Participants n=5 Participants
Sex: Female, Male Female	131 Participants n=5 Participants	133 Participants n=7 Participants	264 Participants n=5 Participants
Sex: Female, Male Male	176 Participants n=5 Participants	173 Participants n=7 Participants	349 Participants n=5 Participants
Race/Ethnicity, Customized White	266 Participants n=5 Participants	265 Participants n=7 Participants	531 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Not available	38 Participants n=5 Participants	37 Participants n=7 Participants	75 Participants n=5 Participants
Region of Enrollment Argentina	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Region of Enrollment Romania	20 Participants n=5 Participants	19 Participants n=7 Participants	39 Participants n=5 Participants
Region of Enrollment Hungary	23 Participants n=5 Participants	23 Participants n=7 Participants	46 Participants n=5 Participants
Region of Enrollment United States	32 Participants n=5 Participants	30 Participants n=7 Participants	62 Participants n=5 Participants
Region of Enrollment Czechia	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Region of Enrollment United Kingdom	10 Participants n=5 Participants	11 Participants n=7 Participants	21 Participants n=5 Participants
Region of Enrollment Portugal	10 Participants n=5 Participants	5 Participants n=7 Participants	15 Participants n=5 Participants
Region of Enrollment Spain	62 Participants n=5 Participants	63 Participants n=7 Participants	125 Participants n=5 Participants
Region of Enrollment Greece	12 Participants n=5 Participants	13 Participants n=7 Participants	25 Participants n=5 Participants
Region of Enrollment Lebanon	8 Participants n=5 Participants	9 Participants n=7 Participants	17 Participants n=5 Participants
Region of Enrollment Canada	10 Participants n=5 Participants	7 Participants n=7 Participants	17 Participants n=5 Participants
Region of Enrollment Austria	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Region of Enrollment Netherlands	9 Participants n=5 Participants	9 Participants n=7 Participants	18 Participants n=5 Participants
Region of Enrollment Belgium	9 Participants n=5 Participants	12 Participants n=7 Participants	21 Participants n=5 Participants
Region of Enrollment Brazil	13 Participants n=5 Participants	15 Participants n=7 Participants	28 Participants n=5 Participants
Region of Enrollment Poland	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Region of Enrollment Italy	21 Participants n=5 Participants	20 Participants n=7 Participants	41 Participants n=5 Participants
Region of Enrollment Bulgaria	5 Participants n=5 Participants	6 Participants n=7 Participants	11 Participants n=5 Participants
Region of Enrollment France	11 Participants n=5 Participants	12 Participants n=7 Participants	23 Participants n=5 Participants
Region of Enrollment Germany	33 Participants n=5 Participants	34 Participants n=7 Participants	67 Participants n=5 Participants
Weight	73.0 Kg n=5 Participants	74.0 Kg n=7 Participants	73.4 Kg n=5 Participants
Height	168 cm n=5 Participants	168 cm n=7 Participants	168 cm n=5 Participants
Body surface area	1.8 m^2 n=5 Participants	1.8 m^2 n=7 Participants	1.8 m^2 n=5 Participants
Body mass index	25.9 Kg/m^2 n=5 Participants	26.0 Kg/m^2 n=7 Participants	25.9 Kg/m^2 n=5 Participants
Eastern Cooperative Oncology Group Performance Status PS 0	95 Participants n=5 Participants	95 Participants n=7 Participants	190 Participants n=5 Participants
Eastern Cooperative Oncology Group Performance Status PS 1	197 Participants n=5 Participants	204 Participants n=7 Participants	401 Participants n=5 Participants
Eastern Cooperative Oncology Group Performance Status PS 2	15 Participants n=5 Participants	7 Participants n=7 Participants	22 Participants n=5 Participants
Smoking status Former	197 Participants n=5 Participants	199 Participants n=7 Participants	396 Participants n=5 Participants
Smoking status Current	91 Participants n=5 Participants	89 Participants n=7 Participants	180 Participants n=5 Participants
Smoking status Never	19 Participants n=5 Participants	18 Participants n=7 Participants	37 Participants n=5 Participants
Time from first diagnosis to randomization	9.3 months n=5 Participants	9.1 months n=7 Participants	9.2 months n=5 Participants
Disease stage Limited	25 Participants n=5 Participants	28 Participants n=7 Participants	53 Participants n=5 Participants
Disease stage Extensive	282 Participants n=5 Participants	278 Participants n=7 Participants	560 Participants n=5 Participants
Number of sites involved <3 sites	38 Participants n=5 Participants	31 Participants n=7 Participants	69 Participants n=5 Participants
Number of sites involved ≥3 sites	269 Participants n=5 Participants	275 Participants n=7 Participants	544 Participants n=5 Participants
Number of sites involved	4.0 sites n=5 Participants	4.0 sites n=7 Participants	4.0 sites n=5 Participants
Bulky disease	144 Participants n=5 Participants	127 Participants n=7 Participants	271 Participants n=5 Participants
Central Nervous System involvement	46 Participants n=5 Participants	49 Participants n=7 Participants	95 Participants n=5 Participants
Paraneoplastic syndrome	9 Participants n=5 Participants	11 Participants n=7 Participants	20 Participants n=5 Participants
Prior radiotherapy	237 Participants n=5 Participants	236 Participants n=7 Participants	473 Participants n=5 Participants
Prior surgery	27 Participants n=5 Participants	39 Participants n=7 Participants	66 Participants n=5 Participants
Lines of anticancer therapy	1.0 lines of therapies n=5 Participants	1.0 lines of therapies n=7 Participants	1.0 lines of therapies n=5 Participants
Best response to last prior chemotherapy Complete response	17 Participants n=5 Participants	15 Participants n=7 Participants	32 Participants n=5 Participants
Best response to last prior chemotherapy Partial response	192 Participants n=5 Participants	191 Participants n=7 Participants	383 Participants n=5 Participants
Best response to last prior chemotherapy Stable disease	71 Participants n=5 Participants	63 Participants n=7 Participants	134 Participants n=5 Participants
Best response to last prior chemotherapy Progressive disease	17 Participants n=5 Participants	21 Participants n=7 Participants	38 Participants n=5 Participants
Best response to last prior chemotherapy Unknown	10 Participants n=5 Participants	16 Participants n=7 Participants	26 Participants n=5 Participants
Prior immunotherapy against PD-1 or PD-L1	19 Participants n=5 Participants	17 Participants n=7 Participants	36 Participants n=5 Participants
Time-to-progression to prior chemotherapy	7.4 months n=5 Participants	7.4 months n=7 Participants	7.4 months n=5 Participants
Time from last prior progressive disease to randomization	25.0 days n=5 Participants	25.5 days n=7 Participants	25.0 days n=5 Participants
Time from end date of last prior chemotherapy to randomization	157.0 days n=5 Participants	153.0 days n=7 Participants	155 days n=5 Participants
Chemotherapy-free interval	115.0 days n=5 Participants	120.5 days n=7 Participants	120 days n=5 Participants
Chemotherapy-free interval <90 days	99 Participants n=5 Participants	101 Participants n=7 Participants	200 Participants n=5 Participants
Chemotherapy-free interval 90-179 days	115 Participants n=5 Participants	116 Participants n=7 Participants	231 Participants n=5 Participants
Chemotherapy-free interval ≥180 days	93 Participants n=5 Participants	89 Participants n=7 Participants	182 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=307 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=306 Participants 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 Survival (OS)	8.6 months Interval 7.1 to 9.4	7.6 months Interval 6.6 to 8.2

SECONDARY outcome

Timeframe: At 12 months

Population: Patients with Cyclophosphamide, Doxorubicin and Vincristine (CAV) as best Investigator's choice

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).

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=184 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=179 Participants 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
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	29.6 percentage of participants Interval 22.8 to 36.3	24.4 percentage of participants Interval 17.9 to 31.0

SECONDARY outcome

Timeframe: At 18 months

Population: Patients with Cyclophosphamide, Doxorubicin and Vincristine (CAV) as best Investigator's choice

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).

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=184 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=179 Participants 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
Difference in Overall Survival Between Lurbinectedin/DOX and CAV in Patients With CAV as Best Investigator's Choice: Overall Survival Rate at 18 Months	13.9 percentage of participants Interval 8.8 to 19.1	15.9 percentage of participants Interval 10.3 to 21.4

SECONDARY outcome

Timeframe: At 24 months

Population: Patients with Cyclophosphamide, Doxorubicin and Vincristine (CAV) as best Investigator's choice

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).

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=184 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=179 Participants 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
Difference in Overall Survival Between Lurbinectedin/DOX and CAV in Patients With CAV as Best Investigator's Choice: Overall Survival Rate at 24 Months	8.6 percentage of participants Interval 4.1 to 13.1	8.7 percentage of participants Interval 4.1 to 13.4

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=307 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=306 Participants 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
Progression-free Survival (PFS) by Independent Review Committee	4.0 months Interval 2.8 to 4.2	4.0 months Interval 3.0 to 4.1

SECONDARY outcome

Timeframe: At 6 months

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=307 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=306 Participants 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
Progression-free Survival Rate at 6 Months by Independent Review Committee	31.3 percentage of participants Interval 25.7 to 36.8	24.4 percentage of participants Interval 18.9 to 29.9

SECONDARY outcome

Timeframe: at 12 months

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=307 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=306 Participants 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
Progression-free Survival Rate at 12 Months by Independent Review Committee	10.8 percentage of participants Interval 6.7 to 14.9	4.4 percentage of participants Interval 1.4 to 7.4

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=307 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=306 Participants 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
Best Antitumor Response by Independent Review Committee Complete response	8 Participants	4 Participants
Best Antitumor Response by Independent Review Committee Partial response	89 Participants	87 Participants
Best Antitumor Response by Independent Review Committee Stable disease	111 Participants	116 Participants
Best Antitumor Response by Independent Review Committee Progressive disease	74 Participants	52 Participants
Best Antitumor Response by Independent Review Committee Unknown	25 Participants	47 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=307 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=306 Participants 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 Response Rate by Independent Review Committee	31.6 percentage of participants Interval 26.4 to 37.1	29.7 percentage of participants Interval 24.7 to 35.2

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: Patients who have a partial or complete response in the best antitumor response

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

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=97 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=91 Participants 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
Duration of Response by Independent Review Committee	5.7 months Interval 4.1 to 7.1	3.8 months Interval 2.8 to 4.3

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval ≥90 days after first-line chemotherapy

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).

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=208 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=205 Participants 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 Survival in Patients With Chemotherapy-free Interval ≥ 90 Days	10.3 months Interval 9.0 to 11.8	8.7 months Interval 7.8 to 9.8

SECONDARY outcome

Timeframe: Every six weeks up to progression disease, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval ≥90 days after first-line chemotherapy

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=208 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=205 Participants 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
Progression-free Survival in Patients With Chemotherapy-free Interval ≥90 Days	4.8 months Interval 4.1 to 5.6	4.4 months Interval 4.0 to 5.3

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval ≥90 days after first-line chemotherapy

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=208 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=205 Participants 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
Best Antitumor Response in Patients With Chemotherapy-free Interval ≥ 90 Days Complete response	8 Participants	4 Participants
Best Antitumor Response in Patients With Chemotherapy-free Interval ≥ 90 Days Partial response	69 Participants	68 Participants
Best Antitumor Response in Patients With Chemotherapy-free Interval ≥ 90 Days Stable disease	85 Participants	73 Participants
Best Antitumor Response in Patients With Chemotherapy-free Interval ≥ 90 Days Progression disease	32 Participants	35 Participants
Best Antitumor Response in Patients With Chemotherapy-free Interval ≥ 90 Days Unknown	14 Participants	25 Participants

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval ≥90 days after first-line chemotherapy

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=208 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=205 Participants 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 Response Rate in Patients With Chemotherapy-free Interval ≥ 90 Days	37.0 percentage of participants Interval 30.4 to 44.0	35.1 percentage of participants Interval 28.6 to 42.1

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: 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.

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=77 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=72 Participants 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
Duration of Response in Patients With Chemotherapy-free Interval ≥ 90 Days	6.9 months Interval 4.1 to 8.3	4.0 months Interval 3.0 to 4.8

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval \<90 days after first-line chemotherapy

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).

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=99 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=101 Participants 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 Survival in Patients With Chemotherapy-free Interval < 90 Days	5.7 months Interval 4.1 to 6.7	5.3 months Interval 4.2 to 6.1

SECONDARY outcome

Timeframe: Every six weeks up to progression disease, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval \<90 days after first-line chemotherapy

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=99 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=101 Participants 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
Progression-free Survival in Patients With Chemotherapy-free Interval <90 Days	1.6 months Interval 1.4 to 2.7	2.8 months Interval 2.5 to 3.0

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval \<90 days after first-line chemotherapy

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=99 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=101 Participants 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
Best Antitumor Response in Patients With Chemotherapy-free Interval <90 Days Partial response	20 Participants	19 Participants
Best Antitumor Response in Patients With Chemotherapy-free Interval <90 Days Stable disease	26 Participants	43 Participants
Best Antitumor Response in Patients With Chemotherapy-free Interval <90 Days Progression disease	42 Participants	17 Participants
Best Antitumor Response in Patients With Chemotherapy-free Interval <90 Days Unknown	11 Participants	22 Participants

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients had chemotherapy-free interval \<90 days after first-line chemotherapy

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=99 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=101 Participants 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 Response Rate in Patients With Chemotherapy-free Interval <90 Days	20.2 percentage of participants Interval 12.8 to 29.5	18.8 percentage of participants Interval 11.7 to 27.8

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=20 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=19 Participants 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
Duration of Response in Patients With Chemotherapy-free Interval <90 Days	3.0 months Interval 1.4 to 4.5	2.8 months Interval 1.4 to 4.1

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients without Central Nervous System Involvement at Baseline

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).

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=261 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=257 Participants 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 Survival in Patients Without Central Nervous System Involvement at Baseline	9.1 months Interval 8.1 to 10.2	7.7 months Interval 6.7 to 8.6

SECONDARY outcome

Timeframe: Every six weeks up to progression disease, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients without Central Nervous System Involvement at Baseline

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=261 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=257 Participants 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
Progression-free Survival in Patients Without Central Nervous System Involvement at Baseline	4.2 months Interval 3.7 to 4.8	4.1 months Interval 3.1 to 4.3

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients without Central Nervous System Involvement at Baseline

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=261 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=257 Participants 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
Best Antitumor Response in Patients Without Central Nervous System Involvement at Baseline Complete response	7 Participants	3 Participants
Best Antitumor Response in Patients Without Central Nervous System Involvement at Baseline Partial response	79 Participants	76 Participants
Best Antitumor Response in Patients Without Central Nervous System Involvement at Baseline Stable disease	101 Participants	100 Participants
Best Antitumor Response in Patients Without Central Nervous System Involvement at Baseline Progression disease	55 Participants	40 Participants
Best Antitumor Response in Patients Without Central Nervous System Involvement at Baseline Unknown	19 Participants	38 Participants

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients without Central Nervous System Involvement at Baseline

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=261 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=257 Participants 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 Response Rate in Patients Without Central Nervous System Involvement at Baseline	33.0 percentage of participants Interval 27.3 to 39.0	30.7 percentage of participants Interval 25.2 to 36.8

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: 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

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=86 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=79 Participants 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
Duration of Response in Patients Without Central Nervous System Involvement at Baseline	5.7 months Interval 4.1 to 7.3	4.0 months Interval 3.0 to 4.9

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients with Central Nervous System Involvement at Baseline

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).

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=46 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=49 Participants 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 Survival in Patients With Central Nervous System Involvement at Baseline	4.6 months Interval 3.1 to 6.1	6.6 months Interval 4.0 to 8.8

SECONDARY outcome

Timeframe: Every six weeks up to progression disease, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients with Central Nervous System Involvement at Baseline

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=46 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=49 Participants 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
Progression-free Survival in Patients With Central Nervous System Involvement at Baseline	1.9 months Interval 1.4 to 2.7	2.8 months Interval 1.4 to 3.8

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients with Central Nervous System Involvement at Baseline

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=46 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=49 Participants 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
Best Antitumor Response in Patients With Central Nervous System Involvement at Baseline Complete response	1 Participants	1 Participants
Best Antitumor Response in Patients With Central Nervous System Involvement at Baseline Partial response	10 Participants	11 Participants
Best Antitumor Response in Patients With Central Nervous System Involvement at Baseline Stable disease	10 Participants	16 Participants
Best Antitumor Response in Patients With Central Nervous System Involvement at Baseline Progression disease	19 Participants	12 Participants
Best Antitumor Response in Patients With Central Nervous System Involvement at Baseline Unknown	6 Participants	9 Participants

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: A preplanned exploratory efficacy subgroup analysis was focused on patients with Central Nervous System Involvement at Baseline

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=46 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=49 Participants 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 Response Rate in Patients With Central Nervous System Involvement at Baseline	23.9 percentage of participants Interval 12.6 to 38.8	24.5 percentage of participants Interval 13.3 to 38.9

SECONDARY outcome

Timeframe: Every three months up to death or study termination, a period of approximately 3.5 years

Population: 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

Outcome measures

Outcome measures
Measure	Lurbinectedin/Doxorubicin n=11 Participants 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.	Topotecan or Cyclophosphamide/Doxorubicin/Vincristine n=12 Participants 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
Duration of Response in Patients With Central Nervous System Involvement at Baseline	1.5 months Interval 0.1 to Not reached	2.7 months Interval 1.3 to 4.0

Adverse Events

Lurbinectedin/Doxorubicin

Serious events: 126 serious events

Other events: 292 other events

Deaths: 264 deaths

Topotecan

Serious events: 66 serious events

Other events: 120 other events

Deaths: 100 deaths

Cyclophosphamide/Doxorubicin/Vincristine

Serious events: 75 serious events

Other events: 148 other events

Deaths: 148 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Developtment, Department of PharmaMar´s Oncology., Business Unit.

Pharma Mar S.A.

Phone: 0034 918466000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER