TARMIC: Targeting Microenvironment and Cellular Immunity in Sarcomas Weekly Trabectedin Combined With Metronomic Cyclophosphamide

Sponsor

Institut Bergonié (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02805725

Collaborator

PharmaMar (Industry)

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Assessment of the efficacy and safety of trabectedin and metronomic cyclophosphamide (CP) in patients with advanced pretreated soft-tissue sarcomas, once the Maximum Tolerated Dose (MTD) have been determined (phase I trial).

Condition or Disease	Intervention/Treatment	Phase
Soft-tissue Sarcomas	Drug: Phase 1: Trabectedin Drug: Phase 2: Trabectedin Drug: Phase 1: Cyclophosphamide Drug: Phase 2: Cyclophosphamide	Phase 1/Phase 2

Detailed Description

Phase I: Multicenter Phase I trial based on a dose escalation study design (3+3 traditional design). Phase II: One-arm, multicenter Phase II trial based on two-stage optimal Simon's design.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

71 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Targeting Microenvironment and Cellular Immunity in Sarcomas Weekly Trabectedin Combined With Metronomic Cyclophosphamide (CP) in Patients With Advanced Pretreated Soft-tissue Sarcomas. A Phase I/II Study From the French Sarcoma Group.

Actual Study Start Date :

Dec 1, 2015

Anticipated Primary Completion Date :

Jun 1, 2021

Anticipated Study Completion Date :

Aug 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase 1: Trabectedin + Cyclophosphamide Cyclophosphamide will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule. Trabectedin will be administered intravenously, 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks.	Drug: Phase 1: Trabectedin A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation (withdrawal of consent, intercurrent illness, unacceptable adverse event or any other changes unacceptable for further treatment, etc.) Patients will be allocated 4 doses of Trabectedin following a 3 + 3 design: Drug: Phase 1: Cyclophosphamide A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation (withdrawal of consent, intercurrent illness, unacceptable adverse event or any other changes unacceptable for further treatment, etc.) Cyclophosphamide will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule.
Experimental: Phase 2: Trabectedin + Cyclophosphamide Cyclophosphamide will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule. Trabectedin will be administered intravenously, 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks.	Drug: Phase 2: Trabectedin All patients will be treated at the RP2D of trabectedin defined in the preliminary phase I trial with the same schedule as in the phase I trial. Drug: Phase 2: Cyclophosphamide All patients will be treated with metronomic cyclophosphamide with the same schedule as in the phase I trial.

Arm

Intervention/Treatment

Experimental: Phase 1: Trabectedin + Cyclophosphamide

Cyclophosphamide will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule. Trabectedin will be administered intravenously, 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks.

Drug: Phase 1: Trabectedin

A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation (withdrawal of consent, intercurrent illness, unacceptable adverse event or any other changes unacceptable for further treatment, etc.) Patients will be allocated 4 doses of Trabectedin following a 3 + 3 design:

Drug: Phase 1: Cyclophosphamide

A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation (withdrawal of consent, intercurrent illness, unacceptable adverse event or any other changes unacceptable for further treatment, etc.) Cyclophosphamide will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule.

Experimental: Phase 2: Trabectedin + Cyclophosphamide

Drug: Phase 2: Trabectedin

All patients will be treated at the RP2D of trabectedin defined in the preliminary phase I trial with the same schedule as in the phase I trial.

Drug: Phase 2: Cyclophosphamide

All patients will be treated with metronomic cyclophosphamide with the same schedule as in the phase I trial.

Outcome Measures

Primary Outcome Measures

Phase I: Maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D28) of Trabectedin when administered in association with CP [During the first cycle (28 days)]
Phase II: Assessment of the antitumor activity of the association of Trabectedin and metronomic cyclophosphamide based on 6 month non-progression (CR, PR or SD more than 24 weeks) following RECIST v1.1 criteria [Phase II: 6 months after the beginning of treatment]

Secondary Outcome Measures

Recommended phase II dose (RP2D) of Trabectedin when administered in association with CP [Throughout the treatment period, an average of 6 months]
Dose Limiting Toxicities (DLT) of Trabectedin when administered in association with CP [During the first cycle (28 days)]]
Phase I: Antitumor activity of Trabectedin when administered in association with CP in terms of objective response rate (ORR) as per RECIST V1.1 [Throughout the treatment period, an average of 6 months]
Phase I: Antitumor activity of Trabectedin when administered in association with CP in terms of 6-month Non-progression rate (NPR) as per RECIST 1.1 [6-month Non-progression rate (NPR) as per RECIST]
Phase I: Antitumor activity of Trabectedin when administered in association with CP in terms of 1-year Progression-free survival (PFS) as per RECIST 1.1 [1-year Progression-free survival (PFS)]
Phase I: Antitumor activity of Trabectedin when administered in association with CP in terms of 1-year Overall Survival (OS) [1-year Overall Survival (OS) as per RECIST]
Phase I: PK measurements expressed as Area Under Curve for CP [Day 1 of cycle1, Day 15 of cycle1(Each cycle is 28 days)]]
Phase I: PK measurements expressed as Area Under Curve for Trabectedin [Day 1 of cycle1, Day 15 of cycle1(Each cycle is 28 days)]]
Phase I: PK measurements expressed as half-life for CP [Day 1 of cycle1, Day 15 of cycle1(Each cycle is 28 days)]]
Phase I: PK measurements expressed as half-life for Trabectedin [Day 1 of cycle1, Day 15 of cycle1(Each cycle is 28 days)]
Phase I: PK measurements expressed as concentration peak for CP [Day 1 of cycle1, Day 15 of cycle1(Each cycle is 28 days)]
Phase I: PK measurements expressed as concentration peak for Trabectedin [Day 1 of cycle1, Day 15 of cycle1(Each cycle is 28 days)]
Phase I: Predictive biomarkers analysis (cytokines levels) [Day 1 cycle 1 and Day 1 cycle 2 (Each cycle is 28 days)]
Phase I: Predictive biomarkers analysis (VEGF and TPS-1 levels) [Day 1 cycle 1 and Day 1 cycle 2 (Each cycle is 28 days)]
Phase I: Predictive biomarkers analysis (lymphocytes levels) [Day 1 cycle 1 and Day 1 cycle 2 (Each cycle is 28 days)]
Phase I: Number of participants with exploratory markers available (markers analyzed for Hematoxylin and eosin staining (H&E)) [before treatment initiation and Day 28 cycle 1]
Phase I: Number of participants with exploratory markers available (markers analyzed for Immunohistochemistry (IHC) [before treatment initiation and Day 28 cycle 1]
Phase II: Antitumor activity of Trabectedin when administered in association with CP in terms of objective response rate (ORR) as per RECIST V1.1 [Throughout the treatment period, an average of 6 months]
Phase II: Antitumor activity of Trabectedin when administered in association with CP in terms of 1-year Progression-free survival (PFS) as per RECIST V1.1 [1-year Progression-free survival (PFS) as per RECIST]
Phase II: Antitumor activity of Trabectedin when administered in association with CP in terms of 1-year Overall Survival (OS) [1-year Overall Survival (OS)]
Phase II: Toxicity graded using the common toxicity criteria from the NCI v4.0 [Throughout the treatment period, an average of 6 months]
Phase II (optional): Predictive biomarkers analysis (cytokines levels) [Day 1 cycle 1 and Day 1 cycle 2 (Each cycle is 28 days)]
Phase II (optional): Predictive biomarkers analysis (VEGF and TPS-1 levels) [Day 1 cycle 1 and Day 1 cycle 2 (Each cycle is 28 days)]
Phase II (optional): Predictive biomarkers analysis (lymphocyte levels [Day 1 cycle 1 and Day 1 cycle 2 (Each cycle is 28 days)]
27. Phase II (optional): Number of participants with exploratory markers available (markers analyzed for Hematoxylin and eosin staining (H&E)) [before treatment initiation and Day 28 cycle 1]
28. Phase II (optional): Number of participants with exploratory markers available (markers analyzed for Immunohistochemistry (IHC) [before treatment initiation and Day 28 cycle 1]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with soft-tissue sarcoma histologically confirmed by central review
Metastatic or unresectable locally advanced disease,
Age ≥ 18 years,
Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2,
Life expectancy > 3 months,
Measurable disease according to RECIST v1.1 outside any previously irradiated field,
For patients included in phase II study, progressive disease according to RECIST v1.1 criteria diagnosed on the basis of two CT scan or MRI obtained at an interval less than 6 months in the period of 12 months prior to inclusion and confirmed by central review,
Previous use of Anthracyclines,
Have provided tissue from an archival tissue sample,
At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,
Adequate hematological, renal, metabolic and hepatic function:
Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 10^{9/l, and platelet count ≥ 100 x 10}9/l
Alanine aminotransferase (ALT), aspartate aminotransferase (AST)< or = 2.5 x upper limit of normality (ULN) ( < or = 5 in case of extensive liver involvement) and alkaline phosphatase (AP) < or = 2.5 x ULN
Total bilirubin < or = ULN.
Albumin ≥ 25 g/l
Serum Creatinine < or =1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft formula).
Creatine Phosphokinase (CPK) < or = 2.5 x ULN
Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment. Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier,
No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 4.0),
Patients with a French social security in compliance with the Law relating to biomedical research (Article 1121-11 of French Public Health Code),
Voluntarily signed and dated written informed consent prior to any study specific procedure.

Exclusion Criteria:

Previous treatment with Trabectedin,
Currently active bacterial or fungus infection (> grade 2 CTC [CTCAE] HIV1, HIV2, hepatitis B or hepatitis C infections,
History of chronic alcohol use and/or cirrhosis,
The following unstable cardiac conditions are not allowed:

Congestive heart failure
Angina pectoris
Myocardial infarction within 1 year before registration
Uncontrolled arterial hypertension defined as blood pressure ≥ 150/100 mmHg despite optimal medical therapy
Arrhythmias clinically significant

Patients unable to receive corticotherapy,
Known central nervous system malignancy (CNS),
Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding,
Participation to a study involving a medical or therapeutic intervention in the last 30 days,
Previous enrolment in the present study,
Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
Known hypersensitivity to any involved study drug or any of its formulation components.
Recent vaccination (in the last 2 weeks before inclusion) for yellow fever.