Clinical Trial 23609

• Overview

  Study Title:

  Randomized, Controlled, Open-label, Phase IIb/III Study of Lurbinectedin in Combination with Doxorubicin versus Doxorubicin Alone as First-line Treatment in Patients with Metastatic Leiomyosarcoma

  Summary:

  The primary objective of this phase III study is to evaluate whether the combination of lurbinectedin plus doxorubicin given as first line treatment for metastatic leiomyosarcoma (LMS) prolongs the progression-free survival (PFS) by Independent Review Committee (IRC) when compared to doxorubicin administered as a single agent.

  Objective:

  Primary * The primary objective of this phase IIb/III study is to evaluate whether the combination of lurbinectedin plus doxorubicin given as first line treatment for metastatic leiomyosarcoma (LMS) prolongs the progression-free survival (PFS) by Independent Review Committee (IRC) when compared to doxorubicin administered as a single agent. Secondary Phase IIb: * To select the best lurbinectedin plus doxorubicin combination schedule for the phase III part. Secondary Phase IIb and III: * To determine whether there is a difference between lurbinectedin plus doxorubicin in combination versus doxorubicin alone in terms of: - Overall survival (OS) (key secondary endpoint). - PFS by Investigator Assessment (IA). - Overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 by IRC and IA. - Duration of response (DoR) by IRC and IA. - Clinical Benefit Rate (CBR=objective response plus stable disease ≥ 6 months) by IRC and IA according to the RECIST v.1.1. - PFS on next-line therapy (PFS2) by IA. * To evaluate: - Treatment safety profile according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.5. - Patient-reported outcomes (PRO). - Subgroup analyses. - Pharmacokinetics (PK) of lurbinectedin and/or doxorubicin and its metabolite doxorubicinol in patients treated in the Experimental arms (lurbinectedin plus doxorubicin combination) and in the Control arm (doxorubicin alone). - PK/pharmacodynamic (PD) correlations in patients treated in the experimental arms (lurbinectedin plus doxorubicin combination), if any. * To conduct an exploratory pharmacogenomic (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 plus doxorubicin combination compared to doxorubicin alone.

• Treatments

  Therapies:

  Chemotherapy (NOS)

  Medications:

  Adriamycin (doxorubicin); PM01183 (lurbinectedin); doxorubicin (); lurbinectedin ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Voluntary signed and dated written informed consent of the participants obtained before any study-specific procedure.
  • Age ≥ 18 years.
  • Histologically confirmed diagnosis of metastatic LMS, in participants not candidates for curative resection.
  • Radiologically measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
  • 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. Prior line/s of hormone therapy in the adjuvant/metastatic setting are also allowed.
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1.
  • Adequate hematological, renal, metabolic and hepatic function.
  • Wash-out periods: 1) At least three weeks since last prior systemic treatment. 2) At least three weeks since last prior major surgery and one week since last prior minor surgery (port placement is excluded from this wash-out period). 3) At least two weeks since last prior radiotherapy.
  • 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. Fertile male participants with WOCBP partners should use condoms during treatment and for four months following the last investigational medicinal product (IMP) dose.
  • Additional criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Prior treatment with anthracyclines, lurbinectedin or trabectedin.
  • Known low grade leiomyosarcoma (i.e., grade I).
  • Known hypersensitivity to any of the components of the IV formulation of lurbinectedin or doxorubicin.
  • Concomitant diseases/conditions as defined in the protocol.
  • Use of strong inducers of CYP3A4 activity within two weeks prior to the first infusion of lurbinectedin.
  • Prior irradiation of a RECIST v.1.1 target lesion if only one target lesion is available, unless progression of the lesion has been confirmed.
  • Known myopathy (history of resolved steroid-induced myopathy is allowed).
  • History of malignancies other than LMS within three years prior to enrollment, except for malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, non-muscle-invasive urothelial carcinomas, ductal carcinoma in situ, or stage I uterine cancer. Prior malignancies should have received curative treatment and should remain in remission. The Investigator should ensure, based on histology or clinical information, that the current metastatic sites are leiomyosarcoma and not recurrence of the original malignancy.
  • Limitation of the participant's ability to comply with the treatment or to follow-up the protocol.
  • Women who are pregnant or breast feeding and fertile participants (men and women) who are not using a highly effective method of contraception.
  • Participants in whom rapid tumor shrinkage is needed (e.g., when a tumor is close to a critical structure).
  • Additional criteria may apply.

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