Study on Trabectedin in Advanced Rearranged Mesenchymal Chondrosarcoma (ISG-MCS)

Phase II Study on Trabectedin in Advanced Rearranged Mesenchymal Chondrosarcoma

Prospective, uncontrolled, investigator-initiated, phase II clinical study to explore the activity of trabectedin in a population of patients aged ≥16 years with progressive, advanced (locally advanced or metastatic)

Study Overview

• Status: Recruiting
• Conditions: Mesenchymal Chondrosarcoma
• Intervention / Treatment: Drug: Trabectedin

Detailed Description

Prospective, uncontrolled, multicenter, Italian, investigator-initiated, phase II clinical study to explore the activity of trabectedin in a population of patients aged ≥16 years with progressive, advanced (locally advanced or metastatic), HEY1-NCOA2 positive MCS) , pre-treated with anthracycline-based chemotherapy.

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Silvia Stacchiotti, MD; Phone Number: 2804 39022390; Email: silvia.stacchiotti@istitutotumori.mi.it

Study Locations

• Italy
  • Bologna, Italy, 40136
    • Recruiting
    • Istituto Ortopedico Rizzoli - Unit of Chemotherapy of Muscoloskeletal Tumors
    • Contact: Toni Ibrahim, MD; Phone Number: 199 +390516366; Email: toni.ibrahim@ior.it
    • Principal Investigator: Toni Ibrahim, MD
  • Milan, Italy, 20133
    • Recruiting
    • Fondazione IRCSS Istituto Nazionale dei Tumori
    • Contact: Silvia Stacchiotti, MD; Phone Number: +39022390; Email: silvia.stacchiotti@istitutotumori.mi.it
    • Principal Investigator: Silvia Stacchiotti, MD
  • Palermo, Italy
    • Recruiting
    • Ospedale Giaccone
    • Principal Investigator: Giuseppe Badalamenti, MD
    • Contact: Giuseppe Badalamenti, MD; Email: giuseppe.badalamenti@unipa.it
  • Roma, Italy, 00128
    • Recruiting
    • Istituti Fisioterapici Ospitalieri - Ospedale Regina Elena
    • Contact: Virginia Ferraresi, MD; Email: virginia.ferraresi@ifo.it
  • Firenze
    • Prato, Firenze, Italy, 59100
      • Recruiting
      • Nuovo Ospedale di Prato
      • Contact: Giacomo G. Baldi, MD; Phone Number: 4766 0039057443; Email: giacomogiulio.baldi@uslcentro.toscana.it
      • Principal Investigator: Giacomo G. Baldi, MD
  • RM
    • Roma, RM, Italy, 00128
      • Not yet recruiting
      • Policlinico Universitario Campus Biomedico
      • Principal Investigator: Bruno Vincenzi, MD
      • Contact: Bruno Vincenzi, MD; Phone Number: 1123 003906-22541; Email: b.vincenzi@unicampus.it
  • Torino
    • Candiolo, Torino, Italy, 10060
      • Recruiting
      • Fondazione Del Piemonte Per L'Oncologia Ircc Candiolo
      • Principal Investigator: Giovanni Grignani, MD
      • Contact: Sandra Aliberti, MD; Phone Number: 3623 0039-011-993; Email: sandra.aliberti@ircc.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age ≥ 16 years old
2. Histological centrally confirmed diagnosis of skeletal or extra-skeletal MCS with the documented presence of HEY1-NCOA2 fusion
3. Locally advanced disease and/or metastatic disease
4. Measurable or evaluable disease with RECIST v1.1
5. Evidence of progression by RECIST v1.1 during the 6 months before study entry
6. Patients must be pre-treated with at least one prior chemotherapy treatment containing anthracyclines for the advanced phase of disease and with a maximum of 3 lines
7. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2
8. Adequate bone marrow function
9. Adequate organ function
10. Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation each cycle of chemotherapy.
11. Cardiac ejection fraction ≥50% as measured by echocardiogram
12. No history of arterial and/or venous thromboembolic event within the previous 12 months
13. 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 and any locally required authorisation before any study-specific procedures, including screening evaluations, sampling, and analyses.
14. Any other factors, that, at judgment of investigator, could affect the safety of the patients according to the available trabectedin safety data

Exclusion Criteria:

1. Other primary malignancy with <5 years clinically assessed disease free interval, except basal cell skin cancer, cervical carcinoma in situ or other neoplasm judged to entail a low risk of relapse
2. Previous treatment with radiation therapy within 14 days of first day of study drug dosing, or patients who have not recovered from adverse events due to agents previously administered
3. Previous radiotherapy to 25% of the bone marrow
4. Major surgery within 2 weeks prior to study entry
5. Participation in another clinical study with an investigational product, which last dose was taken less than 4 weeks prior to the start of the treatment.
6. Persistent toxicities (≥ grade 2) with the exception of alopecia, caused by previous anticancer therapies.
7. Pregnancy or breast feeding
8. Grade III/IV cardiac problems as defined by the New York Heart Association Criteria
9. Medical history of arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within 6 months prior to the initiation of study treatment
10. Known brain metastasis
11. Known chronic liver disease (i.e. chronic active hepatitis and cirrhosis)
12. Known diagnosis oh human deficiency virus (HIV) infection
13. Active or chronic hepatitis B or C requiring treatment with antiviral therapy
14. Medical history of hemorrhage or a bleeding event ≥ Grade 3 within 4 weeks prior to the initiation of study treatment
15. Evidence of any other serious or unstable illness, or medical, psychological, or social condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject's participation in the study or evaluation of the study results
16. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
17. Expected non-compliance to medical regimens

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trabectedin; Trabectedin: 1.5 mg/m² - 1.3 mg/m² (at investigator's discretion, with a top-dose of 2.6 total mg per cycle), given in 24-hour continuous infusion	Drug: Trabectedin; Treatment with trabectedin: 1.5 mg/m² - 1.3 mg/m² (at investigator's discretion, with a top-dose of 2.6 total mg per cycle), given in 24-hour continuous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall tumour Response Rate, according to RECIST v 1.	Response rate according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1	At weeks 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Choi criteria response rate	Response rate according Choi criteria	At weeks 6, 12,18, 30, 42
Overall Survival	Proportion of patients who are still alive at 36 and 60 months after have started the treatment	At 3 and 5 years
Progression Free Survival (PFS)	Survival without disease progression	At 3 and 5 years
Clinical Benefit Rate	Proportion of patient alive, without disease progression, after 6 months of treatment.	Month 6
Duration of response	Duration of time between the date of first documented response and the date of first documented progression or death due to any cause	At weeks 6, 12,18, 30, 42
Adverse events related to the treatment	Safety in term of grading 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 24, week 36, week 48, week 60, week 72

Collaborators and Investigators

• Sponsor: Italian Sarcoma Group
• Collaborators: PharmaMar
• Investigators: Principal Investigator: Silvia Stacchiotti, MD, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

Publications and helpful links

General Publications

• Lee AF, Hayes MM, Lebrun D, Espinosa I, Nielsen GP, Rosenberg AE, Lee CH. FLI-1 distinguishes Ewing sarcoma from small cell osteosarcoma and mesenchymal chondrosarcoma. Appl Immunohistochem Mol Morphol. 2011 May;19(3):233-8. doi: 10.1097/PAI.0b013e3181fd6697.
• Wang L, Motoi T, Khanin R, Olshen A, Mertens F, Bridge J, Dal Cin P, Antonescu CR, Singer S, Hameed M, Bovee JV, Hogendoorn PC, Socci N, Ladanyi M. Identification of a novel, recurrent HEY1-NCOA2 fusion in mesenchymal chondrosarcoma based on a genome-wide screen of exon-level expression data. Genes Chromosomes Cancer. 2012 Feb;51(2):127-39. doi: 10.1002/gcc.20937. Epub 2011 Oct 27.
• Morioka H, Takahashi S, Araki N, Sugiura H, Ueda T, Takahashi M, Yonemoto T, Hiraga H, Hiruma T, Kunisada T, Matsumine A, Susa M, Nakayama R, Nishimoto K, Kikuta K, Horiuchi K, Kawai A. Results of sub-analysis of a phase 2 study on trabectedin treatment for extraskeletal myxoid chondrosarcoma and mesenchymal chondrosarcoma. BMC Cancer. 2016 Jul 14;16:479. doi: 10.1186/s12885-016-2511-y.
• Forni C, Minuzzo M, Virdis E, Tamborini E, Simone M, Tavecchio M, Erba E, Grosso F, Gronchi A, Aman P, Casali P, D'Incalci M, Pilotti S, Mantovani R. Trabectedin (ET-743) promotes differentiation in myxoid liposarcoma tumors. Mol Cancer Ther. 2009 Feb;8(2):449-57. doi: 10.1158/1535-7163.MCT-08-0848. Epub 2009 Feb 3.
• Huvos AG, Rosen G, Dabska M, Marcove RC. Mesenchymal chondrosarcoma. A clinicopathologic analysis of 35 patients with emphasis on treatment. Cancer. 1983 Apr 1;51(7):1230-7. doi: 10.1002/1097-0142(19830401)51:73.0.co;2-q.

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2021
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: March 9, 2020
• First Submitted That Met QC Criteria: March 11, 2020
• First Posted (Actual): March 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

• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Connective Tissue; Sarcoma; Chondrosarcoma; Chondrosarcoma, Mesenchymal; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Trabectedin
• Other Study ID Numbers: ISG-MCS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No