Trial in Patients With Metastatic or Locally Advanced Leiomyosarcoma (ISG-ARTICLE)

September 12, 2023 updated by: Italian Sarcoma Group

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

100

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Italy
      • Bologna, Italy, 40136
        • Recruiting
        • Istituto Ortopedico Rizzoli - Unit of Chemotherapy of Muscoloskeletal Tumors
        • Contact:
        • Principal Investigator:
          • Toni Ibrahim, MD
      • Genova, Italy
      • Milano, Italy
      • Milano, Italy, 20133
        • Not yet recruiting
        • Fondazione IRCCS INT Milano
        • Principal Investigator:
          • Roberta Sanfilippo, MD
        • Contact:
      • Napoli, Italy
      • Padova, Italy
        • Recruiting
        • IRCCS Istituto Oncologico Veneto (IOV)
        • Principal Investigator:
          • Antonella Brunello, MD
        • Contact:
      • Palermo, Italy
      • Rome, Italy, 00100
        • Recruiting
        • Istituto Regina Elena - IFO
        • Contact:
      • Torino, Italy, 10153
        • Recruiting
        • ASL Città di Torino (Dipartimento di Oncologia)
        • Contact:
        • Contact:
          • Boglione, MD
        • Principal Investigator:
          • Antonella Boglione, MD
    • BO
      • Bologna, BO, Italy, 40138
        • Recruiting
        • Azienda Ospedaliera S. Orsola-Malpighi
        • Contact:
        • Principal Investigator:
          • Margherita Nannini, MD
    • FC
      • Meldola, FC, Italy
        • Recruiting
        • Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori - IRST
        • Contact:
        • Principal Investigator:
          • Valentina Fausti, MD
    • Firenze
      • Prato, Firenze, Italy, 59100
    • MI
      • Rozzano, MI, Italy, 20089
    • PD
      • Aviano, PD, Italy, 33081
        • Not yet recruiting
        • Centro di Riferimento Oncologico di Aviano
        • Contact:
        • Principal Investigator:
          • Angela Buonadonna, MD
    • RM
      • Roma, RM, Italy, 00128
        • Recruiting
        • Policlinico Universitario Campus Biomedico
        • Principal Investigator:
          • Bruno Vincenzi, MD
        • Contact:
    • Torino
      • Candiolo, Torino, Italy, 10060
        • Recruiting
        • IRCCS Fondazione Piemonte per l'Oncologia
        • Sub-Investigator:
          • Sandra Aliberti, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Patients with histologically documented diagnosis of leiomyosarcoma
  2. Patients with diagnosis of unresectable or metastatic leiomyosarcoma
  3. Patients who received at least on previous systemic treatment with anthracycline-based chemotherapy.
  4. Patients suitable to receive gemcitabine or trabectedin therapy.
  5. Measurable or evaluable disease with RECIST 1.1 criteria.
  6. Evidence of progression according RECIST 1.1 during the 6 months before study entry.
  7. Age ≥18 years
  8. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
  9. All previous anticancer treatments must have completed ≥ 3 weeks prior to first dose of study drug.
  10. 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
  11. Adequate bone marrow, liver and renal function
  12. Left Ventricular Ejection Fraction ≥ 50% and/or above lower institutional limit of normality.
  13. Female patients of child-bearing potential must have negative pregnancy test within 7 days before initiation each cycle of chemotherapy.
  14. No history of arterial and/or venous thromboembolic event within the previous 12 months.
  15. 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:

  1. Prior treatment with Trabectedin and/or Gemcitabine
  2. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
  3. 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.
  4. Persistent toxicities with the exception of alopecia, caused by previous anticancer therapies
  5. Metastatic brain or meningeal tumors
  6. Active viral hepatitis
  7. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus
  8. Patients with any severe and/or uncontrolled medical conditions
  9. 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
  10. Active clinically serious infections
  11. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus
  12. Previous treatment with radiation therapy within 14 days of first day of study drug dosing,
  13. Major surgery within 4 weeks prior to study entry
  14. Concomitant use of known strong CYP3A inhibitors or moderate CYP3A inhibitors
  15. Concomitant use of known strong or moderate CYP3A inducers
  16. Patients undergoing renal dialysis or with Creatinin Clearance <30 ml/min or Creatinine >1,5 mg/dL
  17. Pregnant or breast feeding patients
  18. 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm A
Trabectedin at the dose of 1.5 mg/m2-1.3 mg/m2 with a top-dose of 2.6 total mg per cycle (according the clinical practice in pretreated patients and in all our ISG studies) will be administered via a central venous catheter as a 24-hour infusion on day 1 of 21-days treatment cycles
Drug: Trabectedin
Trabectedin in monotherapy
Other Names:
  • Trabectedin arm
Active Comparator: Arm B
Gemcitabine 800-1000 mg/m2 will be administered via a central venous catheter on days 1,8 every 21 days
Drug: Gemcitabine
Gemcitabine, control arm
Other Names:
  • Gemcitabine arm
Active Comparator: Observational Cohort
Treatmen according clinical practice (not defined in advance). The patient who will refuse randomization between Arm A and B can choose to participate to the observational cohort to the study, where they will be treated according clinical practice
Drug: No Intervention: Observational Cohort
Treatment according clinical practice

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Ratio of Time To Progression with the nth line (TTPn) of therapy to the TTPn-1 with the n-1th line.
Week 6, week 12, week 18, week 27, week 36 and week 45

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Response Rate
Time Frame: Week 6, week 12, week 18, week 27, week 36 and week 45
Overall response rate according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Week 6, week 12, week 18, week 27, week 36 and week 45
Overall Survival (OS)
Time Frame: 3 years and 5 years
Survival from the first dose treatment to death for any cause
3 years and 5 years
Progression free Survival (PFS)
Time Frame: 6 months
Survival without disease progression
6 months
Duration of response
Time Frame: Week 6, week 12, week 18, week 27, week 36 and week 45
Duration of tumor control according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
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
Safety in term of adverse event is evaluate from the first treatment dose throughout the study according to CTCAE 5.0
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
Ratio of Time To Progression with the Mth line (TTPn) of therapy to the TTPn-1 with the n-1th line.
Week 6, week 12, week 18, week 27, week 36 and week 45

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Exploratory objectives
Time Frame: week 6, and at up to week 53
Identify gene mutations that may be associated to response/resistance to the treatment and to clinical outcomes parameters.
week 6, and at up to week 53

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Italian Sarcoma Group

Collaborators

PharmaMar

Investigators

  • Principal Investigator: Bruno Vincenzi, Prof/MD, Campus Biomedico of Rome

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 29, 2021

Primary Completion (Estimated)

June 30, 2024

Study Completion (Estimated)

September 1, 2024

Study Registration Dates

First Submitted

May 4, 2020

First Submitted That Met QC Criteria

May 6, 2020

First Posted (Actual)

May 12, 2020

Study Record Updates

Last Update Posted (Actual)

September 13, 2023

Last Update Submitted That Met QC Criteria

September 12, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ISG-ARTICLE

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Not applicable no plan to share IPD

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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