Trabectedin, Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma
Primary Purpose
Leiomyosarcoma
Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Trabectedin
Doxorubicin
Olaratumab
Sponsored by
About this trial
This is an interventional treatment trial for Leiomyosarcoma focused on measuring Advanced Leiomyosarcoma, Recurrent Leiomyosarcoma
Eligibility Criteria
Inclusion Criteria:
- 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.
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.
- Life expectancy greater than 3 months.
- Male or female, age ≥18 years
- Eastern Cooperative Oncology Group (ECOG) performance status 0, 1.
- Resolution of clinically significant toxic effects of prior surgery, radiotherapy or systemic anticancer therapy.
- 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.
- Patients should be free of active infections requiring antibiotics (with exception of urinary tract infection).
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.
- 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.
- Patients must have adequate cardiac function (ejection fraction ≥ 45%) to receive therapy.
- Ability to understand the investigational nature, potential risks and benefits of the research study and to provide valid written informed consent.
Exclusion Criteria:
- Patients without histologically confirmed LMS
- Patients without measurable disease by RECIST 1.1 criteria
- Prior doxorubicin, trabectedin, or olaratumab chemotherapy
- Patients with an ECOG of 2, 3 or 4 (Appendix C)
- Patient with known allergies to pegfilgrastim/filgrastim.
- Patients with known active central nervous system (CNS) metastasis and/or carcinomatous meningitis.
- 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.
- Patients with a known sensitivity to humanized antibodies or sensitivity attributed to compounds of similar chemical or biological composition to alkylating agents or anthracyclines.
- A QT interval corrected for heart rate using the Bazett's formula (QTcB) ≥ 480 msec.
- Patients on combination antiretroviral therapy are ineligible.
- 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.
- Adults unable to consent, pregnant or nursing women or prisoners.
- Any serious medical or psychiatric illness/condition likely in the judgment of the Investigator(s) to interfere or limit compliance with study requirements/treatment.
- Diagnosis of another primary malignancy within the past 5 years with the exception of non-melanoma skin cancer.
- Patients with a prior history of grade 3 capillary leak syndrome (CLS) or <grade 3 CLS with pulmonary involvement.
- Unwilling to abstain from alcohol ingestion for duration of the study
- Patients with elevated liver function or bilirubin not meeting criteria for treatment
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
TDO Dose Level
Arm Description
Trabectedin [T], Doxorubicin [D], and Olaratumab [O]
Outcomes
Primary Outcome Measures
Recommended Phase 2 Dose (RP2D) of Trabectedin in Combination with Doxorubucin and Olaratumab
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
Toxicity in Study Participants
Determination of the safety, tolerability, and toxicity profile of administering TDO in metastatic or recurrent LMS patients, including assessment of dose-limiting toxicities (DLTs).
Clinical Benefit Rate in Study Participants
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.
Full Information
NCT ID
NCT03437070
First Posted
February 10, 2018
Last Updated
March 14, 2019
Sponsor
University of Miami
Collaborators
Janssen Scientific Affairs, LLC
1. Study Identification
Unique Protocol Identification Number
NCT03437070
Brief Title
Trabectedin, Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma
Official Title
A Phase I Study of Trabectedin in Combination With Fixed Doses of Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Withdrawn
Why Stopped
Sponsor Decision
Study Start Date
June 2019 (Anticipated)
Primary Completion Date
June 2021 (Anticipated)
Study Completion Date
June 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Miami
Collaborators
Janssen Scientific Affairs, LLC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leiomyosarcoma
Keywords
Advanced Leiomyosarcoma, Recurrent Leiomyosarcoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Model Description
Dose escalation
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
TDO Dose Level
Arm Type
Experimental
Arm Description
Trabectedin [T], Doxorubicin [D], and Olaratumab [O]
Intervention Type
Drug
Intervention Name(s)
Trabectedin
Other Intervention Name(s)
Yondelis
Intervention Description
Administered intravenously per protocol on Day 1 for 21-day cycles.
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
Doxorubicin Hydrochloride
Intervention Description
Administered intravenously per protocol on Day 1 for 21-day cycles.
Intervention Type
Drug
Intervention Name(s)
Olaratumab
Other Intervention Name(s)
Lartruvo
Intervention Description
Administered intravenously per protocol
Primary Outcome Measure Information:
Title
Recommended Phase 2 Dose (RP2D) of Trabectedin in Combination with Doxorubucin and Olaratumab
Description
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).
Time Frame
About 21 days, one cycle of protocol therapy
Secondary Outcome Measure Information:
Title
Toxicity in Study Participants
Description
Determination of the safety, tolerability, and toxicity profile of administering TDO in metastatic or recurrent LMS patients, including assessment of dose-limiting toxicities (DLTs).
Time Frame
Up to 8 months
Title
Clinical Benefit Rate in Study Participants
Description
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.
Time Frame
From Baseline to End of Treatment, up to 8 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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.
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.
Life expectancy greater than 3 months.
Male or female, age ≥18 years
Eastern Cooperative Oncology Group (ECOG) performance status 0, 1.
Resolution of clinically significant toxic effects of prior surgery, radiotherapy or systemic anticancer therapy.
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.
Patients should be free of active infections requiring antibiotics (with exception of urinary tract infection).
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.
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.
Patients must have adequate cardiac function (ejection fraction ≥ 45%) to receive therapy.
Ability to understand the investigational nature, potential risks and benefits of the research study and to provide valid written informed consent.
Exclusion Criteria:
Patients without histologically confirmed LMS
Patients without measurable disease by RECIST 1.1 criteria
Prior doxorubicin, trabectedin, or olaratumab chemotherapy
Patients with an ECOG of 2, 3 or 4 (Appendix C)
Patient with known allergies to pegfilgrastim/filgrastim.
Patients with known active central nervous system (CNS) metastasis and/or carcinomatous meningitis.
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.
Patients with a known sensitivity to humanized antibodies or sensitivity attributed to compounds of similar chemical or biological composition to alkylating agents or anthracyclines.
A QT interval corrected for heart rate using the Bazett's formula (QTcB) ≥ 480 msec.
Patients on combination antiretroviral therapy are ineligible.
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.
Adults unable to consent, pregnant or nursing women or prisoners.
Any serious medical or psychiatric illness/condition likely in the judgment of the Investigator(s) to interfere or limit compliance with study requirements/treatment.
Diagnosis of another primary malignancy within the past 5 years with the exception of non-melanoma skin cancer.
Patients with a prior history of grade 3 capillary leak syndrome (CLS) or <grade 3 CLS with pulmonary involvement.
Unwilling to abstain from alcohol ingestion for duration of the study
Patients with elevated liver function or bilirubin not meeting criteria for treatment
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marilyn Huang, MD, MS
Organizational Affiliation
University of Miami
Official's Role
Principal Investigator
12. IPD Sharing Statement
Learn more about this trial
Trabectedin, Doxorubicin and Olaratumab in Patients With Metastatic or Recurrent Leiomyosarcoma
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