Phase 3 Study to Compare the Efficacy and Safety of Eribulin With Dacarbazine in Subjects With Soft Tissue Sarcoma

• Sponsor: Eisai Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01327885
• Collaborator: (none)
• Enrollment: 452
• Locations: 119
• Arms: 2
• Actual Duration (Months): 65.1
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a randomized, open-label, multicenter, Phase 3 study comparing the efficacy and safety of eribulin with dacarbazine in subjects with advanced soft tissue sarcoma who have disease progression within 6 months prior to study enrolment following standard therapies which must have included an anthracycline, unless contraindicated and then at least one additional regimen after failure of the anthracycline.

Condition or Disease	Intervention/Treatment	Phase
Soft Tissue Sarcoma	Drug: Eribulin mesylate 1.4 mg/m^2 intravenous; Drug: Dacarbazine of 850 mg/m^2, or 1,000 mg/m^2, or 1,200 mg/m^2 IV	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 452 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label, Multicenter, Phase 3 Study to Compare the Efficacy and Safety of Eribulin With Dacarbazine in Subjects With Soft Tissue Sarcoma
• Actual Study Start Date: Mar 10, 2011
• Actual Primary Completion Date: Jan 2, 2015
• Actual Study Completion Date: Aug 10, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A	Drug: Eribulin mesylate 1.4 mg/m^2 intravenous; Administration of eribulin mesylate at a dose of 1.4 mg/m^2 as an intravenous (IV) bolus infusion over 2-5 minutes on Days 1 and 8 of every cycle, where the duration of each cycle is 21 days.
Active Comparator: Arm B	Drug: Dacarbazine of 850 mg/m^2, or 1,000 mg/m^2, or 1,200 mg/m^2 IV; Administration of dacarbazine at a dose of 850 mg/m^2, or 1,000 mg/m^2, or 1,200 mg/m^2 selected by the Principal Investigator [PI] or designee according to the subject's clinical status as an IV infusion over 15-30 minutes on Day 1 of every cycle, where the duration of each cycle is 21 days.

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [From date of treatment start until date of death from any cause, up to 5 years 5 months]

   OS was defined as the time in months from the date of treatment start until death, regardless of cause. In the absence of confirmation of death, participants were censored either at the date that participant was last known to be alive or the date of study cut-off, whichever was earlier. Participants who died on the date of randomization had a survival time of 0.5 day. Allocation of randomization numbers were performed based upon the following stratification factors: (a) Histology (adipocytic [ADI] or leiomyosarcoma [LMS]), (b) Region (Region 1: USA and Canada; or Region 2: Western Europe, Australia, Israel; or Region 3: Eastern Europe, Latin America, and Asia), and (c) Number of prior regimens for advanced soft tissue sarcoma (STS) (2 or greater than [>] 2 prior regimens).

Secondary Outcome Measures

1. Progression-Free Survival (PFS) [Randomization (day 1) to the date of first documentation of disease progression, or date of death (whichever occurred first), up to 5 years 5 months]

   PFS was defined as the time from the date of randomization to the date of first documentation of disease progression, or date of death (whichever occurred first). The date of disease progression was defined as the date of radiologic disease progression as assessed by the investigator or designee based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Participants who did not have an event (i.e., participants who were lost to follow-up or who did not progress or die at the date of data cut-off), were censored. Participants who discontinued study treatment without disease progression were censored on the date of their last radiological assessment (scan date).

2. Progression-Free Rate at 12 Weeks (PFR12wks) [From date of randomization start until Week 12]

   The PFR12wks was defined as the percentage of participants who were still alive without disease progression at 12 weeks from the date of randomization. Tumor assessment by the investigator or designee was based on RECIST criteria 1.1.

3. Clinical Benefit Rate (CBR) [From date of treatment start (Day 1) until disease progression, development of unacceptable toxicity, withdrawal of consent, participant's choice to stop study treatment, up to 5 years 5 months]

   CBR was defined as the percentage of participants who have best overall response (BOR) of complete response (CR), or partial response (PR), or duration of stable disease (dSD) greater than or equal to 11 weeks, between Arm A and Arm B. CBR was estimated by treatment arm based on the tumor response evaluation performed by the PI or designee according to RECIST 1.1. CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Histologically confirmed diagnosis of soft tissue sarcoma of high or intermediate grade with one of the following histological subtypes:

• Adipocytic sarcoma, including:

• Dedifferentiated

• Myxoid

• Round Cell

• Pleomorphic - Leiomyosarcoma

1. Documented evidence of advanced (locally recurrent, locally advanced and/or metastatic) adipocytic (restricted to subtypes listed in Inclusion 1) or leiomyosarcoma, incurable by surgery and/or radiotherapy.

2. Subjects should have received at least two standard systematic regimens for advanced soft tissue sarcoma one of which must have included an anthracycline (unless contraindicated).

3. Radiographic evidence of disease progression by RECIST criteria on or after the last anti-cancer therapy within the 6 months prior to randomization.

4. Presence of measurable disease meeting the following criteria:

• At least one lesion of greater than or equal to 1.0 cm in long-axis diameter for non lymph nodes or greater than or equal to 1.5 cm in short-axis diameter for lymph nodes which is serially measurable according to RECIST 1.1 using either computerized tomography or magnetic resonance imaging or panoramic and close-up color photography.

• Lesions that have had radiotherapy must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion.

1. Eastern Cooperative Oncology Group, performance status of 0, 1 or 2.

2. Adequate renal function defined as calculated creatinine clearance greater than 50 mL/min per the Cockroft and Gault formula.

3. Adequate bone marrow function, defined as:

• Absolute neutrophil count (ANC) greater than or equal to 1,500/mm3 or greater than or equal to 1.5 x 10^9/L.

• Platelet count greater than or equal to 100,000/mm3 or greater than or equal to 100 x 10^9/L.

• Hemoglobin (Hb) greater than or equal to 10g/dL at baseline (blood transfusions,hematopoietic growth factors and hematinics are allowed during the Prerandomization Phase to correct Hb values less than 10g/dL).

1. Adequate liver function, defined as:

• Bilirubin less than or equal to 1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome.

• Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 times ULN. For total ALP greater than 3 times ULN, the ALP liver isoenzyme must be less than or equal to 3 times ULN.

1. All female subjects will be considered to be of child-bearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea, in the appropriate age group and without other known or suspected cause), or have been sterilized surgically (i.e., bilateral tubal ligation greater than or equal to 1 menstrual cycle prior to randomization, or have undergone a hysterectomy and/or bilateral oophorectomy).

Female subjects of child-bearing potential must agree to use two forms of highly effective contraception from the last menstrual period prior to randomization (or use a double barrier method as described below until they are on two forms of highly effective contraception for at least one menstrual cycle), during the study treatment, and for 3 months after the final dose of study treatment. Female subjects exempt from this requirement are subjects who practice total abstinence. If currently abstinent, the subject must agree to use a double barrier method of contraception, i.e., condom and occlusive cap (diaphragm or cervical/vault caps) with spermicide or until they are on two forms of highly effective contraception for at least one menstrual cycle if they become sexually active during the study treatment and for 3 months after the final dose of study treatment. Highly effective contraception includes:

• Placement of intrauterine device or system,

• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault cap) with spermicide,

• Established hormonal contraceptive methods: oral, injectable or implant. Female subjects who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product from the last menstrual period prior to randomization, and must continue to use the same hormonal contraceptive product during study treatment, and for 3 months after the first dose of study treatment.

• Vasectomized partner with confirmed azoospermia.

1. Male subjects and their female partner who are of child-bearing potential (as defined in Inclusion 10), and are not practicing total abstinence, must agree to use two forms of highly effective contraception from the last menstrual period of their female partner prior to randomization (or use a double barrier method as described above until they are on two forms of highly effective contraception for at least one menstrual cycle), during study treatment, and for 3 months (or 6 months if they received dacarbazine) after the final dose of study treatment. If currently abstinent, must agree to use a double barrier method of contraception if they become sexually active, or until they are on two forms of highly effective contraception as described above.

2. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

3. Males or females aged greater than or equal to 18 years at the time of informed consent.

Exclusion Criteria:

1. Subjects who have received any anti-cancer therapy, including radiotherapy, cytotoxic, hormonal, biological (including humanized antibodies) and targeted agents within 21 days, or five half-lives of the drug (whichever is longer) prior to randomization.

2. Subjects who have not recovered from acute toxicities as a result of prior anti-cancer therapy to less than or equal to Grade 1, according to Common Terminology Criteria for Adverse Events (CTCAE), except for peripheral neuropathy (see Exclusion 6) and alopecia.

3. Subjects that have previously been treated with dacarbazine or its analogue temozolomide or eribulin.

4. Major surgery within 21 days prior to randomization.

5. Pre-existing peripheral neuropathy greater than CTCAE Grade 2.

6. Significant cardiovascular impairment, defined as:

• Cardiac failure, New York Heart Association (NYHA) Class II according to the NYHA Functional Classification,

• Unstable angina or myocardial infarction within 6 months of enrolment,

• Serious and potentially life-threatening arrhythmia.

1. Subjects with a high probability of Long QT Syndrome or QTc interval prolongation of more than or equal to 501 msec on at least two separate ECGs, following correction of any electrolyte imbalance.

2. Subjects with known central nervous system metastases.

3. Any serious concomitant illness or infectious disease requiring treatment, or infectious disease not requiring treatment, but with significant risks for myelosuppressive complications associated with chemotherapy.

4. Any malignancy that required treatment, or has shown evidence of recurrence (except for soft tissue sarcoma, non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ) during the 5 years prior to randomization.

5. Female subjects must not be pregnant as documented by a negative beta-human chorionic gonadotropin (beta-hCG) test with a minimum sensitivity 25 IU/L or equivalent unit of beta-hCG at Screening and Baseline, or breastfeeding.

6. Hypersensitivity to the active substance, or any of the excipients of the eribulin drug product, or dacarbazine, (please refer to the dacarbazine prescribing information).

7. Any medical or other condition which, in the opinion of the PI or designee, will preclude participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tucson	Arizona	United States
2		Los Angeles	California	United States
3		Orange	California	United States
4		Santa Monica	California	United States
5		Stanford	California	United States
6		Aurora	Colorado	United States
7		Denver	Colorado	United States
8		Newark	Delaware	United States
9		Washington	District of Columbia	United States
10		Tampa	Florida	United States
11		Atlanta	Georgia	United States
12		Post Falls	Idaho	United States
13		Chicago	Illinois	United States
14		Park Ridge	Illinois	United States
15		Urbana	Illinois	United States
16		Iowa City	Iowa	United States
17		Boston	Massachusetts	United States
18		Saint Louis	Missouri	United States
19		Newark	New Jersey	United States
20		Buffalo	New York	United States
21		New York	New York	United States
22		Rochester	New York	United States
23		Durham	North Carolina	United States
24		Cleveland	Ohio	United States
25		Portland	Oregon	United States
26		Philadelphia	Pennsylvania	United States
27		Pittsburgh	Pennsylvania	United States
28		Houston	Texas	United States
29		Burlington	Vermont	United States
30		Seattle	Washington	United States
31		Ciudad de Buenos Aires		Argentina
32		San Miguel de Tucuman		Argentina
33		San Salvador de Jujuy		Argentina
34		Camperdown	New South Wales	Australia
35		St Leonards	New South Wales	Australia
36		Woolloongabba	Queensland	Australia
37		Woodville South	South Australia	Australia
38		Nedlands	Western Australia	Australia
39		Graz		Austria
40		Salzburg		Austria
41		Wien		Austria
42		Bruxelles		Belgium
43		Leuven		Belgium
44		Liege		Belgium
45		Porto Alegre	Rio Grande Do Sul	Brazil
46		Florianopolis	Santa Catarina	Brazil
47		Barretos		Brazil
48		Curitiba		Brazil
49		Jau		Brazil
50		Porto Alegre		Brazil
51		Salvador		Brazil
52		Sao Paulo		Brazil
53		Ottawa	Ontario	Canada
54		Toronto	Ontario	Canada
55		Montreal	Quebec	Canada
56		Brno		Czechia
57		Hradec kralove		Czechia
58		Novy Jicin		Czechia
59		Praha 5		Czechia
60		Herlev		Denmark
61		Angers		France
62		Bordeaux		France
63		Lyon		France
64		Marseille		France
65		Nantes		France
66		Paris		France
67		Poitiers		France
68		Saint-Priest en Jarez		France
69		Villejuif		France
70		Berlin		Germany
71		Dresden		Germany
72		Essen		Germany
73		Hannover		Germany
74		Koln		Germany
75		Mannheim		Germany
76		Tubingen		Germany
77		Haifa		Israel
78		Jerusalem		Israel
79		Ramat-Gan		Israel
80		Tel Aviv		Israel
81		Aviano	Pordenone	Italy
82		Candiolo		Italy
83		Milano		Italy
84		Monza		Italy
85		Padova		Italy
86		Rozzano (MI)		Italy
87		Torino		Italy
88		Daejeon		Korea, Republic of
89		Seongnam		Korea, Republic of
90		Seoul		Korea, Republic of
91		Amsterdam		Netherlands
92		Leiden		Netherlands
93		Christchurch		New Zealand
94		Gdansk		Poland
95		Gliwice		Poland
96		Warszawa		Poland
97		Cluj-Napoca		Romania
98		Craiova		Romania
99		Iasi		Romania
100		Sibiu		Romania
101		Chelyabinsk		Russian Federation
102		Kazan		Russian Federation
103		Moscow		Russian Federation
104		Obninsk		Russian Federation
105		Singapore		Singapore
106		Palma de Mallorca	Baleares	Spain
107		Badalona	Cataluna	Spain
108		L'Hospitalet de Llobregat	Cataluna	Spain
109		Madrid	Comunidad De Madrid	Spain
110		Barcelona		Spain
111		Valencia		Spain
112		Hat Yai	Songkhla	Thailand
113		Bangkok		Thailand
114		Chiang Mai		Thailand
115		Pathum Wan		Thailand
116		Glasgow		United Kingdom
117		London		United Kingdom
118		Manchester		United Kingdom
119		Swansea		United Kingdom

Sponsors and Collaborators

• Eisai Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eisai Inc.
• ClinicalTrials.gov Identifier: NCT01327885
• Other Study ID Numbers: E7389-G000-309; 2010-024483-17
• First Posted: Apr 4, 2011
• Last Update Posted: Jul 29, 2020
• Last Verified: Feb 1, 2018

• Additional relevant MeSH terms: Sarcoma; Dacarbazine

Study Results

Participant Flow

Arm/Group Title	Arm A: Eribulin Mesylate	Arm B: Dacarbazine
Arm/Group Description	Eribulin mesylate at a dose of 1.4 milligram per square meter (mg/m^2) was administered intravenously (IV) as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.	Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the Principal Investigator [PI] or designee prior to randomization according to the participant's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.
Period Title: Overall Study
STARTED	228	224
COMPLETED	0	0
NOT COMPLETED	228	224

Baseline Characteristics

Arm/Group Title	Arm A: Eribulin Mesylate	Arm B: Dacarbazine	Total
Arm/Group Description	Eribulin mesylate at a dose of 1.4 mg/m^2 was administered IV as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.	Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the Principal Investigator [PI] or designee prior to randomization according to the participant's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.	Total of all reporting groups
Overall Participants	228	224	452
Age (Years) [Geometric Mean (Standard Deviation) ]
Geometric Mean (Standard Deviation) [Years]	55.6 (11.01)	55.7 (10.35)	55.7 (10.68)
Sex: Female, Male (Count of Participants)
Female	161 70.6%	142 63.4%	303 67%
Male	67 29.4%	82 36.6%	149 33%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time in months from the date of treatment start until death, regardless of cause. In the absence of confirmation of death, participants were censored either at the date that participant was last known to be alive or the date of study cut-off, whichever was earlier. Participants who died on the date of randomization had a survival time of 0.5 day. Allocation of randomization numbers were performed based upon the following stratification factors: (a) Histology (adipocytic [ADI] or leiomyosarcoma [LMS]), (b) Region (Region 1: USA and Canada; or Region 2: Western Europe, Australia, Israel; or Region 3: Eastern Europe, Latin America, and Asia), and (c) Number of prior regimens for advanced soft tissue sarcoma (STS) (2 or greater than [>] 2 prior regimens).
Time Frame	From date of treatment start until date of death from any cause, up to 5 years 5 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) (Intent-to-Treat (ITT) analysis set) included all participants who were randomized.

Arm/Group Title	Arm A: Eribulin Mesylate	Arm B: Dacarbazine
Arm/Group Description	Eribulin mesylate at a dose of 1.4 mg/m^2 was administered IV as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.	Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the Principal Investigator [PI] or designee prior to randomization according to the participant's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.
Measure Participants	228	224
Median (95% Confidence Interval) [Months]	13.5	11.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Eribulin Mesylate, Arm B: Dacarbazine
	Comments	Statistical analysis was designed to detect superiority of Arm A (eribulin) over Arm B (dacarbazine). OS was compared between the two treatment arms using a two-sided stratified log-rank test at a nominal significance level of 0.0455 (adjusted for the interim analysis). This was the primary analysis that was performed when the target number of events (~353 deaths) was observed.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	=0.0169
	Comments	The P-value was calculated by 2-sided log-rank test as stratified by histology, geographic region, and number of prior regimens for advanced STS.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.768
	Confidence Interval	(2-Sided) 95%; 0.618 to 0.954
	Parameter Dispersion	Type: Value:
	Estimation Comments	The Hazard Ratio is based on a stratified Cox regression model including treatment as covariate, and histology, geographic region, and number of prior regimens for advanced STS as strata.

2. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS was defined as the time from the date of randomization to the date of first documentation of disease progression, or date of death (whichever occurred first). The date of disease progression was defined as the date of radiologic disease progression as assessed by the investigator or designee based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Participants who did not have an event (i.e., participants who were lost to follow-up or who did not progress or die at the date of data cut-off), were censored. Participants who discontinued study treatment without disease progression were censored on the date of their last radiological assessment (scan date).
Time Frame	Randomization (day 1) to the date of first documentation of disease progression, or date of death (whichever occurred first), up to 5 years 5 months

Outcome Measure Data

Analysis Population Description

FAS (ITT analysis set) included all participants who were randomized.

Arm/Group Title	Arm A: Eribulin Mesylate	Arm B: Dacarbazine
Arm/Group Description	Eribulin mesylate at a dose of 1.4 mg/m^2 was administered IV as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.	Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the PI or designee prior to randomization according to the participant's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.
Measure Participants	228	224
Median (95% Confidence Interval) [Months]	2.6	2.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Eribulin Mesylate, Arm B: Dacarbazine
	Comments	The PFS and PFS rate at 3, 6, and 12 months (95% confidence interval (CI)) was calculated using Kaplan-Meier (K-M) product-limit method and Greenwood Formula. PFS was compared between the treatment arms using two-sided stratified log-rank test, stratified by histology, geographic region, and number of prior regimens for advanced STS.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	=0.2287
	Comments	P-value was calculated by 2-sided log-rank test, as stratified by histology, geographic region, and number of prior regimens for advanced STS.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.877
	Confidence Interval	(2-Sided) 95%; 0.710 to 1.085
	Parameter Dispersion	Type: Value:
	Estimation Comments	The Hazard Ratio is based on a stratified Cox regression model including treatment as covariate, and histology, geographic region, and number of prior regimens for advanced STS as strata.

3. Secondary Outcome

Title	Progression-Free Rate at 12 Weeks (PFR12wks)
Description	The PFR12wks was defined as the percentage of participants who were still alive without disease progression at 12 weeks from the date of randomization. Tumor assessment by the investigator or designee was based on RECIST criteria 1.1.
Time Frame	From date of randomization start until Week 12

Outcome Measure Data

Analysis Population Description

FAS (ITT analysis set) included all participants who were randomized.

Arm/Group Title	Arm A: Eribulin Mesylate	Arm B: Dacarbazine
Arm/Group Description	Eribulin mesylate at a dose of 1.4 mg/m^2 was administered IV as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.	Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the PI or designee prior to randomization according to the participant's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.
Measure Participants	228	224
Number (95% Confidence Interval) [Percentage of participants]	33.3 14.6%	28.6 12.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Eribulin Mesylate, Arm B: Dacarbazine
	Comments	The PFR12wks was compared between the treatment arms using stratified Cochran-Mantel-Haenszel (CMH) chi-square test stratified by histology, geographic region, and number of prior regimens for advanced STS.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.253
	Comments	The P-value was calculated using the stratified CMH method, the stratified factors included histology, geographic region, and number of prior regimens for advanced STS.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.3
	Confidence Interval	(2-Sided) 95%; 0.8 to 1.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds ratio between eribulin and dacarbazine was calculated by stratified CMH method. The stratified factors were as described above. The 2-sided 95% CI of the odds ratio is based on asymptotic normal approximation.

4. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	CBR was defined as the percentage of participants who have best overall response (BOR) of complete response (CR), or partial response (PR), or duration of stable disease (dSD) greater than or equal to 11 weeks, between Arm A and Arm B. CBR was estimated by treatment arm based on the tumor response evaluation performed by the PI or designee according to RECIST 1.1. CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter.
Time Frame	From date of treatment start (Day 1) until disease progression, development of unacceptable toxicity, withdrawal of consent, participant's choice to stop study treatment, up to 5 years 5 months

Outcome Measure Data

Analysis Population Description

FAS (ITT analysis set) included all participants who were randomized.

Arm/Group Title	Arm A: Eribulin Mesylate	Arm B: Dacarbazine
Arm/Group Description	Eribulin mesylate at a dose of 1.4 mg/m^2 was administered IV as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.	Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the PI or designee prior to randomization according to the participant's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.
Measure Participants	228	224
Number (95% Confidence Interval) [Percentage of participants]	46.1 20.2%	47.8 21.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: Eribulin Mesylate, Arm B: Dacarbazine
	Comments	The PFR12wks was compared between the treatment arms using stratified CMH chi-square test stratified by histology, geographic region, and number of prior regimens for advanced STS.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	=0.741
	Comments	The P-value was calculated using the CMH method. The stratified factors were histology, geographic region, and number of prior regimens for advanced STS.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; 0.7 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	The Odds Ratio between eribulin and dacarbazine was calculated by stratified CMH method. The stratified factors were as described above. The 2-sided 95% CI of Odds Ratio is based on asymptotic normal approximation.

Adverse Events

Time Frame	From date of signing of informed consent up to 30 days after the last dose of study treatment, up to 5 years 5 months
Arm/Group Title	Arm A: Eribulin Mesylate		Arm B: Dacarbazine
Arm/Group Description	Eribulin mesylate at a dose of 1.4 mg/m^2 was administered IV as a bolus infusion over 2-5 minutes on Days 1 and 8 of every 21-day treatment cycle.		Dacarbazine at a dose of 850 mg/m^2, 1000 mg/m^2, or 1200 mg/m^2 (as selected by the Principal Investigator [PI] or designee prior to randomization according to the participant's clinical status) was administered as an IV infusion over 15-30 minutes (or up to 60 minutes as per institutional guidelines) on Day 1 of every 21-day treatment cycle.
All Cause Mortality
	Arm A: Eribulin Mesylate		Arm B: Dacarbazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	198/228 (86.8%)		206/224 (92%)
Serious Adverse Events
	Arm A: Eribulin Mesylate		Arm B: Dacarbazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	76/228 (33.3%)		71/224 (31.7%)
Blood and lymphatic system disorders
Neutropenia	11/228 (4.8%)		10/224 (4.5%)
Anaemia	5/228 (2.2%)		9/224 (4%)
Leukopenia	3/228 (1.3%)		3/224 (1.3%)
Febrile neutropenia	2/228 (0.9%)		2/224 (0.9%)
Lymphopenia	1/228 (0.4%)		0/224 (0%)
Pancytopenia	0/228 (0%)		3/224 (1.3%)
Thrombocytopenia	0/228 (0%)		13/224 (5.8%)
Cardiac disorders
Atrial fibrillation	1/228 (0.4%)		1/224 (0.4%)
Pericardial effusion	1/228 (0.4%)		0/224 (0%)
Cardiac arrest	0/228 (0%)		1/224 (0.4%)
Gastrointestinal disorders
Abdominal pain	4/228 (1.8%)		4/224 (1.8%)
Intestinal obstruction	4/228 (1.8%)		5/224 (2.2%)
Diarrhoea	2/228 (0.9%)		2/224 (0.9%)
Small intestinal obstruction	2/228 (0.9%)		3/224 (1.3%)
Constipation	1/228 (0.4%)		0/224 (0%)
Ileus	1/228 (0.4%)		0/224 (0%)
Intestinal ischaemia	1/228 (0.4%)		0/224 (0%)
Large intestine perforation	1/228 (0.4%)		0/224 (0%)
Oesophagitis	1/228 (0.4%)		0/224 (0%)
Retroperitoneal haemorrhage	1/228 (0.4%)		0/224 (0%)
Subileus	1/228 (0.4%)		0/224 (0%)
Abdominal distension	0/228 (0%)		1/224 (0.4%)
Abdominal pain upper	0/228 (0%)		1/224 (0.4%)
Diverticulum	0/228 (0%)		1/224 (0.4%)
Duodenal fistula	0/228 (0%)		1/224 (0.4%)
Gastrointestinal haemorrhage	0/228 (0%)		1/224 (0.4%)
Gastrointestinal ulcer haemorrhage	0/228 (0%)		1/224 (0.4%)
Intestinal haemorrhage	0/228 (0%)		1/224 (0.4%)
Large intestinal obstruction	0/228 (0%)		1/224 (0.4%)
General disorders
Pyrexia	10/228 (4.4%)		4/224 (1.8%)
Asthenia	3/228 (1.3%)		1/224 (0.4%)
General physical health deterioration	2/228 (0.9%)		1/224 (0.4%)
Fatigue	1/228 (0.4%)		0/224 (0%)
Non-cardiac chest pain	0/228 (0%)		1/224 (0.4%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/228 (0.9%)		0/224 (0%)
Biliary dilatation	1/228 (0.4%)		0/224 (0%)
Hepatotoxicity	1/228 (0.4%)		0/224 (0%)
Cholangitis	0/228 (0%)		1/224 (0.4%)
Cholecystitis	0/228 (0%)		1/224 (0.4%)
Immune system disorders
Hypersensitivity	1/228 (0.4%)		0/224 (0%)
Drug hypersensitivity	0/228 (0%)		1/224 (0.4%)
Infections and infestations
Urinary tract infection	4/228 (1.8%)		1/224 (0.4%)
Pneumonia	3/228 (1.3%)		2/224 (0.9%)
Lung infection	2/228 (0.9%)		0/224 (0%)
Peritonitis bacterial	2/228 (0.9%)		0/224 (0%)
Arthritis bacterial	1/228 (0.4%)		0/224 (0%)
Bronchopneumonia	1/228 (0.4%)		0/224 (0%)
Catheter site infection	1/228 (0.4%)		0/224 (0%)
Device related infection	1/228 (0.4%)		1/224 (0.4%)
Lower respiratory tract infection fungal	1/228 (0.4%)		0/224 (0%)
Neutropenic sepsis	1/228 (0.4%)		0/224 (0%)
Peritonitis	1/228 (0.4%)		0/224 (0%)
Pseudomonal bacteraemia	1/228 (0.4%)		0/224 (0%)
Pyelonephritis	1/228 (0.4%)		0/224 (0%)
Septic shock	1/228 (0.4%)		0/224 (0%)
Serratia bacteraemia	1/228 (0.4%)		0/224 (0%)
Staphylococcal bacteraemia	1/228 (0.4%)		0/224 (0%)
Staphylococcal infection	1/228 (0.4%)		0/224 (0%)
Cellulitis	0/228 (0%)		1/224 (0.4%)
Erysipelas	0/228 (0%)		1/224 (0.4%)
Respiratory tract infection	0/228 (0%)		1/224 (0.4%)
Vestibular neuronitis	0/228 (0%)		1/224 (0.4%)
Injury, poisoning and procedural complications
Humerus fracture	1/228 (0.4%)		0/224 (0%)
Post procedural haemorrhage	1/228 (0.4%)		0/224 (0%)
Radiation pneumonitis	1/228 (0.4%)		0/224 (0%)
Wound dehiscence	1/228 (0.4%)		0/224 (0%)
Toxicity to various agents	0/228 (0%)		1/224 (0.4%)
Investigations
Alanine aminotransferase increased	1/228 (0.4%)		1/224 (0.4%)
Aspartate aminotransferase increased	1/228 (0.4%)		1/224 (0.4%)
Electrocardiogram QT prolonged	1/228 (0.4%)		0/224 (0%)
International normalised ratio increased	1/228 (0.4%)		0/224 (0%)
Neutrophil count decreased	1/228 (0.4%)		1/224 (0.4%)
White blood cell count decreased	1/228 (0.4%)		0/224 (0%)
Haemoglobin decreased	0/228 (0%)		2/224 (0.9%)
Platelet count decreased	0/228 (0%)		1/224 (0.4%)
Metabolism and nutrition disorders
Hypokalaemia	1/228 (0.4%)		0/224 (0%)
Hyponatraemia	1/228 (0.4%)		0/224 (0%)
Hypophosphataemia	1/228 (0.4%)		0/224 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/228 (0.9%)		0/224 (0%)
Pathological fracture	2/228 (0.9%)		1/224 (0.4%)
Musculoskeletal pain	0/228 (0%)		1/224 (0.4%)
Spinal pain	0/228 (0%)		1/224 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	2/228 (0.9%)		0/224 (0%)
Metastases to bone	1/228 (0.4%)		0/224 (0%)
Metastases to lung	1/228 (0.4%)		1/224 (0.4%)
Metastases to neck	1/228 (0.4%)		0/224 (0%)
Metastatic pain	1/228 (0.4%)		0/224 (0%)
Myxoid liposarcoma	1/228 (0.4%)		0/224 (0%)
Tumour associated fever	1/228 (0.4%)		0/224 (0%)
Tumour haemorrhage	1/228 (0.4%)		0/224 (0%)
Intracranial tumour haemorrhage	0/228 (0%)		1/224 (0.4%)
Leiomyosarcoma	0/228 (0%)		1/224 (0.4%)
Malignant ascites	0/228 (0%)		1/224 (0.4%)
Malignant pleural effusion	0/228 (0%)		2/224 (0.9%)
Tumour pain	0/228 (0%)		1/224 (0.4%)
Nervous system disorders
Convulsion	1/228 (0.4%)		0/224 (0%)
Monoplegia	1/228 (0.4%)		0/224 (0%)
Spinal cord compression	1/228 (0.4%)		0/224 (0%)
Neuralgia	0/228 (0%)		1/224 (0.4%)
Peripheral motor neuropathy	0/228 (0%)		1/224 (0.4%)
Renal and urinary disorders
Renal failure acute	1/228 (0.4%)		1/224 (0.4%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	4/228 (1.8%)		1/224 (0.4%)
Respiratory failure	4/228 (1.8%)		2/224 (0.9%)
Dyspnoea	2/228 (0.9%)		4/224 (1.8%)
Acute respiratory failure	1/228 (0.4%)		0/224 (0%)
Pneumonia aspiration	1/228 (0.4%)		0/224 (0%)
Pneumothorax	1/228 (0.4%)		1/224 (0.4%)
Atelectasis	0/228 (0%)		1/224 (0.4%)
Dyspnoea exertional	0/228 (0%)		1/224 (0.4%)
Epistaxis	0/228 (0%)		1/224 (0.4%)
Hiccups	0/228 (0%)		1/224 (0.4%)
Pleural effusion	0/228 (0%)		2/224 (0.9%)
Vascular disorders
Superior vena cava syndrome	1/228 (0.4%)		0/224 (0%)
Vena cava thrombosis	1/228 (0.4%)		0/224 (0%)
Deep vein thrombosis	0/228 (0%)		3/224 (1.3%)
Hypotension	0/228 (0%)		2/224 (0.9%)
Other (Not Including Serious) Adverse Events
	Arm A: Eribulin Mesylate		Arm B: Dacarbazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	224/228 (98.2%)		218/224 (97.3%)
Blood and lymphatic system disorders
Neutropenia	95/228 (41.7%)		51/224 (22.8%)
Anaemia	66/228 (28.9%)		68/224 (30.4%)
Thrombocytopenia	13/228 (5.7%)		60/224 (26.8%)
Leukopenia	36/228 (15.8%)		22/224 (9.8%)
Eye disorders
Lacrimation increased	18/228 (7.9%)		1/224 (0.4%)
Gastrointestinal disorders
Nausea	91/228 (39.9%)		106/224 (47.3%)
Constipation	70/228 (30.7%)		58/224 (25.9%)
Abdominal pain	42/228 (18.4%)		32/224 (14.3%)
Vomiting	43/228 (18.9%)		50/224 (22.3%)
Diarrhoea	38/228 (16.7%)		35/224 (15.6%)
Stomatitis	31/228 (13.6%)		11/224 (4.9%)
Abdominal pain upper	19/228 (8.3%)		13/224 (5.8%)
Dyspepsia	18/228 (7.9%)		7/224 (3.1%)
Abdominal distension	16/228 (7%)		12/224 (5.4%)
Dry mouth	12/228 (5.3%)		4/224 (1.8%)
General disorders
Fatigue	98/228 (43%)		86/224 (38.4%)
Pyrexia	58/228 (25.4%)		28/224 (12.5%)
Asthenia	46/228 (20.2%)		51/224 (22.8%)
Oedema peripheral	27/228 (11.8%)		17/224 (7.6%)
Infections and infestations
Urinary tract infection	23/228 (10.1%)		11/224 (4.9%)
Upper respiratory tract infection	20/228 (8.8%)		9/224 (4%)
Investigations
Aspartate aminotransferase increased	21/228 (9.2%)		5/224 (2.2%)
Neutrophil count decreased	19/228 (8.3%)		12/224 (5.4%)
Alanine aminotransferase increased	18/228 (7.9%)		8/224 (3.6%)
White blood cell count decreased	16/228 (7%)		15/224 (6.7%)
Electrocardiogram QT prolonged	14/228 (6.1%)		11/224 (4.9%)
Blood lactate dehydrogenase increased	12/228 (5.3%)		7/224 (3.1%)
Platelet count decreased	2/228 (0.9%)		17/224 (7.6%)
Metabolism and nutrition disorders
Decreased appetite	43/228 (18.9%)		43/224 (19.2%)
Hypokalaemia	23/228 (10.1%)		9/224 (4%)
Hyperglycaemia	17/228 (7.5%)		6/224 (2.7%)
Musculoskeletal and connective tissue disorders
Back pain	33/228 (14.5%)		31/224 (13.8%)
Myalgia	23/228 (10.1%)		17/224 (7.6%)
Pain in extremity	20/228 (8.8%)		18/224 (8%)
Arthralgia	19/228 (8.3%)		13/224 (5.8%)
Muscle spasms	13/228 (5.7%)		7/224 (3.1%)
Musculoskeletal pain	12/228 (5.3%)		11/224 (4.9%)
Nervous system disorders
Peripheral sensory neuropathy	46/228 (20.2%)		8/224 (3.6%)
Headache	41/228 (18%)		21/224 (9.4%)
Dizziness	21/228 (9.2%)		16/224 (7.1%)
Paraesthesia	20/228 (8.8%)		7/224 (3.1%)
Dysgeusia	18/228 (7.9%)		5/224 (2.2%)
Psychiatric disorders
Insomnia	22/228 (9.6%)		10/224 (4.5%)
Anxiety	12/228 (5.3%)		14/224 (6.3%)
Respiratory, thoracic and mediastinal disorders
Cough	39/228 (17.1%)		28/224 (12.5%)
Dyspnoea	34/228 (14.9%)		33/224 (14.7%)
Oropharyngeal pain	12/228 (5.3%)		5/224 (2.2%)
Skin and subcutaneous tissue disorders
Alopecia	79/228 (34.6%)		6/224 (2.7%)
Vascular disorders
Hypotension	13/228 (5.7%)		4/224 (1.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.