Lurbinectedin plus Doxorubicin for the Treatment of Advanced or Metastatic Soft Tissue Sarcoma or Leiomyosarcoma
This phase Ib/II trial studies the side effects and best dose of lurbinectedin in combination with doxorubicin in patients with soft tissue sarcoma or leiomyosarcoma that has spread to other places in the body (advanced or metastatic). Lurbinectedin is a synthetically derived chemical that binds to deoxyribonucleic acid (DNA) (is the molecule that contains the genetic code of organisms). The binding to DNA likely induces cell death. Doxorubicin is a cytotoxic chemotherapy drug that kills tumor cells by several mechanisms including binding to DNA. Taking lurbinectedin in combination with doxorubicin may lead to tumor cell death and be beneficial to the disease status of patients with advanced or metastatic soft tissue sarcoma or leiomyosarcoma.
Inclusion Criteria
- FOR ENROLLMENT TO PHASE 1B: Participants must have histologically confirmed advanced or metastatic soft-tissue sarcoma and no curative multimodality treatment options available
- FOR ENROLLMENT TO PHASE 2: Participants must have histologically confirmed advanced or metastatic leiomyosarcoma (LMS) and no curative multimodality treatment options available
- Participants must have measurable disease per RECIST 1.1 criteria
- Age >= 18 years. Because no dosing or adverse event data are currently available on the use of lurbinectedin in combination with doxorubicin in participants < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Absolute neutrophil count >= 1,500/mcL (transfusion and growth factor support are permitted and there is no washout period)
- Hemoglobin (Hgb) >= 8 g/dl (transfusion support permitted)
- Platelet count >= 100,000/mcL (transfusion and growth factor support are permitted and there is no washout period)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (transfusion and growth factor support are permitted and there is no washout period)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) /alanine aminotransferase (ALT) (serum glutamate-pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN, OR AST (SGOT) / ALT (SGPT) =< 5 x institutional ULN if elevation is a result of metastases (transfusion and growth factor support are permitted and there is no washout period)
- Creatinine =< 1.5 x institutional ULN, OR creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above 1.5 x institutional normal (calculated via the Cockcroft-Gault equation) (transfusion and growth factor support are permitted and there is no washout period)
- Creatine phosphokinase (CPK) < 2.5 x institutional ULN (transfusion and growth factor support are permitted and there is no washout period)
- For participants with known chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- Left ventricular ejection fraction (LVEF) >= 50% on screening echocardiogram (ECHO) or multigated acquisition (MUGA) scan
- The effects of lurbinectedin or doxorubicin on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child-bearing potential and men 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. Alternatively, documentation by the medical provider of vasectomy for males or surgical sterilization/last menstrual period (LMP) > 12 months for females of childbearing potential is acceptable. 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 and women treated or enrolled on this protocol must agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of study agent administration
- Ability to understand and the willingness to sign a written informed consent document
- Participants must have archival tissue available for analysis in the form of a formalin-fixed paraffin embedded (FFPE) block or unstained slides. Participants without archival tissue available may be enrolled with approval of the Sponsor-Investigator. In the event that archival tissue is not available, and the Sponsor-Investigator approves enrollment, tissue from a subsequent biopsy/surgery performed 1. while on study, and 2. for standard of care purposes only, may be provided. If tissue is not provided, this will not be considered a violation. Note: confirmation of availability of archival tissue is the only requirement for eligibility, archival tissue does not need to be received by the study team or site prior to enrollment
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen as assessed by the treating investigator may be included with the approval of the sponsor-investigator
Exclusion Criteria
- Participants who have received prior anthracycline or trabectedin (Yondelis, ET-743), including prior exposure to doxorubicin or liposomal doxorubicin
- Participants who have received more than 2 prior lines of cytotoxic chemotherapy for the phase 1b study and more than 1 prior line of cytotoxic chemotherapy for the phase 2 study. There is no limit on the number of prior lines of non-cytotoxic chemotherapy (e.g., pazopanib, immunotherapy)
- Prior exposure to lurbinectedin
- Participants who have received or undergone prior chemotherapy within 14 days of cycle 1 day 1, therapeutic radiation therapy within 21 days of cycle 1 day 1 or major surgery within 21 days of cycle 1 day 1
- Participants who have received prior palliative radiation therapy within 7 days of cycle 1 day 1
- Participants who have received prior antibody-based therapy (e.g., nivolumab) within 4 weeks or 3 half-lives (whichever is shorter) of cycle 1 day 1
- Participants who have received prior small molecule or tyrosine kinase inhibitor (TKI) therapy within 2 weeks or 3 half-lives (whichever is shorter) of cycle 1 day 1
- Participants who have not recovered to =< Grade 1 or baseline from adverse events attributed to any prior anti-cancer therapy, with the exceptions of alopecia, controlled endocrine toxicity (e.g., hypothyroidism), and cutaneous toxicity which will be permitted at Grade 2
- Participants who are receiving any other investigational agents
- Participants with known central nervous system (CNS) disease involvement, with the exception of patients with brain metastases that have been previously treated and have remained stable on magnetic resonance imaging (MRI) >= 28 days prior to cycle 1 day 1 without use of steroids or anti-epileptic medications
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to lurbinectedin or doxorubicin
- Participants receiving any medications or substances that are strong or moderate inhibitors or inducers of CYP3A (including grapefruit and grapefruit juice), CYP2D6, or P-gp, and are unable to discontinue the medication/substance, are ineligible. As part of the enrollment/informed consent procedures, the participant must be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product
- Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Known cardiomyopathy
- Pregnant women are excluded from this study because lurbinectedin and doxorubicin are anti-cancer agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with lurbinectedin or doxorubicin, breastfeeding must be discontinued if the mother is treated with lurbinectedin or doxorubicin. A negative pregnancy test is required for women of childbearing potential prior to the first dose of study medication
- Immunocompromised patients, including patients who are known to be seropositive for human immunodeficiency virus (HIV) due to the increased risk of lethal infections when treated with marrow-suppressive therapy. HIV testing is not required as part of screening
Additional locations may be listed on ClinicalTrials.gov for NCT05099666.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lurbinectedin with doxorubicin hydrochloride (doxorubicin) in participants with advanced soft-tissue sarcoma. (Phase 1b)
II. Determine the progression-free survival (PFS) rate of lurbinectedin with doxorubicin compared to doxorubicin alone in participants with advanced leiomyosarcoma (LMS). (Phase 2)
SECONDARY OBJECTIVES:
I. Evaluate the preliminary anti-tumor activity of lurbinectedin with doxorubicin, including the disease control rate (DCR) at 6 and 12 months, and the rates of PFS, overall survival (OS), and objective response (OR) assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. (Phase 1b)
II. Evaluate the anti-tumor activity of lurbinectedin with doxorubicin, including the DCR at 6 and 12 months, and the rates of OS and OR assessed by RECIST version 1.1 criteria. (Phase 2)
III. Evaluate the safety and tolerability of lurbinectedin with doxorubicin. (Phase Ib & 2)
EXPLORATORY OBJECTIVE:
I. Explore correlations between selected biomarkers and response to lurbinectedin and doxorubicin combination therapy, including along the homologous recombination repair deficiency (HRD) and DNA damage response (DDR) pathways. (Phase Ib & 2)
OUTLINE: This is a phase Ib, dose-escalation study followed by a randomized phase II study.
PHASE IB: Patients receive lurbinectedin intravenously (IV) over 60 minutes and doxorubicin IV on day 1 or days 1 and 8 of each cycle. Cycles of doxorubicin repeats every 21 days in the absence of disease progression or unacceptable toxicity, or until the lifetime dose maximum is reached. Cycles of lurbinectedin repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and imaging during screening and on the trial.
PHASE II: Patients are randomized into 1 of 2 arms.
ARM I: Patients receive lurbinectedin IV over 60 minutes and doxorubicin IV on day 1 or days 1 and 8 of each cycle. Cycles of doxorubicin repeats every 21 days in the absence of disease progression or unacceptable toxicity, or until the lifetime dose maximum is reached. Cycles of lurbinectedin repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA during screening and imaging during screening and on the trial. Patients also undergo blood sample collection on the trial.
ARM II: Patients receive doxorubicin IV on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity, or until the lifetime dose maximum is reached. Patients undergo ECHO or MUGA during screening and imaging during screening and on the trial. Patients also undergo blood sample collection on the trial.
After completion of the study treatment, patients are followed up at 30 days and then every 3 months for 2 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorGregory Michael Cote
- Primary ID21-437
- Secondary IDsNCI-2022-00578
- ClinicalTrials.gov IDNCT05099666