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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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.

Conditions
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Soft-tissue Sarcomas

Intervention / Treatment
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* Drug: Phase 1: Trabectedin
* Drug: Phase 2: Trabectedin
* Drug: Phase 1: Cyclophosphamide
* Drug: Phase 2: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Trabectedin 0.30 mg/m2 IV + CP<br>Trabectedin 0.30 mg/m2 will be administered intravenously (IV), 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks, in cohort 1 of dose escalation. Cyclophosphamide (CP) will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule. 1 cycle = 28 days | Drug: Phase 1: Trabectedin<br>* Phase I trial based on a dose escalating study design (3+3 traditional design) assessing four dose levels of Trabectedin in combination with metronomic cyclophosphamide (CP). 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.)<br>Drug: Phase 1: Cyclophosphamide<br>* 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.<br>|
| Experimental: Cohort 2: Trabectedin 0.40 mg/m2 IV + CP<br>Trabectedin 0.40 mg/m2 will be administered intravenously (IV), 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks, in cohort 2 of dose escalation. Cyclophosphamide (CP) will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule. 1 cycle = 28 days | Drug: Phase 1: Trabectedin<br>* Phase I trial based on a dose escalating study design (3+3 traditional design) assessing four dose levels of Trabectedin in combination with metronomic cyclophosphamide (CP). 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.)<br>Drug: Phase 1: Cyclophosphamide<br>* 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.<br>|
| Experimental: Cohort 3: Trabectedin 0.50 mg/m2 IV + CP<br>Trabectedin 0.50 mg/m2 will be administered intravenously (IV), 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks, in cohort 3 of dose escalation. Cyclophosphamide (CP) will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule. 1 cycle = 28 days | Drug: Phase 1: Trabectedin<br>* Phase I trial based on a dose escalating study design (3+3 traditional design) assessing four dose levels of Trabectedin in combination with metronomic cyclophosphamide (CP). 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.)<br>Drug: Phase 1: Cyclophosphamide<br>* 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.<br>|
| Experimental: Cohort 4: Trabectedin 0.60 mg/m2 IV + CP<br>Trabectedin 0.60 mg/m2 will be administered intravenously (IV), 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks, in cohort 4 of dose escalation. Cyclophosphamide (CP) will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule. 1 cycle = 28 days | Drug: Phase 1: Trabectedin<br>* Phase I trial based on a dose escalating study design (3+3 traditional design) assessing four dose levels of Trabectedin in combination with metronomic cyclophosphamide (CP). 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.)<br>Drug: Phase 1: Cyclophosphamide<br>* 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.<br>|
| Experimental: Phase II: Trabectedin 0.50 mg/m2 IV + CP<br>Trabectedin 0.50 mg/m2 will be administered intravenously (IV), 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks, in the phase II part of the study. Cyclophosphamide (CP) will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule. 1 cycle = 28 days | Drug: Phase 2: Trabectedin<br>* Patients will be included in a single-arm phase II trial. Administrated dose will be the RP2D defined in the dose escalation part of the trial. The design will follow a two-stage Simon's optimal design. 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.<br>Drug: Phase 2: Cyclophosphamide<br>* All patients will be treated with metronomic cyclophosphamide with the same schedule as in the phase I trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Tolerated Dose (MTD) of Trabectedin When Administered in Association With CP. | MTD was determined by testing increasing doses of trabectedin up to 0.60 mg/m2 via IV on dose escalation cohorts 1 to 4 with 3 to 6 participants each.The MTD is defined as the highest dose at which no more than 1 in 6 of the patients in the cohort experienced a DLT in the first treatment cycle. See subsequent primary outcome measure for the DLT definition. | During the first cycle (28 days) | 
| Phase I: Number of Patients Who Experienced Dose-Limiting Toxicities (DLTs) | A DLT was defined as a treatment-related (at least possibly related) adverse event using the CTCAE V4.0, occuring during the fist cycle of treatment (28 days), that meets one of the following criteria: Any grade-4 toxicity (except for vomiting without maximal symptomatic/prophylactic treatment) Grade-3 non-haematological toxicity lasting > 7days (except for 1rst episode of nausea without maximal symptomatic/ prophylactic treatment and if toxicity is transaminitis, which may last > 7 days if total bilirubin is normal or grade-1) Grade-3 hematologic toxicity lasting for > 7days Grade 4 neutropenia with fever Grade > 2 thrombocytopenia with bleeding Is unrelated to disease, disease progression, inter-current illness, or concomitant medications. | During the first cycle (28 days) | 
| Phase II: Percentage of Patients in Non-progression at 6 Months (RECIST V1.1) | Non-progression is defined as complete or partial response (CR, PR) or stable disease (SD), as per RECIST v1.1. According to RECIST v1.1: Complete Response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as a >=30% decrease in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at baseline (SSD); Stable disease (SD) is defined as Neither sufficient shrinkage (compared to baseline) to qualify for PR or CR nor sufficient increase (taking as reference the SSD or while on study, whichever is smallest) to qualify for progressive disease (PD). | Phase II : 6 months after the start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Percentage of Patients With Objective Response (RECIST V1.1) | Objective response is defined as complete or partial response (CR, PR) as per RECIST v1.1. According to RECIST v1.1: Complete Response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as a >=30% decrease in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at baseline (SSD). | Throughout the treatment period, an average of 6 months | 
| Phase II: Median Overall Survival | Overall survival is defined as the time from the study initiation to death (any cause). Median overall survival was reported using kaplan-Meier method for calculation. | From start of treatment, and during treatment until death for any cause for up to 12 months. | 
| Phase II: Median Profression-free Survival | Progression-free survival is defined as the time from study treatment initiation to disease progression or death (of any cause), whichever occurs first. Progression is defined using RECIST v1.1, as a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), or a unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. Median PFS was reported using kaplan-Meier method for calculation. | From start of treatment, and during treatment until progression or death for any cause for up to 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid tumor, Advanced pretreated soft tissue sarcomas, Phase I/II trial, Dose escalation, PK study