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Trabectedin, Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03437070
Recruitment Status : Withdrawn (Sponsor Decision)
First Posted : February 19, 2018
Last Update Posted : March 18, 2019
Janssen Scientific Affairs, LLC
Information provided by (Responsible Party):
Marilyn Huang, University of Miami

Brief Summary:
This study seeks to determine if addition of trabectedin (T) to combination doxorubicin (D) and olaratumab (O), is feasible and tolerable with antitumor activity in metastatic or recurrent Leiomyosarcomas (LMS) patients who have limited therapeutic options.

Condition or disease Intervention/treatment Phase
Leiomyosarcoma Drug: Trabectedin Drug: Doxorubicin Drug: Olaratumab Phase 1

Detailed Description:

This is a traditional 3+3 phase I trial design to identify the recommended phase II dose (RP2D) of Trabectedin [T] that can be used in combination with Doxorubicin [D] and Olaratumab [O] for the treatment of patients with advanced stage or recurrent LMS.

Patients will be treated at an assigned dose level of combination therapy per dose escalation design.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Dose escalation
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Trabectedin in Combination With Fixed Doses of Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma
Estimated Study Start Date : June 2019
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2023

Arm Intervention/treatment
Experimental: TDO Dose Level
Trabectedin [T], Doxorubicin [D], and Olaratumab [O]
Drug: Trabectedin
Administered intravenously per protocol on Day 1 for 21-day cycles.
Other Name: Yondelis

Drug: Doxorubicin
Administered intravenously per protocol on Day 1 for 21-day cycles.
Other Name: Doxorubicin Hydrochloride

Drug: Olaratumab
Administered intravenously per protocol
Other Name: Lartruvo

Primary Outcome Measures :
  1. Recommended Phase 2 Dose (RP2D) of Trabectedin in Combination with Doxorubucin and Olaratumab [ Time Frame: About 21 days, one cycle of protocol therapy ]
    Determination of the recommended phase 2 dose (RP2D) of Trabectedin [T] to be used in combination with Doxorubicin [D] and Olaratumab [O] for the treatment of patients with metastatic or recurrent LMS. Patients will be treated at one of 4-6 dose levels according to the standard dose escalation/de-escalation scheme. In accordance with this scheme, the RP2D of TDO will be established as the highest dose level tested for which no more than 2 out of 12 patients experiences dose-limiting toxicity (DLT).

Secondary Outcome Measures :
  1. Toxicity in Study Participants [ Time Frame: Up to 8 months ]
    Determination of the safety, tolerability, and toxicity profile of administering TDO in metastatic or recurrent LMS patients, including assessment of dose-limiting toxicities (DLTs).

  2. Clinical Benefit Rate in Study Participants [ Time Frame: From Baseline to End of Treatment, up to 8 months ]
    Clinical benefit rate (CBR), as defined by best response, (Complete Response (CR), Partial Response (PR) or Stable Disease (SD)) will be assessed using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Histologically confirmed metastatic, advanced, or recurrent, LMS. Note: Patients should have tissue, either archival or fresh biopsy, submitted for pathologic review to confirm diagnosis of LMS. For patients with recurrent disease with disease free interval greater than six months, a fresh biopsy must be obtained.
  2. All patients with recurrent or metastatic LMS deemed unresectable must have measurable disease as defined by RECIST 1.1.

    All patients with advanced LMS may be enrolled after an initial cytoreductive surgery if there is measurable disease as defined by RECIST 1.1.

  3. Life expectancy greater than 3 months.
  4. Male or female, age ≥18 years
  5. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1.
  6. Resolution of clinically significant toxic effects of prior surgery, radiotherapy or systemic anticancer therapy.
  7. Patients must not have received prior doxorubicin chemotherapy; only 1 prior chemotherapy line allowable and must be discontinued at least 4 weeks prior to first day of study treatment.
  8. Patients should be free of active infections requiring antibiotics (with exception of urinary tract infection).
  9. Patients must have adequate organ and marrow function as defined below: Absolute neutrophil count (ANC) ≥1,500 cells/mm³

    • Platelet count ≥100,000/mm³
    • Hemoglobin ≥9.0g/dL
    • Total bilirubin <1.0 upper limit of normal (ULN)
    • Alkaline phosphatase of non-osseous origin ≤ 2.5 x ULN
    • Aminotransferase (AST and ALT) ≤ 2.5 x ULN
    • Creatinine phosphokinase (CPK) ≤ 2.5 x ULN
    • Isotope Dilution Mass Spectrometry (IDMS) creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/min
    • Albumin ≤ 3 g/dL*
    • *Hypoalbuminemia < 3 g/dL should be considered carefully but in and of itself, not exclusionary.
  10. Women of child-bearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation until 3 months for women and 5 months for men after completion of study drug administration. WOCBP must have a negative serum or urine test at time of enrollment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study therapy, and 5 months after completion of study drug administration.
  11. Patients must have adequate cardiac function (ejection fraction ≥ 45%) to receive therapy.
  12. Ability to understand the investigational nature, potential risks and benefits of the research study and to provide valid written informed consent.

Exclusion Criteria:

  1. Patients without histologically confirmed LMS
  2. Patients without measurable disease by RECIST 1.1 criteria
  3. Prior doxorubicin, trabectedin, or olaratumab chemotherapy
  4. Patients with an ECOG of 2, 3 or 4 (Appendix C)
  5. Patient with known allergies to pegfilgrastim/filgrastim.
  6. Patients with known active central nervous system (CNS) metastasis and/or carcinomatous meningitis.
  7. Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study therapy and during the study.
  8. Patients with a known sensitivity to humanized antibodies or sensitivity attributed to compounds of similar chemical or biological composition to alkylating agents or anthracyclines.
  9. A QT interval corrected for heart rate using the Bazett's formula (QTcB) ≥ 480 msec.
  10. Patients on combination antiretroviral therapy are ineligible.
  11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infections (including viral hepatitis), decompensated cirrhosis or chronic liver disease, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with the study requirements.
  12. Adults unable to consent, pregnant or nursing women or prisoners.
  13. Any serious medical or psychiatric illness/condition likely in the judgment of the Investigator(s) to interfere or limit compliance with study requirements/treatment.
  14. Diagnosis of another primary malignancy within the past 5 years with the exception of non-melanoma skin cancer.
  15. Patients with a prior history of grade 3 capillary leak syndrome (CLS) or <grade 3 CLS with pulmonary involvement.
  16. Unwilling to abstain from alcohol ingestion for duration of the study
  17. Patients with elevated liver function or bilirubin not meeting criteria for treatment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03437070

Sponsors and Collaborators
University of Miami
Janssen Scientific Affairs, LLC
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Principal Investigator: Marilyn Huang, MD, MS University of Miami
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Responsible Party: Marilyn Huang, Associate Professor, University of Miami Identifier: NCT03437070    
Other Study ID Numbers: 20170991
First Posted: February 19, 2018    Key Record Dates
Last Update Posted: March 18, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Marilyn Huang, University of Miami:
Advanced Leiomyosarcoma
Recurrent Leiomyosarcoma
Additional relevant MeSH terms:
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Neoplasms, Muscle Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Alkylating
Alkylating Agents