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

Phase 1

Completed

Conditions: Soft-tissue Sarcomas

Registration Number: NCT02805725

Lead Sponsor: Institut Bergonié

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).

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 50

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:
1. 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
2. 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
3. Total bilirubin < or = ULN.
4. Albumin ≥ 25 g/l
5. Serum Creatinine < or =1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft formula).
6. 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Phase I: Maximum Tolerated Dose (MTD) of Trabectedin When Administered in Association With CP.	During the first cycle (28 days)	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.
Phase I: Number of Patients Who Experienced Dose-Limiting Toxicities (DLTs)	During the first cycle (28 days)	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.
Phase II: Percentage of Patients in Non-progression at 6 Months (RECIST V1.1)	Phase II : 6 months after the start of treatment	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).

Secondary Outcome Measures

Name	Time	Method
Phase II: Median Overall Survival	From start of treatment, and during treatment until death for any cause for up to 12 months.	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.
Phase I: Percentage of Patients With Objective Response (RECIST V1.1)	Throughout the treatment period, an average of 6 months	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).
Phase II: Median Profression-free Survival	From start of treatment, and during treatment until progression or death for any cause for up to 12 months.	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.