Trial in Patients With Metastatic or Locally Advanced Leiomyosarcoma

Official title

A Randomized Phase II Trial Comparing the Activity of trabectedIn vs Gemcitabine in Patients With Metastatic or Locally Advanced Leiomyosarcoma Pretreated With Conventional Chemotherapy

Overview

Study is aimed at evaluating the activity of Trabectedin (arm A) in advanced leiomyosarcomas, having Gemcitabine (arm B) as the comparator. In addition to the randomized cohort, the study has also an observational prospective cohort which include patients who will refuse the randomization or for whom the investigator will not judge the randomization as an appropriate option. In order to allow the participation of sites only to the prospective-observational (non randomized) cohort, it was introduced the possibility to participate to the study and receive the ethical approval only to the Observational Prospective Cohort In parallel an optional translational study will be performed, in both cohorts, to identify factors predictive of the activity of Trabectedin or Gemcitabine in this specific histotype.

Detailed description

The management of patients with leiomyosarcomas determines many difficulties. Despite patients with metastatic disease at diagnosis or who recur after initial treatment have a dismal prognosis and, except for a subset of selected patients with completely resectable disease, the median survival is less than two years.

At the advanced-disease stage, the main aim of treatment is to improve patient's quality of life, possibly survival, with the best compromise between toxicity and symptoms. Trabectedin (T) is a marine-derived cytotoxic approved by European MEdicine Agency (EMEA) and FDA.

It is indicated for the treatment of patients with advanced soft tissue sarcoma, after failure of anthracyclines-based chemotherapy or who are unsuitable to receive these agents.

Among Soft Tissue Sarcoma (STS), activity has been mainly detected in synovial sarcoma, liposarcoma and leiomyosarcoma. Although the response rate did not exceed 10%, T was demonstrated to provide disease control, with progression arrest rates exceeding 50% and progression-free survival rates exceeding 20% at 6 months. So far no phase II or III studies have been addressed to test the activity of T in leiomyosarcoma specifically (without differentiation between site of primary localization) in comparison with Gemcitabine.

This study is aimed at evaluating the activity of Trabectedin (arm A) in advanced leiomyosarcomas, having Gemcitabine (arm B) as the comparator. In parallel an optional translational study will be performed to identify factors predictive of the activity of Trabectedin or Gemcitabine in this specific histotype.

In addition to the randomized cohort, the study has also an observational prospective cohort which include patients who will refuse the randomization or for whom the investigator will not judge the randomization as an appropriate option.

In order to allow the participation of sites only to the prospective-observational (non randomized) cohort, it was introduced the possibility to participate to the study and receive the ethical approval only to the Observational Prospective Cohort In parallel an optional translational study will be performed, in both cohorts, to identify factors predictive of the activity of Trabectedin or Gemcitabine in this specific histotype.

Interventions

• Drug Trabectedin
  Trabectedin in monotherapy
• Drug Gemcitabine
  Gemcitabine, control arm
• Drug No Intervention: Observational Cohort
  Treatment according clinical practice

Primary outcome measures

• Compare the Growth Modulation Index (GMI) in patients treated with Trabectedin or Gemcitabine in second line [Time frame: Week 6, week 12, week 18, week 27, week 36 and week 45]

Secondary outcome measures (6)

• Overall Response Rate [Time frame: Week 6, week 12, week 18, week 27, week 36 and week 45]
• Overall Survival (OS) [Time frame: 3 years and 5 years]
• Progression free Survival (PFS) [Time frame: 6 months]
• Duration of response [Time frame: Week 6, week 12, week 18, week 27, week 36 and week 45]
• Adverse events related to the treatment [Time frame: Week 3, week 6, week 9, week 12, week 18, week 27, week 36, week 45]
• Compare the Growth Modulation Index (GMI) in patients treated with Trabectedin or Gemcitabine after second line [Time frame: Week 6, week 12, week 18, week 27, week 36 and week 45]

Eligibility criteria

Inclusion criteria

• Patients with histologically documented diagnosis of leiomyosarcoma
• Patients with diagnosis of unresectable or metastatic leiomyosarcoma
• Patients who received at least on previous systemic treatment with anthracycline-based chemotherapy.
• Patients suitable to receive gemcitabine or trabectedin therapy.
• Measurable or evaluable disease with RECIST 1.1 criteria.
• Evidence of progression according RECIST 1.1 during the 6 months before study entry.
• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
• All previous anticancer treatments must have completed ≥ 3 weeks prior to first dose of study drug.
• The patient has resolution of adverse events, with the exception of alopecia, and of all clinically significant toxic effects of prior loco-regional therapy, surgery, radiotherapy or systemic anticancer therapy to ≤ Grade 1, by National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
• Adequate bone marrow, liver and renal function
• Left Ventricular Ejection Fraction ≥ 50% and/or above lower institutional limit of normality.
• Female patients of child-bearing potential must have negative pregnancy test within 7 days before initiation each cycle of chemotherapy.
• No history of arterial and/or venous thromboembolic event within the previous 12 months.
• The patient or legal representative must be able to read and understand the informed consent form and must have been willing to give written informed consent prior to any study specific procedure. The subject may also provide an optional consent for the biological/translational sub-study associated.

Exclusion criteria

• Prior treatment with Trabectedin and/or Gemcitabine
• Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
• History of other malignancies (except basal cell carcinoma or cervical carcinoma in situ, adequately treated), unless in remission from 5 years or more and judged of negligible potential of relapse.
• Persistent toxicities with the exception of alopecia, caused by previous anticancer therapies
• Metastatic brain or meningeal tumors
• Active viral hepatitis
• Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus
• Patients with any severe and/or uncontrolled medical conditions
• Medical history of hemorrhage or a bleeding event ≥ Grade 3 (NCI-CTCAE v 5.0) within 4 weeks prior to the initiation of study treatment
• Active clinically serious infections
• Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus
• Previous treatment with radiation therapy within 14 days of first day of study drug dosing,
• Major surgery within 4 weeks prior to study entry
• Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitors
• Concomitant use of known strong or moderate CYP3A inducers
• Patients undergoing renal dialysis or with Creatinin Clearance <30 ml/min or Creatinine >1,5 mg/dL
• Pregnant or breast feeding patients
• Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Treatment

Study locations

Italy · 17 centers

• Azienda Ospedaliera S. Orsola-Malpighi — Bologna
• Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori - IRST — Meldola
• Nuovo Ospedale di Prato — Prato
• Istituto Clinico Humanitas — Rozzano
• Centro di Riferimento Oncologico di Aviano — Aviano
• Policlinico Universitario Campus Biomedico — Roma
• IRCCS Fondazione Piemonte per l'Oncologia — Candiolo
• A.O.U.San Luigi Gonzaga — Orbassano
• … and 9 more centers

Publications

• Hensley ML, Miller A, O'Malley DM, Mannel RS, Behbakht K, Bakkum-Gamez JN, Michael H. Randomized phase III trial of gemcitabine plus docetaxel plus bevacizumab or placebo as first-line treatment for metastatic uterine leiomyosarcoma: an NRG Oncology/Gynecologic Oncology Group study. J Clin Oncol. 2015 Apr 1;33(10):1180-5. doi: 10.1200/JCO.2014.58.3781. Epub 2015 Feb 23. PMID 25713428
• Pautier P, Floquet A, Chevreau C, Penel N, Guillemet C, Delcambre C, Cupissol D, Selle F, Isambert N, Piperno-Neumann S, Thyss A, Bertucci F, Bompas E, Alexandre J, Collard O, Lavau-Denes S, Soulie P, Toulmonde M, Le Cesne A, Lacas B, Duffaud F; French Sarcoma Group. Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a n PMID 25795402
• Demetri GD, Chawla SP, von Mehren M, Ritch P, Baker LH, Blay JY, Hande KR, Keohan ML, Samuels BL, Schuetze S, Lebedinsky C, Elsayed YA, Izquierdo MA, Gomez J, Park YC, Le Cesne A. Efficacy and safety of trabectedin in patients with advanced or metastatic liposarcoma or leiomyosarcoma after failure of prior anthracyclines and ifosfamide: results of a randomized phase II study of two different sched PMID 19652065
• Patel SR, Gandhi V, Jenkins J, Papadopolous N, Burgess MA, Plager C, Plunkett W, Benjamin RS. Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol. 2001 Aug 1;19(15):3483-9. doi: 10.1200/JCO.2001.19.15.3483. PMID 11481354
• Pautier P, Floquet A, Penel N, Piperno-Neumann S, Isambert N, Rey A, Bompas E, Cioffi A, Delcambre C, Cupissol D, Collin F, Blay JY, Jimenez M, Duffaud F. Randomized multicenter and stratified phase II study of gemcitabine alone versus gemcitabine and docetaxel in patients with metastatic or relapsed leiomyosarcomas: a Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) French Sarc PMID 22907974
• Seddon B, Strauss SJ, Whelan J, Leahy M, Woll PJ, Cowie F, Rothermundt C, Wood Z, Benson C, Ali N, Marples M, Veal GJ, Jamieson D, Kuver K, Tirabosco R, Forsyth S, Nash S, Dehbi HM, Beare S. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised controlled phase 3 trial. Lancet Onc PMID 28882536

Identifiers

NCT: NCT04383119 · ISG-ARTICLE

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗