A Study Comparing the Combination of Trabectedin (YONDELIS) and DOXIL/CAELYX With DOXIL/CAELYX for the Treatment of Advanced-Relapsed Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01846611
• Collaborator: PharmaMar (Industry)
• Enrollment: 581
• Locations: 142
• Arms: 2
• Actual Duration (Months): 61
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy and safety of trabectedin+DOXIL as a third-line chemotherapy regimen (treatment) in patients with platinum-sensitive advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who received 2 previous lines of platinum-based chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Neoplasms; Peritoneal Neoplasms; Fallopian Tube Neoplasms	Drug: Trabectedin; Drug: DOXIL; Drug: Dexamethasone; Drug: DOXIL	Phase 3

Detailed Description

This is a randomized (individuals assigned to study treatment by chance), open - label (identity of assigned study drug will be known), active - controlled study in adult female patients with platinum-sensitive advanced - relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer who received 2 previous lines of platinum - based chemotherapy. Approximately 670 participants will be enrolled. Patients will be stratified by 4 criteria defined in the protocol and randomly assigned in a 1:1 ratio to the trabectedin+DOXIL combination therapy group (Arm A) or to the DOXIL (pegylated liposomal doxorubicin) monotherapy group (Arm B). During the treatment phase, patients will receive study drug infusions according to 21 - day cycles in Arm A and 28 - day cycles in Arm B. Treatment will continue until the occurrence of disease progression or unacceptable treatment toxicity, or until 2 cycles after assessment of a complete response (CR). Efficacy assessments will be evaluated using Response Evaluation Criteria in Solid Tumors. Disease assessments, including assessments for patients who discontinue treatment for reasons other than disease progression, will be performed until disease progression, the start of subsequent anticancer therapy, withdrawal of consent, or the clinical cutoff date. Collection of survival status will continue until at least 514 deaths have been observed or until the clinical data cutoff date. Serial pharmacokinetic (PK) samples will be collected in a subset of patients who voluntarily consent to the PK portion of the study. Safety will be monitored throughout the study. An interim analysis of overall survival (OS) will be performed after approximately 308 participants have died. The final analysis of OS will occur when approximately 514 deaths have been observed or until the clinical cutoff date. As of Amendment 6, no new participants will be randomized to study treatment, and treatment with trabectedin should be immediately discontinued for participants assigned to Arm A (trabectedin+DOXIL). All study participants (Arm A or Arm B) currently on study who, in the opinion of the investigator, are deriving clinical benefit may continue treatment with single-agent DOXIL as per the local standard of care.

Study Design

• Study Type: Interventional
• Actual Enrollment: 581 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label Study Comparing the Combination of YONDELIS and DOXIL/CAELYX With DOXIL/CAELYX Monotherapy for the Treatment of Advanced-Relapsed Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
• Actual Study Start Date: Oct 16, 2013
• Actual Primary Completion Date: Jan 18, 2018
• Actual Study Completion Date: Nov 16, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: trabectedin + DOXIL Participants will receive DOXIL 30 millgram per meter square (mg/m^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m^2 administered as an IV infusion over approximately 3hours, every 3 weeks. Participants will be pretreated with 20 mg dexamethasone IV (or the IV equivalent) approximately 30 minutes before DOXIL study drug. As of Amendment 6, treatment with trabectedin will be discontinued for participants on treatment with trabectedin and no new participants will receive trabectedin. Participants who, in the opinion of the investigator, are deriving clinical benefit may continue treatment with single-agent DOXIL as per the local standard of care.	Drug: Trabectedin; 1.1 mg/m^2 administered intravenously over approximately 3 hours on Day 1 of each 21-day treatment cycle.; Drug: DOXIL; 30 mg/m^2 administered intravenously over approximately 90 minutes on Day 1 of each 21-day treatment cycle.; Drug: Dexamethasone; 20 mg administered intravenously on Day 1 of each 21-day treatment cycle approximately 30 minutes prior to study drug infusion.
Active Comparator: Arm B: DOXIL Participants will receive DOXIL, 50 mg/m^2 administered as an IV infusion over approximately 90 minutes every 4 weeks.	Drug: DOXIL; 50 mg/m^2 administered intravenously over approximately 90 minutes on Day 1 of each 28-day treatment cycle.

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [Up to 4.3 years]

   OS is defined as the time between the date of randomization and the date of death. Participants who died, regardless of the cause of death, were considered to have had an event.

Secondary Outcome Measures

1. Progression-Free Survival (PFS) [Up to 4.3 years]

   PFS is defined as the time between the date of randomization and the date of disease progression or death. PFS was assessed using the response evaluation criteria in solid tumors (RECIST) Version 1.1. As per criteria progressive disease in case of target lesions means at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). Progressive disease in case of non-target lesions means unequivocal progression of existing non-target lesions. In both cases the appearance of one or more new lesions is also considered progression.

2. Objective Response Rate (ORR) [Up to 4.3 years]

   ORR is defined as the percentage of participants with measurable disease achieving a best overall response of either complete response (CR) or partial response (PR) based on RECIST. CR: disappearance of all target and non-target lesions and normalization of tumor marker levels in non-target lesions. PR: at least a 30 percent (%) decrease in the sum of longest diameter (LD) of target lesions or persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically proven advanced-relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer

• Eastern Cooperative Oncology Group (ECOG) performance status grade of 0 or 1

• Received first-line treatment with a platinum-based regimen and had no evidence of disease progression for >= 6 months after the last dose

• Received second-line treatment with a platinum-based regimen, with progression of disease after attaining a response

• Progression of disease based on imaging after the second-line platinum-based regimen (individuals treated with a pegylated liposomal doxorubicin-containing regimen as a second-line therapy are eligible if subsequent disease progression occurs >=9 months from the first dose)

• Evidence of measurable disease at screening as evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1)

• Participants no longer need to be able to receive intravenous (IV) dexamethasone or an equivalent IV corticosteroid

• Have a known BRCA 1/2 mutation status (for participants who do not have a known BRCA 1/2 status at screening, a blood sample will be collected to determine the status with the results available prior to randomization

• Laboratory values within protocol -defined parameters

• Have left ventricular ejection fraction by multigated acquisition scan (MUGA) scan or 2D-ECHO within normal limits for the institution

• Have side effects (except alopecia) of prior treatment resolved to at least Grade 1 according to the National Cancer Institute - Common Terminology Criteria of Adverse Events (NCICTCAE) (Version 4.0)

• Have a negative urine or serum pregnancy test at screening

• Agrees to protocol-defined use of effective contraception

Exclusion Criteria:

• Diagnosis of ovarian carcinoma with mucinous histology

• Had more than 2 prior lines of systemic therapy. Maintenance therapies and hormonal therapies are not considered additional lines of therapy

• Participants who had a prior exposure to trabectedin or hypersensitivity to any of the excipients will not be excluded from receiving single-agent Doxil

• Prior treatment with doxorubicin or other anthracycline at cumulative doses greater than 300 mg/m2 (calculated using doxorubicin equivalent doses: 1 mg doxorubicin = 1 mg Doxil/Caelyx = 1.8 mg epirubicin = 0.3 mg mitoxantrone = 0.25 mg idarubicin)

• Participants unwilling or unable to have a central venous catheter placed will not be excluded from receiving single-agent Doxil

• Pregnant or breast-feeding

• Would receive study treatment within 3 weeks from radiation therapy, experimental therapy, hormonal therapy, prior chemotherapy, or biological therapy; use an invasive investigational device; or is currently enrolled in an investigational study

• History of another invasive malignancy (except non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin or cervical carcinoma in situ adequately treated) unless in remission for >=5 years, or a non - invasive malignancy requiring ongoing therapy

• Known allergies, hypersensitivity, or intolerance to Doxil, dexamethasone, or their excipients

• Known history of central nervous system metastasis

• Known significant chronic liver disease, such as cirrhosis or active hepatitis (potential participants who test positive for hepatitis B surface antigen or hepatitis C antibodies are allowed provided they do not have active disease requiring antiviral therapy)

• Had a myocardial infarct within 6 months before enrollment, New York Heart Association (NYHA) Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities

• Has any of the following medical conditions: uncontrolled diabetes, psychiatric disorder (including dementia) that prevents compliance with protocol, uncontrolled seizures, newly diagnosed deep vein thrombosis, active systemic infection that is likely to interfere with study procedure or results

• Has any condition that, in the opinion of the investigator, would compromise the well-being of the participant or the study or prevent the participant from meeting or performing study requirements

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Phoenix	Arizona	United States
3		Scottsdale	Arizona	United States
4		Sedona	Arizona	United States
5		Tucson	Arizona	United States
6		Hot Springs	Arkansas	United States
7		Greenbrae	California	United States
8		La Jolla	California	United States
9		Los Angeles	California	United States
10		Orange	California	United States
11		Sacramento	California	United States
12		Englewood	Colorado	United States
13		New Britain	Connecticut	United States
14		New Haven	Connecticut	United States
15		Stamford	Connecticut	United States
16		Fort Myers	Florida	United States
17		Jacksonville	Florida	United States
18		Miami	Florida	United States
19		Saint Petersburg	Florida	United States
20		Sarasota	Florida	United States
21		Tampa	Florida	United States
22		Atlanta	Georgia	United States
23		Savannah	Georgia	United States
24		Chicago	Illinois	United States
25		Park Ridge	Illinois	United States
26		Indianapolis	Indiana	United States
27		Louisville	Kentucky	United States
28		Covington	Louisiana	United States
29		New Orleans	Louisiana	United States
30		Scarborough	Maine	United States
31		Worcester	Massachusetts	United States
32		Detroit	Michigan	United States
33		Lansing	Michigan	United States
34		Duluth	Minnesota	United States
35		Edina	Minnesota	United States
36		Columbia	Missouri	United States
37		Kansas City	Missouri	United States
38		Hackensack	New Jersey	United States
39		Morristown	New Jersey	United States
40		New Brunswick	New Jersey	United States
41		Summit	New Jersey	United States
42		Brightwaters	New York	United States
43		Hawthorne	New York	United States
44		New York	New York	United States
45		Pinehurst	North Carolina	United States
46		Akron	Ohio	United States
47		Cincinnati	Ohio	United States
48		Cleveland	Ohio	United States
49		Columbus	Ohio	United States
50		Tulsa	Oklahoma	United States
51		Portland	Oregon	United States
52		Abington	Pennsylvania	United States
53		Pittsburgh	Pennsylvania	United States
54		Providence	Rhode Island	United States
55		Charleston	South Carolina	United States
56		Greenville	South Carolina	United States
57		Nashville	Tennessee	United States
58		Austin	Texas	United States
59		Bedford	Texas	United States
60		Dallas	Texas	United States
61		Fort Worth	Texas	United States
62		Houston	Texas	United States
63		San Antonio	Texas	United States
64		The Woodlands	Texas	United States
65		Webster	Texas	United States
66		Salt Lake City	Utah	United States
67		Annandale	Virginia	United States
68		Newport News	Virginia	United States
69		Roanoke	Virginia	United States
70		Spokane	Washington	United States
71		Vancouver	Washington	United States
72		Green Bay	Wisconsin	United States
73		Madison	Wisconsin	United States
74		Milwaukee	Wisconsin	United States
75		Wauwatosa	Wisconsin	United States
76		Adelaide		Australia
77		Ballarat		Australia
78		Brisbane		Australia
79		Gosford		Australia
80		Parkville		Australia
81		Subiaco		Australia
82		Toorak Gardens		Australia
83		Townsville		Australia
84		Wodonga		Australia
85		Woodville		Australia
86		Guangzhou		China
87		Jinan		China
88		Shanghai		China
89		Shenyang		China
90		Beer Sheva		Israel
91		Haifa		Israel
92		Holon		Israel
93		Jerusalem		Israel
94		Kfar Saba		Israel
95		Petah Tikva		Israel
96		Ramat-Gan		Israel
97		Rehovot		Israel
98		Tel Aviv		Israel
99		Zerifin		Israel
100		Auckland		New Zealand
101		Wellington		New Zealand
102		Bydgoszcz		Poland
103		Gdańsk		Poland
104		Lublin		Poland
105		Poznan		Poland
106		Warszawa		Poland
107		Arkhangelsk		Russian Federation
108		Chelyabinsk		Russian Federation
109		Ivanovo		Russian Federation
110		Kirov		Russian Federation
111		Krasnodar		Russian Federation
112		Moscow N/a		Russian Federation
113		Moscow		Russian Federation
114		Nalchik		Russian Federation
115		Nizhniy Novgorod		Russian Federation
116		Nizhny Novgorod		Russian Federation
117		Omsk		Russian Federation
118		Orenburg		Russian Federation
119		Pyatigorsk		Russian Federation
120		Ryazan		Russian Federation
121		Saint Petersburg		Russian Federation
122		Saint-Petersburg,		Russian Federation
123		Sochi		Russian Federation
124		St Petersburg		Russian Federation
125		Ufa		Russian Federation
126		Yaroslavl		Russian Federation
127		Amanzimtoti		South Africa
128		Cape Town		South Africa
129		Durban		South Africa
130		Johannesburg		South Africa
131		Port Elizabeth		South Africa
132		Pretoria		South Africa
133		Bern		Switzerland
134		Zurich		Switzerland
135		Bebington		United Kingdom
136		Glasgow		United Kingdom
137		Guilford		United Kingdom
138		London		United Kingdom
139		Maidstone		United Kingdom
140		Manchester		United Kingdom
141		Plymouth		United Kingdom
142		Swansea		United Kingdom

Sponsors and Collaborators

• Janssen Research & Development, LLC
• PharmaMar

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

• Study Protocol - Jan 9, 2018
• Statistical Analysis Plan - Apr 12, 2018

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT01846611
• Other Study ID Numbers: CR100983; ET743OVC3006; 2012-004808-34
• First Posted: May 3, 2013
• Last Update Posted: Apr 1, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by Janssen Research & Development, LLC: Ovarian neoplasms; Peritoneal neoplasms; Fallopian tube neoplasms; Advanced-relapsed epithelial ovarian cancer; Advanced-relapsed primary peritoneal cancer; Advanced-relapsed fallopian tube cancer; Trabectedin; Yondelis; Doxil; Caelyx; Platinum sensitive; Tthird-line; BRCA; Patient related outcome
• Additional relevant MeSH terms: Neoplasms; Fallopian Tube Neoplasms; Ovarian Neoplasms; Peritoneal Neoplasms; Dexamethasone; Liposomal doxorubicin; Doxorubicin; Trabectedin

Study Results

Participant Flow

Pre-assignment Detail	Total 581 participants were enrolled. Out of which 5 participants who were enrolled at the time of study termination were not assigned to any treatment group. Therefore, these 5 participants were not considered as randomized participants and excluded from result analysis.

Arm/Group Title	Trabectedin + DOXIL	DOXIL
Arm/Group Description	Participants received DOXIL 30 milligram per meter square (mg/m^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m^2 administered as an IV infusion over approximately 3 hours, on Day 1 of each treatment cycle (21 days cycle) every 3 weeks. Participants were pretreated with 20 mg dexamethasone IV (or an equivalent IV corticosteroid) approximately 30 minutes prior to initiation of infusion of DOXIL IV.	Participants received DOXIL 50 mg/m^2 administered as an IV infusion over approximately 90 minutes on Day 1 of each treatment cycle (28 days cycle), every 4 weeks.
Period Title: Overall Study
STARTED	289	287
Treated	286	282
COMPLETED	251	244
NOT COMPLETED	38	43

Baseline Characteristics

Arm/Group Title	Trabectedin + DOXIL	DOXIL	Total
Arm/Group Description	Participants received DOXIL 30 milligram per meter square (mg/m^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m^2 administered as an IV infusion over approximately 3 hours, on Day 1 of each treatment cycle (21 days cycle) every 3 weeks. Participants were pretreated with 20 mg dexamethasone IV (or an equivalent IV corticosteroid) approximately 30 minutes prior to initiation of infusion of DOXIL IV.	Participants received DOXIL 50 mg/m^2 administered as an IV infusion over approximately 90 minutes on Day 1 of each treatment cycle (28 days cycle), every 4 weeks.	Total of all reporting groups
Overall Participants	289	287	576
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.8 (10.16)	59.9 (10.35)	59.9 (10.25)
Sex: Female, Male (Count of Participants)
Female	289 100%	287 100%	576 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 3.5%	5 1.7%	15 2.6%
Not Hispanic or Latino	270 93.4%	278 96.9%	548 95.1%
Unknown or Not Reported	9 3.1%	4 1.4%	13 2.3%
Race/Ethnicity, Customized (Count of Participants)
Asian	15 5.2%	23 8%	38 6.6%
Black or African American	3 1%	4 1.4%	7 1.2%
Hispanic or Latino	8 2.8%	3 1%	11 1.9%
Other	15 5.2%	11 3.8%	26 4.5%
White Non-Hispanic	248 85.8%	246 85.7%	494 85.8%
Region of Enrollment (Count of Participants)
AUSTRALIA	15 5.2%	14 4.9%	29 5%
CHINA	9 3.1%	18 6.3%	27 4.7%
ISRAEL	2 0.7%	8 2.8%	10 1.7%
NEW ZEALAND	10 3.5%	8 2.8%	18 3.1%
POLAND	3 1%	5 1.7%	8 1.4%
RUSSIAN FEDERATION	124 42.9%	122 42.5%	246 42.7%
SOUTH AFRICA	7 2.4%	4 1.4%	11 1.9%
SWITZERLAND	1 0.3%	0 0%	1 0.2%
UNITED KINGDOM	15 5.2%	7 2.4%	22 3.8%
UNITED STATES	103 35.6%	101 35.2%	204 35.4%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time between the date of randomization and the date of death. Participants who died, regardless of the cause of death, were considered to have had an event.
Time Frame	Up to 4.3 years

Outcome Measure Data

Analysis Population Description

All randomized analysis set included all participants who were randomized to study treatment independent of whether they received study drug.

Arm/Group Title	Trabectedin + DOXIL	DOXIL
Arm/Group Description	Participants received DOXIL 30 milligram per meter square (mg/m^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m^2 administered as an IV infusion over approximately 3 hours, on Day 1 of each treatment cycle (21 days cycle) every 3 weeks. Participants were pretreated with 20 mg dexamethasone IV (or an equivalent IV corticosteroid) approximately 30 minutes prior to initiation of infusion of DOXIL IV.	Participants received DOXIL 50 mg/m^2 administered as an IV infusion over approximately 90 minutes on Day 1 of each treatment cycle (28 days cycle), every 4 weeks.
Measure Participants	289	287
Median (95% Confidence Interval) [months]	23.82	22.21

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trabectedin + DOXIL, DOXIL
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.5236
	Comments
	Method	Unstratified log rank test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.925
	Confidence Interval	(2-Sided) 95%; 0.727 to 1.177
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS is defined as the time between the date of randomization and the date of disease progression or death. PFS was assessed using the response evaluation criteria in solid tumors (RECIST) Version 1.1. As per criteria progressive disease in case of target lesions means at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeter (mm). Progressive disease in case of non-target lesions means unequivocal progression of existing non-target lesions. In both cases the appearance of one or more new lesions is also considered progression.
Time Frame	Up to 4.3 years

Outcome Measure Data

Analysis Population Description

All randomized analysis set included all participants who were randomized to study treatment independent of whether they received study drug.

Arm/Group Title	Trabectedin + DOXIL	DOXIL
Arm/Group Description	Participants received DOXIL 30 milligram per meter square (mg/m^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m^2 administered as an IV infusion over approximately 3 hours, on Day 1 of each treatment cycle (21 days cycle) every 3 weeks. Participants were pretreated with 20 mg dexamethasone IV (or an equivalent IV corticosteroid) approximately 30 minutes prior to initiation of infusion of DOXIL IV.	Participants received DOXIL 50 mg/m^2 administered as an IV infusion over approximately 90 minutes on Day 1 of each treatment cycle (28 days cycle), every 4 weeks.
Measure Participants	289	287
Median (95% Confidence Interval) [months]	7.52	7.26

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trabectedin + DOXIL, DOXIL
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.5174
	Comments
	Method	Unstratified log rank test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.935
	Confidence Interval	(2-Sided) 95%; 0.762 to 1.147
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	ORR is defined as the percentage of participants with measurable disease achieving a best overall response of either complete response (CR) or partial response (PR) based on RECIST. CR: disappearance of all target and non-target lesions and normalization of tumor marker levels in non-target lesions. PR: at least a 30 percent (%) decrease in the sum of longest diameter (LD) of target lesions or persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits.
Time Frame	Up to 4.3 years

Outcome Measure Data

Analysis Population Description

All randomized analysis set included all participants who were randomized to study treatment independent of whether they received study drug.

Arm/Group Title	Trabectedin + DOXIL	DOXIL
Arm/Group Description	Participants received DOXIL 30 milligram per meter square (mg/m^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m^2 administered as an IV infusion over approximately 3 hours, on Day 1 of each treatment cycle (21 days cycle) every 3 weeks. Participants were pretreated with 20 mg dexamethasone IV (or an equivalent IV corticosteroid) approximately 30 minutes prior to initiation of infusion of DOXIL IV.	Participants received DOXIL 50 mg/m^2 administered as an IV infusion over approximately 90 minutes on Day 1 of each treatment cycle (28 days cycle), every 4 weeks.
Measure Participants	289	287
Number (95% Confidence Interval) [Percentage of participants]	46.0 15.9%	35.9 12.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trabectedin + DOXIL, DOXIL
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0142
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.523
	Confidence Interval	(2-Sided) 95%; 1.075 to 2.158
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Up to 4.3 years
Adverse Event Reporting Description	Safety population included all-treated participants who received at least 1 dose of study drug.
Arm/Group Title	Trabectedin + DOXIL		DOXIL
Arm/Group Description	Participants received DOXIL 30 milligram per meter square (mg/m^2) administered as an intravenous (IV) infusion over approximately 90 minutes followed by trabectedin 1.1 mg/m^2 administered as an IV infusion over approximately 3 hours, on Day 1 of each treatment cycle (21 days cycle) every 3 weeks. Participants were pretreated with 20 mg dexamethasone IV (or an equivalent IV corticosteroid) approximately 30 minutes prior to initiation of infusion of DOXIL IV.		Participants received DOXIL 50 mg/m^2 administered as an IV infusion over approximately 90 minutes on Day 1 of each treatment cycle (28 days cycle), every 4 weeks.
All Cause Mortality
	Trabectedin + DOXIL		DOXIL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	132/286 (46.2%)		131/282 (46.5%)
Serious Adverse Events
	Trabectedin + DOXIL		DOXIL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	118/286 (41.3%)		58/282 (20.6%)
Blood and lymphatic system disorders
Anaemia	9/286 (3.1%)		2/282 (0.7%)
Febrile Neutropenia	14/286 (4.9%)		1/282 (0.4%)
Leukopenia	3/286 (1%)		1/282 (0.4%)
Neutropenia	12/286 (4.2%)		4/282 (1.4%)
Thrombocytopenia	10/286 (3.5%)		1/282 (0.4%)
Cardiac disorders
Atrial Fibrillation	1/286 (0.3%)		1/282 (0.4%)
Cardiac Failure Congestive	1/286 (0.3%)		0/282 (0%)
Cardiopulmonary Failure	1/286 (0.3%)		0/282 (0%)
Tachycardia	1/286 (0.3%)		0/282 (0%)
Endocrine disorders
Inappropriate Antidiuretic Hormone Secretion	1/286 (0.3%)		0/282 (0%)
Gastrointestinal disorders
Abdominal Pain	6/286 (2.1%)		3/282 (1.1%)
Abdominal Pain Lower	0/286 (0%)		1/282 (0.4%)
Abdominal Pain Upper	1/286 (0.3%)		0/282 (0%)
Ascites	3/286 (1%)		8/282 (2.8%)
Constipation	5/286 (1.7%)		2/282 (0.7%)
Diarrhoea	2/286 (0.7%)		0/282 (0%)
Dyspepsia	1/286 (0.3%)		0/282 (0%)
Enteritis	1/286 (0.3%)		0/282 (0%)
Gastrointestinal Haemorrhage	1/286 (0.3%)		0/282 (0%)
Gastrointestinal Obstruction	1/286 (0.3%)		0/282 (0%)
Gastrooesophageal Reflux Disease	0/286 (0%)		1/282 (0.4%)
Ileus	0/286 (0%)		3/282 (1.1%)
Intestinal Obstruction	3/286 (1%)		1/282 (0.4%)
Nausea	8/286 (2.8%)		3/282 (1.1%)
Neutropenic Colitis	0/286 (0%)		1/282 (0.4%)
Oral Pain	0/286 (0%)		1/282 (0.4%)
Oral Pruritus	0/286 (0%)		1/282 (0.4%)
Pancreatitis	1/286 (0.3%)		0/282 (0%)
Rectal Haemorrhage	1/286 (0.3%)		0/282 (0%)
Small Intestinal Obstruction	4/286 (1.4%)		14/282 (5%)
Stomatitis	0/286 (0%)		2/282 (0.7%)
Subileus	1/286 (0.3%)		0/282 (0%)
Upper Gastrointestinal Haemorrhage	1/286 (0.3%)		0/282 (0%)
Vomiting	10/286 (3.5%)		7/282 (2.5%)
General disorders
Asthenia	0/286 (0%)		1/282 (0.4%)
Catheter Site Inflammation	1/286 (0.3%)		0/282 (0%)
Chest Discomfort	0/286 (0%)		1/282 (0.4%)
Chest Pain	0/286 (0%)		1/282 (0.4%)
Death	4/286 (1.4%)		2/282 (0.7%)
Fatigue	4/286 (1.4%)		1/282 (0.4%)
Influenza Like Illness	1/286 (0.3%)		0/282 (0%)
Multiple Organ Dysfunction Syndrome	2/286 (0.7%)		1/282 (0.4%)
Oedema Peripheral	1/286 (0.3%)		0/282 (0%)
Pain	0/286 (0%)		1/282 (0.4%)
Pyrexia	9/286 (3.1%)		3/282 (1.1%)
Hepatobiliary disorders
Drug-Induced Liver Injury	1/286 (0.3%)		0/282 (0%)
Hepatitis Toxic	2/286 (0.7%)		0/282 (0%)
Infections and infestations
Abdominal Wall Abscess	0/286 (0%)		1/282 (0.4%)
Catheter Site Infection	0/286 (0%)		1/282 (0.4%)
Cellulitis	2/286 (0.7%)		1/282 (0.4%)
Device Related Infection	3/286 (1%)		1/282 (0.4%)
Device Related Sepsis	1/286 (0.3%)		0/282 (0%)
Enterobacter Bacteraemia	1/286 (0.3%)		0/282 (0%)
Gastroenteritis	0/286 (0%)		1/282 (0.4%)
Infection	1/286 (0.3%)		0/282 (0%)
Neutropenic Sepsis	2/286 (0.7%)		1/282 (0.4%)
Oral Candidiasis	0/286 (0%)		1/282 (0.4%)
Peritonitis	2/286 (0.7%)		0/282 (0%)
Peritonitis Bacterial	1/286 (0.3%)		0/282 (0%)
Pneumocystis Jirovecii Pneumonia	2/286 (0.7%)		1/282 (0.4%)
Pneumonia	4/286 (1.4%)		0/282 (0%)
Pseudomonal Sepsis	1/286 (0.3%)		0/282 (0%)
Pyelonephritis Acute	0/286 (0%)		1/282 (0.4%)
Sepsis	4/286 (1.4%)		2/282 (0.7%)
Septic Shock	1/286 (0.3%)		0/282 (0%)
Soft Tissue Infection	1/286 (0.3%)		0/282 (0%)
Staphylococcal Bacteraemia	1/286 (0.3%)		0/282 (0%)
Upper Respiratory Tract Infection	1/286 (0.3%)		0/282 (0%)
Urinary Tract Infection	5/286 (1.7%)		1/282 (0.4%)
Injury, poisoning and procedural complications
Anastomotic Ulcer	1/286 (0.3%)		0/282 (0%)
Gastrointestinal Stoma Complication	1/286 (0.3%)		0/282 (0%)
Head Injury	0/286 (0%)		1/282 (0.4%)
Hip Fracture	1/286 (0.3%)		0/282 (0%)
Infusion Related Reaction	0/286 (0%)		2/282 (0.7%)
Joint Dislocation	0/286 (0%)		1/282 (0.4%)
Spinal Compression Fracture	1/286 (0.3%)		0/282 (0%)
Investigations
Alanine Aminotransferase Increased	14/286 (4.9%)		0/282 (0%)
Aspartate Aminotransferase Increased	9/286 (3.1%)		0/282 (0%)
Blood Creatine Phosphokinase Increased	1/286 (0.3%)		0/282 (0%)
Blood Creatinine Increased	1/286 (0.3%)		0/282 (0%)
Ejection Fraction Decreased	2/286 (0.7%)		1/282 (0.4%)
Gamma-Glutamyltransferase Increased	1/286 (0.3%)		0/282 (0%)
Neutrophil Count Decreased	5/286 (1.7%)		0/282 (0%)
Platelet Count Decreased	3/286 (1%)		0/282 (0%)
Transaminases Increased	1/286 (0.3%)		0/282 (0%)
Weight Decreased	1/286 (0.3%)		0/282 (0%)
White Blood Cell Count Decreased	4/286 (1.4%)		0/282 (0%)
Metabolism and nutrition disorders
Dehydration	6/286 (2.1%)		0/282 (0%)
Fluid Overload	1/286 (0.3%)		0/282 (0%)
Hyperkalaemia	1/286 (0.3%)		0/282 (0%)
Hypokalaemia	1/286 (0.3%)		1/282 (0.4%)
Hyponatraemia	2/286 (0.7%)		0/282 (0%)
Hypophagia	0/286 (0%)		1/282 (0.4%)
Musculoskeletal and connective tissue disorders
Back Pain	1/286 (0.3%)		1/282 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphangiosis Carcinomatosa	1/286 (0.3%)		0/282 (0%)
Malignant Pleural Effusion	0/286 (0%)		1/282 (0.4%)
Metastases to Abdominal Wall	0/286 (0%)		1/282 (0.4%)
Metastases to Central Nervous System	0/286 (0%)		1/282 (0.4%)
Myelodysplastic Syndrome	1/286 (0.3%)		0/282 (0%)
Renal Cell Carcinoma	0/286 (0%)		1/282 (0.4%)
Nervous system disorders
Headache	0/286 (0%)		1/282 (0.4%)
Lethargy	1/286 (0.3%)		0/282 (0%)
Seizure	1/286 (0.3%)		1/282 (0.4%)
Syncope	1/286 (0.3%)		0/282 (0%)
Product Issues
Device Malfunction	0/286 (0%)		1/282 (0.4%)
Renal and urinary disorders
Acute Kidney Injury	4/286 (1.4%)		2/282 (0.7%)
Renal Failure	1/286 (0.3%)		1/282 (0.4%)
Urinary Retention	0/286 (0%)		1/282 (0.4%)
Reproductive system and breast disorders
Pelvic Fluid Collection	0/286 (0%)		1/282 (0.4%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	1/286 (0.3%)		0/282 (0%)
Chronic Obstructive Pulmonary Disease	1/286 (0.3%)		0/282 (0%)
Cough	1/286 (0.3%)		0/282 (0%)
Dyspnoea	1/286 (0.3%)		1/282 (0.4%)
Epistaxis	1/286 (0.3%)		0/282 (0%)
Hypoxia	2/286 (0.7%)		0/282 (0%)
Interstitial Lung Disease	0/286 (0%)		1/282 (0.4%)
Pleural Effusion	4/286 (1.4%)		2/282 (0.7%)
Pleurisy	2/286 (0.7%)		2/282 (0.7%)
Pulmonary Embolism	6/286 (2.1%)		2/282 (0.7%)
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysaesthesia Syndrome	0/286 (0%)		1/282 (0.4%)
Vascular disorders
Capillary Leak Syndrome	0/286 (0%)		1/282 (0.4%)
Deep Vein Thrombosis	3/286 (1%)		0/282 (0%)
Embolism	1/286 (0.3%)		0/282 (0%)
Flushing	0/286 (0%)		1/282 (0.4%)
Hypertension	0/286 (0%)		1/282 (0.4%)
Pelvic Venous Thrombosis	1/286 (0.3%)		0/282 (0%)
Thrombophlebitis	2/286 (0.7%)		0/282 (0%)
Other (Not Including Serious) Adverse Events
	Trabectedin + DOXIL		DOXIL
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	282/286 (98.6%)		273/282 (96.8%)
Blood and lymphatic system disorders
Anaemia	135/286 (47.2%)		70/282 (24.8%)
Febrile Neutropenia	9/286 (3.1%)		2/282 (0.7%)
Leukopenia	53/286 (18.5%)		38/282 (13.5%)
Neutropenia	149/286 (52.1%)		104/282 (36.9%)
Thrombocytopenia	63/286 (22%)		18/282 (6.4%)
Cardiac disorders
Palpitations	7/286 (2.4%)		6/282 (2.1%)
Tachycardia	9/286 (3.1%)		2/282 (0.7%)
Ear and labyrinth disorders
Vertigo	6/286 (2.1%)		6/282 (2.1%)
Gastrointestinal disorders
Abdominal Distension	20/286 (7%)		15/282 (5.3%)
Abdominal Pain	54/286 (18.9%)		44/282 (15.6%)
Abdominal Pain Lower	6/286 (2.1%)		7/282 (2.5%)
Abdominal Pain Upper	12/286 (4.2%)		8/282 (2.8%)
Ascites	12/286 (4.2%)		17/282 (6%)
Constipation	82/286 (28.7%)		61/282 (21.6%)
Diarrhoea	59/286 (20.6%)		47/282 (16.7%)
Dry Mouth	5/286 (1.7%)		10/282 (3.5%)
Dyspepsia	23/286 (8%)		18/282 (6.4%)
Dysphagia	1/286 (0.3%)		8/282 (2.8%)
Flatulence	7/286 (2.4%)		8/282 (2.8%)
Gastrooesophageal Reflux Disease	12/286 (4.2%)		15/282 (5.3%)
Mouth Ulceration	6/286 (2.1%)		14/282 (5%)
Nausea	212/286 (74.1%)		114/282 (40.4%)
Oral Pain	5/286 (1.7%)		10/282 (3.5%)
Stomatitis	52/286 (18.2%)		91/282 (32.3%)
Vomiting	141/286 (49.3%)		54/282 (19.1%)
General disorders
Asthenia	39/286 (13.6%)		16/282 (5.7%)
Chills	8/286 (2.8%)		5/282 (1.8%)
Fatigue	171/286 (59.8%)		113/282 (40.1%)
Malaise	7/286 (2.4%)		5/282 (1.8%)
Mucosal Inflammation	22/286 (7.7%)		33/282 (11.7%)
Non-Cardiac Chest Pain	11/286 (3.8%)		8/282 (2.8%)
Oedema Peripheral	32/286 (11.2%)		22/282 (7.8%)
Pain	11/286 (3.8%)		5/282 (1.8%)
Peripheral Swelling	9/286 (3.1%)		6/282 (2.1%)
Pyrexia	38/286 (13.3%)		26/282 (9.2%)
Infections and infestations
Pneumonia	5/286 (1.7%)		8/282 (2.8%)
Sinusitis	5/286 (1.7%)		7/282 (2.5%)
Upper Respiratory Tract Infection	14/286 (4.9%)		6/282 (2.1%)
Urinary Tract Infection	12/286 (4.2%)		15/282 (5.3%)
Viral Upper Respiratory Tract Infection	7/286 (2.4%)		11/282 (3.9%)
Injury, poisoning and procedural complications
Contusion	8/286 (2.8%)		3/282 (1.1%)
Investigations
Alanine Aminotransferase Increased	151/286 (52.8%)		12/282 (4.3%)
Aspartate Aminotransferase Increased	100/286 (35%)		11/282 (3.9%)
Bilirubin Conjugated Increased	24/286 (8.4%)		2/282 (0.7%)
Blood Alkaline Phosphatase Increased	73/286 (25.5%)		16/282 (5.7%)
Blood Bilirubin Increased	24/286 (8.4%)		3/282 (1.1%)
Blood Creatine Phosphokinase Increased	13/286 (4.5%)		9/282 (3.2%)
Blood Creatinine Increased	20/286 (7%)		21/282 (7.4%)
Blood Urea Increased	6/286 (2.1%)		4/282 (1.4%)
Ejection Fraction Decreased	20/286 (7%)		10/282 (3.5%)
Gamma-Glutamyltransferase Increased	13/286 (4.5%)		5/282 (1.8%)
Haemoglobin Decreased	6/286 (2.1%)		1/282 (0.4%)
Lymphocyte Count Decreased	8/286 (2.8%)		4/282 (1.4%)
Neutrophil Count Decreased	52/286 (18.2%)		37/282 (13.1%)
Platelet Count Decreased	52/286 (18.2%)		16/282 (5.7%)
Weight Decreased	13/286 (4.5%)		16/282 (5.7%)
White Blood Cell Count Decreased	33/286 (11.5%)		29/282 (10.3%)
Metabolism and nutrition disorders
Decreased Appetite	83/286 (29%)		52/282 (18.4%)
Dehydration	21/286 (7.3%)		9/282 (3.2%)
Hyperglycaemia	10/286 (3.5%)		6/282 (2.1%)
Hypoalbuminaemia	21/286 (7.3%)		8/282 (2.8%)
Hypokalaemia	22/286 (7.7%)		12/282 (4.3%)
Hypomagnesaemia	19/286 (6.6%)		6/282 (2.1%)
Hyponatraemia	14/286 (4.9%)		6/282 (2.1%)
Hypophosphataemia	6/286 (2.1%)		2/282 (0.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	25/286 (8.7%)		12/282 (4.3%)
Back Pain	24/286 (8.4%)		15/282 (5.3%)
Bone Pain	11/286 (3.8%)		4/282 (1.4%)
Flank Pain	8/286 (2.8%)		2/282 (0.7%)
Joint Swelling	6/286 (2.1%)		2/282 (0.7%)
Muscular Weakness	16/286 (5.6%)		9/282 (3.2%)
Musculoskeletal Chest Pain	4/286 (1.4%)		7/282 (2.5%)
Myalgia	16/286 (5.6%)		6/282 (2.1%)
Pain in Extremity	8/286 (2.8%)		16/282 (5.7%)
Nervous system disorders
Dizziness	7/286 (2.4%)		6/282 (2.1%)
Dizziness Postural	10/286 (3.5%)		3/282 (1.1%)
Dysgeusia	35/286 (12.2%)		20/282 (7.1%)
Headache	38/286 (13.3%)		29/282 (10.3%)
Neuropathy Peripheral	11/286 (3.8%)		13/282 (4.6%)
Peripheral Sensory Neuropathy	7/286 (2.4%)		7/282 (2.5%)
Psychiatric disorders
Anxiety	18/286 (6.3%)		8/282 (2.8%)
Depression	8/286 (2.8%)		14/282 (5%)
Insomnia	19/286 (6.6%)		16/282 (5.7%)
Renal and urinary disorders
Pollakiuria	3/286 (1%)		7/282 (2.5%)
Reproductive system and breast disorders
Vulvovaginal Dryness	1/286 (0.3%)		6/282 (2.1%)
Respiratory, thoracic and mediastinal disorders
Cough	41/286 (14.3%)		34/282 (12.1%)
Dyspnoea	44/286 (15.4%)		28/282 (9.9%)
Dyspnoea Exertional	10/286 (3.5%)		3/282 (1.1%)
Epistaxis	12/286 (4.2%)		5/282 (1.8%)
Nasal Congestion	10/286 (3.5%)		14/282 (5%)
Oropharyngeal Pain	16/286 (5.6%)		17/282 (6%)
Productive Cough	7/286 (2.4%)		5/282 (1.8%)
Respiratory Disorder	6/286 (2.1%)		8/282 (2.8%)
Rhinitis Allergic	6/286 (2.1%)		5/282 (1.8%)
Rhinorrhoea	6/286 (2.1%)		4/282 (1.4%)
Skin and subcutaneous tissue disorders
Alopecia	32/286 (11.2%)		22/282 (7.8%)
Dry Skin	22/286 (7.7%)		21/282 (7.4%)
Erythema	3/286 (1%)		7/282 (2.5%)
Night Sweats	5/286 (1.7%)		6/282 (2.1%)
Palmar-Plantar Erythrodysaesthesia Syndrome	58/286 (20.3%)		117/282 (41.5%)
Pigmentation Disorder	5/286 (1.7%)		6/282 (2.1%)
Pruritus	11/286 (3.8%)		14/282 (5%)
Rash	22/286 (7.7%)		26/282 (9.2%)
Rash Maculo-Papular	8/286 (2.8%)		24/282 (8.5%)
Skin Hyperpigmentation	10/286 (3.5%)		12/282 (4.3%)
Skin Toxicity	3/286 (1%)		6/282 (2.1%)
Skin Ulcer	0/286 (0%)		6/282 (2.1%)
Vascular disorders
Hot Flush	7/286 (2.4%)		8/282 (2.8%)
Hypertension	22/286 (7.7%)		7/282 (2.5%)
Hypotension	11/286 (3.8%)		4/282 (1.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If an investigator wishes to publish information from the study, a copy of the manuscript must be provided to the sponsor for review at least 60 days before submission for publication or presentation. If requested by the sponsor in writing, the investigator will withhold such publication for up to an additional 60 days.