A Study of Trabectedin or Dacarbazine for the Treatment of Patients With Advanced Liposarcoma or Leiomyosarcoma

A Randomized Controlled Study of YONDELIS (Trabectedin) or Dacarbazine for the Treatment of Advanced Liposarcoma or Leiomyosarcoma

The purpose of this study is to evaluate whether overall survival for the trabectedin group is superior to the dacarbazine group for patients with advanced L-sarcoma (liposarcoma or leiomyosarcoma).

Study Overview

• Status: Completed
• Conditions: Advanced Liposarcoma or Leiomyosarcoma
• Intervention / Treatment: Drug: Trabectedin; Drug: Dacarbazine

Detailed Description

This is a randomized study (study drug assigned by chance) using a 2:1 randomization. It is an open-label (all people know study drug), active-controlled (comparing to a different drug used for the same condition), parallel-group (different treatment groups continue with separate treatments throughout the study), multicenter study. This study will be divided into 3 phases, screening, treatment, follow-up and optional extension phase (OEP). During screening, potential participants will be assessed for study eligibility after providing signed informed consent. Approximately 570 patients who satisfy all inclusion and exclusion criteria will be randomly assigned in a 2:1 ratio to either the trabectedin (n=380) or dacarbazine (n=190) treatment groups. During the treatment phase, patients will receive study drug once every 3 weeks, until disease progression (defined by Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1 criteria) or signs of toxicity. Assessments will be performed to evaluate the effectiveness of the drug, and patient safety will be monitored. During the follow-up phase, after the last dose of study drug, clinical outcomes for patients will be evaluated. Trabectedin will be administered at a dose of 1.5 milligram per square meters (mg/m^2) through a catheter into a large vein as a 24-hour intravenous (IV) infusion, once every 3 weeks, until disease progression or signs of toxicity. Dacarbazine will be administered at a dose of 1.0 g/m^2 as a 20-120 minute infusion, once every 3 weeks, until disease progression or signs of toxicity. In the OEP, participants who were previously randomized to the dacarbazine group will have the option to receive trabectedin at the discretion of the investigator.

• Study Type: Interventional
• Enrollment (Actual): 579
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Malvern, Australia
  • Randwick, Australia
  • Subiaco, Australia
  • Woolloongabba, Australia
• Brazil
  • Bahia, Brazil
  • Barretos, Brazil
  • Ijuí, Brazil
  • Porto Alegre, Brazil
  • Sao Paulo, Brazil
  • São Paulo, Brazil
• New Zealand
  • Auckland, New Zealand
  • Wellington, New Zealand
• United States
  • Arizona
    • Phoenix, Arizona, United States
    • Tucson, Arizona, United States
  • Arkansas
    • Little Rock, Arkansas, United States
  • California
    • La Jolla, California, United States
    • Los Angeles, California, United States
    • San Diego, California, United States
    • San Francisco, California, United States
    • Santa Monica, California, United States
  • Colorado
    • Aurora, Colorado, United States
    • Denver, Colorado, United States
  • Connecticut
    • Hartford, Connecticut, United States
    • New Haven, Connecticut, United States
  • Florida
    • Boynton Beach, Florida, United States
    • Hollywood, Florida, United States
    • Miami, Florida, United States
    • Orlando, Florida, United States
    • Tampa, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
    • Augusta, Georgia, United States
    • Savannah, Georgia, United States
  • Idaho
    • Post Falls, Idaho, United States
  • Illinois
    • Chicago, Illinois, United States
    • Naperville, Illinois, United States
    • Park Ridge, Illinois, United States
    • Peoria, Illinois, United States
    • Springfield, Illinois, United States
  • Indiana
    • Indianapolis, Indiana, United States
  • Iowa
    • Iowa City, Iowa, United States
    • Sioux City, Iowa, United States
  • Kansas
    • Overland Park, Kansas, United States
    • Wichita, Kansas, United States
  • Kentucky
    • Louisville, Kentucky, United States
  • Louisiana
    • Covington, Louisiana, United States
  • Maryland
    • Baltimore, Maryland, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Michigan
    • Ann Arbor, Michigan, United States
    • Detroit, Michigan, United States
    • Lansing, Michigan, United States
  • Mississippi
    • Jackson, Mississippi, United States
  • Missouri
    • Saint Joseph, Missouri, United States
    • Saint Louis, Missouri, United States
  • Nebraska
    • Omaha, Nebraska, United States
  • Nevada
    • Henderson, Nevada, United States
    • Las Vegas, Nevada, United States
  • New Hampshire
    • Lebanon, New Hampshire, United States
  • New Jersey
    • Hackensack, New Jersey, United States
    • Morristown, New Jersey, United States
    • Newark, New Jersey, United States
  • New Mexico
    • Albuquerque, New Mexico, United States
  • New York
    • Bronx, New York, United States
    • Johnson City, New York, United States
    • New York, New York, United States
    • Syracuse, New York, United States
  • North Carolina
    • Chapel Hill, North Carolina, United States
    • Charlotte, North Carolina, United States
  • Ohio
    • Akron, Ohio, United States
    • Cleveland, Ohio, United States
    • Columbus, Ohio, United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
    • Tulsa, Oklahoma, United States
  • Oregon
    • Portland, Oregon, United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
    • Pittsburgh, Pennsylvania, United States
    • State College, Pennsylvania, United States
  • South Carolina
    • Charleston, South Carolina, United States
  • Tennessee
    • Knoxville, Tennessee, United States
    • Nashville, Tennessee, United States
  • Texas
    • Austin, Texas, United States
    • Dallas, Texas, United States
    • Houston, Texas, United States
    • San Antonio, Texas, United States
  • Utah
    • Salt Lake City, Utah, United States
  • Virginia
    • Fairfax, Virginia, United States
  • Washington
    • Seattle, Washington, United States
  • West Virginia
    • Morgantown, West Virginia, United States
  • Wisconsin
    • Green Bay, Wisconsin, United States
    • Milwaukee, Wisconsin, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically proven, unresectable, locally advanced or metastatic liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) or leiomyosarcoma. Participants must have a pathology report indicating the diagnosis of liposarcoma or leiomyosarcoma that has been reviewed by the sponsor before randomization may occur
• Treated in any order with at least: an anthracycline and ifosfamide containing regimen, or an anthracycline containing regimen and 1 additional cytotoxic chemotherapy regimen
• Measurable disease at baseline in accordance with RECIST Version 1.1
• Pathology specimens (example [e.g.], tumor blocks or unstained slides) for potential centralized pathology review and biomarker studies
• ECOG Performance Status score of 0 or 1
• Adequate recovery from prior therapy, all side effects (except alopecia) have resolved to Grade 1 or less according to the National Cancer Institute - Common Terminology Criteria of Adverse Events (NCI-CTCAE) Version 4.0
• Adequate organ function as evidenced by the following peripheral blood counts or serum chemistry values: hemoglobin 9 gram per deciliters (g/dL), absolute neutrophil count (ANC) 1,500/L, platelet count 100,000/L, serum creatinine 1.5*the upper limit of normal (ULN), creatine phosphokinase (CPK) 2.5 Upper Limit of Normal [ULN]
• Adequate hepatic function as evidenced by the following serum chemistry values: total bilirubin, ULN. If total bilirubin is greater than (>) ULN, measure indirect bilirubin to evaluate for Gilbert's syndrome (if direct bilirubin is within normal range, participant may be eligible) ALP 2.5 x ULN; Trabectedin: if the ALP is >2.5 x ULN, then an ALP liver fraction or 5-nucleotidase must be obtained and ULN, AST and ALT 2.5 ULN
• Negative pregnancy test (urinary or serum beta-HCG) at screening (applicable to women of child bearing potential who are sexually active)
• Female participants must be postmenopausal (no spontaneous menses for at least 2 years), surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), abstinent (at the discretion of the investigator), or if sexually active, be practicing an effective method of birth control. Male participants must agree to use an adequate contraception method as deemed appropriate by the investigator (e.g., vasectomy, double-barrier, partner using effective contraception) and to not donate sperm for a minimum of 5 months after treatment discontinuation

Optional Extension Phase (OEP) Phase:

• Documentation for inclusion criteria histologically proven, unresectable, locally advanced or metastatic liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) or leiomyosarcoma. Participants must have a pathology report indicating the diagnosis of liposarcoma or leiomyosarcoma that has been reviewed by the sponsor before randomization may occur and treated in any order with at least: an anthracycline and ifosfamide containing regimen, or an anthracycline containing regimen and 1 additional cytotoxic chemotherapy regimen do not need to be reviewed by the Sponsor
• Collection of the specimen: Pathology specimens (example (e.g.), tumor blocks or unstained slides) for potential centralized pathology review and biomarker studies is not applicable
• Documentation of inclusion criteria adequate organ function as evidenced by the following peripheral blood counts or serum chemistry values: hemoglobin 9 gram per deciliters (g/dL), absolute neutrophil count (ANC) 1,500/L, platelet count 100,000/L, serum creatinine 1.5*the upper limit of normal (ULN), creatine phosphokinase (CPK) 2.5*ULN and adequate hepatic function as evidenced by the following serum chemistry values: total bilirubin, ULN. If total bilirubin is greater than (>) ULN, measure indirect bilirubin to evaluate for Gilbert's syndrome (if direct bilirubin is within normal range, participant may be eligible) ALP <= 2.5*ULN; Trabectedin: if the ALP is >2.5*ULN, then an ALP liver fraction or 5-nucleotidase must be obtained and ULN, AST and ALT 2.5 ULN will be reviewed by the Sponsor before enrollment in the OEP may occur

Exclusion Criteria:

• Potential participants who meet any of the following criteria will be excluded from participating in the study: Prior exposure to trabectedin or dacarabazine, less than 3 weeks from last dose of systemic cytotoxic therapy, radiation therapy, or therapy with any investigational agent, other malignancy within past 3 years. Exceptions: basal or nonmetastatic squamous cell carcinoma of the skin, cervical carcinoma in situ, or Federation Internationale de Gynecologie et d'Obstetrique (FIGO) Stage 1 carcinoma of the cervix
• Known 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)
• Myocardial infarct within 6 months before enrollment, New York Heart Association 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
• Uncontrolled intercurrent illness including, but not limited to, poorly controlled hypertension or diabetes, ongoing active infection, or psychiatric illness/social situation that may potentially impair the participant's compliance with study procedures
• Unwilling or unable to have a central venous catheter
• Known allergies, hypersensitivity, or intolerance to trabectedin, dacarbazine, dexamethasone, or their excipients
• Pregnant or breast-feeding
• 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

OEP phase:

• Potential participants who meet any of the following criteria will be excluded from Participating in the study: Prior exposure to trabectedin, less than 3 weeks from last dose of systemic cytotoxic therapy, radiation therapy, or therapy with any investigational agent, other malignancy within past 3 years. Exceptions: basal or nonmetastatic squamous cell carcinoma of the skin, cervical carcinoma in situ, or Federation Internationale de Gynecologie et d'Obstetrique (FIGO) Stage 1 carcinoma of the cervix does not apply
• Treated in any order with at least: an anthracycline and ifosfamide containing regimen, or an anthracycline containing regimen and 1 additional cytotoxic chemotherapy regimen with less than 3 weeks from last dose of systemic anticancer therapy, radiation therapy, or therapy with any investigational agent
• Known allergies, hypersensitivity, or intolerance to dacarbazine does not apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dacarbazine	Drug: Dacarbazine; Type=exactly number, unit=g/m2, number=1, form=intravenous infusion, route=intravenous use. Once every 3 weeks until disease progression or signs of toxicity.
Experimental: Trabectedin	Drug: Trabectedin; Type=exactly number, unit=mg/m2, number=1.5, form=intravenous infusion, route=intravenous use. Once every 3 weeks until disease progression or signs of toxicity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	The OS is defined as the time from the date of first dose of study drug to date of death from any cause. If the participant is alive or the vital status is unknown, the participant will be censored at the date the participant will be last known to be alive.	approximately 3 years 8 months (From Study start date [27 May 2011] up to final analysis data cut-off [05 January 2015]

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	The Progression-Free Survival (PFS) was assessed as median number of months from baseline until the first documented sign of disease progression (increase in disease; radiographic, clinical, or both) or death due to any cause, whichever occurred earlier. Independent Data Monitoring Committee performed ongoing safety monitoring and conducted the interim analysis after 189 death events and 329 PFS events were observed.	approximately 2 years 4 months (From Study start date [27 May 2011] up to interim analysis data cut-off [16 September 2013])
Time to Progression	Time interval in months between the date of randomization and the date of disease progression or death due to progression, whichever occurred first. Independent Data Monitoring Committee performed ongoing safety monitoring and conducted the interim analysis after 189 death events and 329 PFS events were observed.	approximately 2 years 4 months (From Study start date [27 May 2011] up to interim analysis data cut-off [16 September 2013])
Objective Response Rate	The objective response rate (ORR) is defined as the percentage of participants who achieved a Complete response (CR) or partial response (PR) as best responses. according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST). CR defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of the diameters of the target lesions taking as reference the Baseline sum diameters. Confirmed responses are those that persist on repeat imaging study for at least 4 weeks after initial documentation of response. Independent Data Monitoring Committee performed ongoing safety monitoring and conducted the interim analysis after 189 death events and 329 PFS events were observed.	approximately 2 years 4 months (From Study start date [27 May 2011] up to interim analysis data cut-off [16 September 2013])
Duration of Response	Duration of response is defined as the time from the date of initial documentation of a response (CR or PR) to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death. Independent Data Monitoring Committee performed ongoing safety monitoring and conducted the interim analysis after 189 death events and 329 PFS events were observed.	approximately 2 years 4 months (From Study start date [27 May 2011] up to interim analysis data cut-off [16 September 2013])
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.	approximately 3 years 8 months (From Study start date [27 May 2011] up to final analysis data cut-off [05 January 2015])

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC
• Collaborators: PharmaMar

Publications and helpful links

General Publications

• Calvo E, Azaro A, Rodon J, Dirix L, Huizing M, Senecal FM, LoRusso P, Yee L, Poggesi I, de Jong J, Triantos S, Park YC, Knoblauch RE, Parekh TV, Demetri GD, von Mehren M. Hepatic safety analysis of trabectedin: results of a pharmacokinetic study with trabectedin in patients with hepatic impairment and experience from a phase 3 clinical trial. Invest New Drugs. 2018 Jun;36(3):476-486. doi: 10.1007/s10637-017-0546-9. Epub 2017 Nov 27.
• Jones RL, Herzog TJ, Patel SR, von Mehren M, Schuetze SM, Van Tine BA, Coleman RL, Knoblauch R, Triantos S, Hu P, Shalaby W, McGowan T, Monk BJ, Demetri GD. Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer. Cancer Med. 2021 Jun;10(11):3565-3574. doi: 10.1002/cam4.3903. Epub 2021 May 7.
• Patel S, von Mehren M, Reed DR, Kaiser P, Charlson J, Ryan CW, Rushing D, Livingston M, Singh A, Seth R, Forscher C, D'Amato G, Chawla SP, McCarthy S, Wang G, Parekh T, Knoblauch R, Hensley ML, Maki RG, Demetri GD. Overall survival and histology-specific subgroup analyses from a phase 3, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma. Cancer. 2019 Aug 1;125(15):2610-2620. doi: 10.1002/cncr.32117. Epub 2019 Jun 7.
• Jones RL, Demetri GD, Schuetze SM, Milhem M, Elias A, Van Tine BA, Hamm J, McCarthy S, Wang G, Parekh T, Knoblauch R, Hensley ML, Maki RG, Patel S, von Mehren M. Efficacy and tolerability of trabectedin in elderly patients with sarcoma: subgroup analysis from a phase III, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma. Ann Oncol. 2018 Sep 1;29(9):1995-2002. doi: 10.1093/annonc/mdy253.
• Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, Milhem M, Elias A, Ganjoo K, Tawbi H, Van Tine BA, Spira A, Dean A, Khokhar NZ, Park YC, Knoblauch RE, Parekh TV, Maki RG, Patel SR. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. J Clin Oncol. 2016 Mar 10;34(8):786-93. doi: 10.1200/JCO.2015.62.4734. Epub 2015 Sep 14.

Study record dates

Study Major Dates

• Study Start: June 1, 2011
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: April 26, 2011
• First Submitted That Met QC Criteria: April 27, 2011
• First Posted (Estimate): April 28, 2011

Study Record Updates

• Last Update Posted (Estimate): August 26, 2016
• Last Update Submitted That Met QC Criteria: July 15, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Anthracycline; Dacarbazine; Trabectedin; Yondelis; Advanced Liposarcoma or Leiomyosarcoma; L-sarcoma
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Neoplasms, Muscle Tissue; Neoplasms, Adipose Tissue; Leiomyosarcoma; Liposarcoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Dacarbazine; Trabectedin
• Other Study ID Numbers: CR018004; ET743SAR3007 (Other Identifier: Janssen Research & Development, LLC)