IRB Study Number 23-970
Status Recruiting
Institute Taussig Cancer Institute
Description
2.1 PRIMARY OBJECTIVE
To evaluate whether the combination of lurbinectedin plus doxorubicin given as first line treatment for metastatic LMS prolongs the progression-free survival (PFS) by Independent Review Committee (IRC) when compared to doxorubicin administered as a single agent.
2.2 SECONDARY OBJECTIVES
Phase IIb:
To select the best lurbinectedin plus doxorubicin combination schedule for the phase III part.
Phase IIb and III:
To determine whether there is a difference between lurbinectedin plus doxorubicin in combination versus doxorubicin alone in terms of:
o PFS by Investigator Assessment (IA).
o ORR according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 by IRC and IA.
o Duration of response (DoR) by IRC and IA.
o Clinical Benefit Rate (CBR=objective response plus stable disease ≥ 6 months) by IRC and IA according to the RECIST v.1.1.
o PFS on next-line therapy (PFS2) by IA.
o Overall survival (OS).
To evaluate:
o Treatment safety profile according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), v.5.
o Patient-reported outcomes (PRO).
o Subgroup analyses.
o Pharmacokinetics (PK) of lurbinectedin and/or doxorubicin and its metabolite doxorubicinol in patients treated in the Experimental arms (lurbinectedin plus doxorubicin combination) and the Control arm (doxorubicin alone).
o PK/pharmacodynamic (PD) correlations in patients treated in the Experimental arms (lurbinectedin plus doxorubicin combination), if any.
To conduct an exploratory PGx analysis in tumor and blood samples from patients who consented to be included in a substudy to identify potential biomarkers of response and/or resistance to lurbinectedin/doxorubicin combination compared to doxorubicin alone.
Inclusion Criteria
1) Voluntary signed and dated written informed consent of the patient obtained before any study-specific procedure.
2) Age ≥ 18 years.
3) Histologically confirmed diagnosis of metastatic LMS, in patients not candidates for curative resection.
4) Radiologically measurable disease according to the RECIST v.1.1.
5) No previous systemic therapy for metastatic disease (i.e., first-line setting) and no previous anthracyclines. Note: prior chemotherapy (without anthracycline) in the context of adjuvant or neoadjuvant therapy is allowed.
6) Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1 (see APPENDIX 1).
7) Adequate hematological, renal, metabolic and hepatic function:
a) Hemoglobin ≥ 9.0 g/dL (patients may have received prior red blood cell [RBC] transfusion); absolute neutrophil count (ANC) ≥ 2.0 x 109/L, and platelet count ≥ 100 x 109/L.
b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x upper limit of normal (ULN).
c) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN if total bilirubin is > ULN.
d) Albumin ≥ 3.0 g/dL.
e) Calculated creatinine clearance (CrCL) ≥ 30 mL/min (using Cockcroft and Gault’s formula).
f) Left ventricular ejection fraction (LVEF) > 50% assessed by multiple-gated acquisition scan (MUGA) or echocardiography (ECHO).
8) Wash-out periods:
a) At least three weeks since last prior systemic treatment.
b) At least three weeks since last prior major surgery and one week since last prior minor surgery.
c) At least two weeks since last prior radiotherapy.
9) Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to seven months after treatment discontinuation. Valid methods to determine the childbearing potential, adequate contraception and requirements for WOCBP partners are described in APPENDIX 2. Fertile male patients with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose.
Exclusion Criteria
1) Prior treatment with anthracyclines, lurbinectedin or trabectedin.
2) Known low grade leiomyosarcoma (i.e., grade I).
3) Known hypersensitivity to any of the components of the i.v. formulation of lurbinectedin or doxorubicin.
4) Concomitant diseases/conditions:
a) History of cardiac disease: myocardial infarction or angina; severe valvular disease; or symptomatic arrhythmia despite ongoing treatment.
b) Patients with any immunodeficiency, including those known to be infected by human immunodeficiency virus (HIV).
c) Known chronic active hepatitis or cirrhosis. For Hepatitis B, this includes positive tests for both Hepatitis B surface antigen and quantitative Hepatitis B polymerase chain reaction (PCR). For Hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR.
d) Active uncontrolled infection.
e) Any other major illness (including severe cardiovascular disease) or risk factors that, in the Investigator’s judgment, will substantially increase the risk associated with the patient’s participation in this study.
5) Use of strong inducers of CYP3A activity within two weeks prior to the first infusion of lurbinectedin.
6) Prior irradiation if only one target lesion (i.e., measurable) is available, unless progression of the lesion has been confirmed.
7) Known myopathy.
8) History of another neoplastic disease except for curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, properly treated carcinoma in situ of the uterine cervix or breast or superficial bladder tumors (Ta, Tis, or T1) that have been successfully and curatively treated with no evidence of recurrent or residual disease within three years prior to randomization. In case of prior malignancy, the Investigator should ensure, based on histology or clinical information, that the metastatic sites are sarcoma and not recurrence of the original malignancy.
9) Limitation of the patient’s ability to comply with the treatment or to follow-up the protocol.
10) Women who are pregnant or breast feeding and fertile patients (men and women) who are not using a highly effective method of contraception.
11) Patients in whom rapid tumor shrinkage is needed (e.g., when a tumor is close to a critical structure).
