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

NCT02805725 | Completed Phase 1 Results DMC

• 1 other identifier: IB 2015-04
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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).

Conditions

Soft-tissue Sarcomas

Keywords

Advanced solid tumor; Advanced pretreated soft tissue sarcomas; Phase I/II trial; Dose escalation; PK study

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (3)

• Phase I: Percentage of Patients With Objective Response (RECIST V1.1)

  Throughout the treatment period, an average of 6 months

• Phase II: Median Overall Survival

  From start of treatment, and during treatment until death for any cause for up to 12 months.

• 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.

Study Arms (5)

Cohort 1: Trabectedin 0.30 mg/m2 IV + CP

EXPERIMENTAL

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; Drug: Phase 1: Cyclophosphamide

Cohort 2: Trabectedin 0.40 mg/m2 IV + CP

EXPERIMENTAL

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; Drug: Phase 1: Cyclophosphamide

Cohort 3: Trabectedin 0.50 mg/m2 IV + CP

EXPERIMENTAL

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; Drug: Phase 1: Cyclophosphamide

Cohort 4: Trabectedin 0.60 mg/m2 IV + CP

EXPERIMENTAL

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; Drug: Phase 1: Cyclophosphamide

Phase II: Trabectedin 0.50 mg/m2 IV + CP

EXPERIMENTAL

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; Drug: Phase 2: Cyclophosphamide

Interventions

Phase 2: Cyclophosphamide DRUG

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

Phase II: Trabectedin 0.50 mg/m2 IV + CP

Phase 1: Trabectedin DRUG

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.)

Cohort 1: Trabectedin 0.30 mg/m2 IV + CP; Cohort 2: Trabectedin 0.40 mg/m2 IV + CP; Cohort 3: Trabectedin 0.50 mg/m2 IV + CP; Cohort 4: Trabectedin 0.60 mg/m2 IV + CP

Phase 2: Trabectedin DRUG

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.

Phase II: Trabectedin 0.50 mg/m2 IV + CP

Phase 1: Cyclophosphamide DRUG

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.

Cohort 1: Trabectedin 0.30 mg/m2 IV + CP; Cohort 2: Trabectedin 0.40 mg/m2 IV + CP; Cohort 3: Trabectedin 0.50 mg/m2 IV + CP; Cohort 4: Trabectedin 0.60 mg/m2 IV + CP

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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,
• 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).

You may not qualify if:

• 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,

Sponsors & Collaborators

• Institut Bergonié: lead
• PharmaMar: collaborator

Study Sites (1)

Institut Bergonié

Bordeaux, 33076, France

Location

MeSH Terms

Conditions

Sarcoma

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Results Point of Contact

• Title: Pr Antoine Italiano
• Organization: Institut Bergonie

a.italiano@bordeaux.unicancer.fr

+ 33 5 47 30 60 88

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 25, 2016
• First Posted: June 20, 2016
• Study Start: December 1, 2015
• Primary Completion: April 1, 2020
• Study Completion: December 1, 2021
• Last Updated: January 14, 2026
• Results First Posted: March 23, 2023

Record last verified: 2026-01

Locations

FR (1)