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

Primary Purpose

Soft-tissue Sarcomas

Status
Completed
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
Phase 1: Trabectedin
Phase 2: Trabectedin
Phase 1: Cyclophosphamide
Phase 2: Cyclophosphamide
Sponsored by
Institut Bergonié
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Soft-tissue Sarcomas focused on measuring Advanced solid tumor, Advanced pretreated soft tissue sarcomas, Phase I/II trial, Dose escalation, PK study

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients with soft-tissue sarcoma histologically confirmed by central review
  2. Metastatic or unresectable locally advanced disease,
  3. Age ≥ 18 years,
  4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2,
  5. Life expectancy > 3 months,
  6. Measurable disease according to RECIST v1.1 outside any previously irradiated field,
  7. 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,
  8. Previous use of Anthracyclines,
  9. Have provided tissue from an archival tissue sample,
  10. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,

  11. 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
  12. 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,
  13. 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,
  14. 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),
  15. Patients with a French social security in compliance with the Law relating to biomedical research (Article 1121-11 of French Public Health Code),
  16. Voluntarily signed and dated written informed consent prior to any study specific procedure.

Exclusion Criteria:

  1. Previous treatment with Trabectedin,
  2. Currently active bacterial or fungus infection (> grade 2 CTC [CTCAE] HIV1, HIV2, hepatitis B or hepatitis C infections,
  3. History of chronic alcohol use and/or cirrhosis,

  4. 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
  5. Patients unable to receive corticotherapy,
  6. Known central nervous system malignancy (CNS),
  7. 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,
  8. Participation to a study involving a medical or therapeutic intervention in the last 30 days,
  9. Previous enrolment in the present study,
  10. Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons,
  11. Known hypersensitivity to any involved study drug or any of its formulation components.
  12. Recent vaccination (in the last 2 weeks before inclusion) for yellow fever.

Sites / Locations

  • Institut Bergonié

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

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 II: Trabectedin 0.50 mg/m2 IV + CP

Arm Description

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

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

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

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

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

Outcomes

Primary Outcome Measures

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.
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.
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).

Secondary Outcome Measures

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).
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.
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.

Full Information

First Posted
May 25, 2016
Last Updated
June 13, 2022
Sponsor
Institut Bergonié
Collaborators
PharmaMar
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1. Study Identification

Unique Protocol Identification Number
NCT02805725
Brief Title
Targeting Microenvironment and Cellular Immunity in Sarcomas Weekly Trabectedin Combined With Metronomic Cyclophosphamide
Acronym
TARMIC
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.
Study Type
Interventional

2. Study Status

Record Verification Date
June 2022
Overall Recruitment Status
Completed
Study Start Date
December 2015 (Actual)
Primary Completion Date
April 2020 (Actual)
Study Completion Date
December 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institut Bergonié
Collaborators
PharmaMar

4. Oversight

Data Monitoring Committee
Yes

5. 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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Soft-tissue Sarcomas
Keywords
Advanced solid tumor, Advanced pretreated soft tissue sarcomas, Phase I/II trial, Dose escalation, PK study

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1: Trabectedin 0.30 mg/m2 IV + CP
Arm Type
Experimental
Arm Description
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
Arm Title
Cohort 2: Trabectedin 0.40 mg/m2 IV + CP
Arm Type
Experimental
Arm Description
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
Arm Title
Cohort 3: Trabectedin 0.50 mg/m2 IV + CP
Arm Type
Experimental
Arm Description
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
Arm Title
Cohort 4: Trabectedin 0.60 mg/m2 IV + CP
Arm Type
Experimental
Arm Description
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
Arm Title
Phase II: Trabectedin 0.50 mg/m2 IV + CP
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Phase 1: Trabectedin
Intervention Description
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.)
Intervention Type
Drug
Intervention Name(s)
Phase 2: Trabectedin
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Phase 1: Cyclophosphamide
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Phase 2: Cyclophosphamide
Intervention Description
All patients will be treated with metronomic cyclophosphamide with the same schedule as in the phase I trial.
Primary Outcome Measure Information:
Title
Phase I: Maximum Tolerated Dose (MTD) of Trabectedin When Administered in Association With CP.
Description
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.
Time Frame
During the first cycle (28 days)
Title
Phase I: Number of Patients Who Experienced Dose-Limiting Toxicities (DLTs)
Description
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.
Time Frame
During the first cycle (28 days)
Title
Phase II: Percentage of Patients in Non-progression at 6 Months (RECIST V1.1)
Description
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).
Time Frame
Phase II : 6 months after the start of treatment
Secondary Outcome Measure Information:
Title
Phase I: Percentage of Patients With Objective Response (RECIST V1.1)
Description
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).
Time Frame
Throughout the treatment period, an average of 6 months
Title
Phase II: Median Overall Survival
Description
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.
Time Frame
From start of treatment, and during treatment until death for any cause for up to 12 months.
Title
Phase II: Median Profression-free Survival
Description
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.
Time Frame
From start of treatment, and during treatment until progression or death for any cause for up to 12 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
Institut Bergonié
City
Bordeaux
ZIP/Postal Code
33076
Country
France

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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

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