Adult patients with unresectable locally advanced or metastatic soft-tissue sarcoma. MedDRA version: 18.0 Level: LLT Classification code 10039494 Term: Sarcoma NOS System Organ Class: 100000004864
Conditions
Interventions
Trade Name: ENDOXAN
Pharmaceutical Form: Coated tablet
INN or Proposed INN: CYCLOPHOSPHAMIDE
CAS Number: 50-18-0
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Sponsors
INSTITUT BERGONIE
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patients with soft-tissue sarcoma histologically confirmed by central review (Pr. Coindre team), except in case of diagnosis was already confirmed by the RRePS Network, 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: a. Hemoglobin = 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) = 1.5 x 109/l, and platelet count = 100 x 109/l b. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) = 2.5 x upper limit of normality (ULN) (= 5 in case of extensive liver involvement) and alkaline phosphatase (AP) = 2.5 x ULN c. Total bilirubin = ULN. d. Albumin = 25 g/l e. Serum Creatinine = 1.5 x ULN or calculated creatinine clearance (CrCl) = 30 ml/min (according to Cockroft formula). f. Creatine Phosphokinase (CPK) = 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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 60 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 11
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I: To establish the recommended phase II dose (RP2D), the maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D28), the safety profile, and the dose limiting toxicities (DLT) of trabectedin given in combination with cyclophosphamide (CP). Phase II: To evaluate the antitumor activity of trabectedin in association with CP in terms of non-progression at 6 months (complete or partial responses or stable disease more than 24 weeks, as per RECIST v1.1 criteria) after centralized radiological review, in patients with advanced STS who already failed anthracycline-containing chemotherapy (CT).;Secondary Objective: Phase I: · To evaluate preliminary signs of antitumor activity of trabectedin given in combination with CP in terms of objective response under treatment (as per RECIST v1.1 criteria), 6-month non-progression, 1-year progression-free survival (PFS) and 1-year overall survival (OS). · To describe the pharmacokinetics (PK) of trabectedin given in combination with CP. · Biomarker study: To perform pharmacodynamic (PD)/mechanism of action (MOA) biomarkers analysis as well as predictive biomarkers analysis (levels of angiogenic and immunologic biomarkers in blood at baseline and different study time points). Phase II: · To evaluate the antitumor activity of trabectedin in association with CP in terms of objective response under treatment (as per RECIST v1.1 criteria), 1- year progression free survival (PFS) and 1-year overall survival (OS). · To evaluate the toxicity of trabectedin in association with CP (NCI-CTC v4).;Primary end point(s): Phase I trial: · Toxicity graded using the common toxicity criteria from the NCI v4.0 · Incidence rate of DLT at each dose level on cycle 1 Phase II trial: · 6-month non-progression as defined above for the phase I escalation study;Timepoint(s) of evaluation of this end point: Phase I trial: - Toxicity is assessed as long as patient is under treatment - Incidence rate of DLT is assessed during th | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase I trial: · 6-month non-progression defined as CR, PR or stable disease more than 24 weeks according to RECIST v1.1 criteria. · 1-year Overall Survival (OS) defined as the time from study treatment initiation to death (of any cause). · 1-year Progression-Free Survival (PFS) defined as the time from study treatment initiation to disease progression (defined as per RECIST v1.1) or death (of any cause), whichever occurs first. · PK measurements expressed as the AUC, the half-life of trabectedin, CP and concentration peak. · Pharmacodynamic study: Blood: Serum/plasma cytokines levels (INF?, TNFa, IL2,4,6,10) by ELISA ; Serum/plasma VEGF and TPS-1 levels by ELISA, monocytes, Treg, CD4+, CD8+ and DR lymphocytes subpopulations monitoring, CD4+/CD8+ ratio (Flow Cytometry), Tumor: Fresh pre-treatment and on-treatment tumor biopsies will be collected to assess pharmacodynamics changes of TAM infiltration and additional tumor markers. Frozen biopsy samples will be analyzed for: - Hematoxylin and eosin staining (H&E). - Immunohistochemistry (IHC) assessments include, but are not limited to the following markers: CSF-1R, CD68/CD163, CD68/MHC class II, CD31 (microvessel density), Ki67 and other exploratory markers. The analysis will be prioritized based on the amount of material available. Phase II trial: Toxicity, objective response under treatment, 1-year OS and 1-year PFS defined above for the phase I escalation study except for the PD study which is optional in this phase II trial.;Timepoint(s) of evaluation of this end point: Phase I trial: -Objective response under treatment: from treatment initiation until the end of treatment -6-months non-progression: 6 months after the beginning of treatment -1-year OS and 1-year PFS: 1 year after treatment initiation -AUC, half-life of trabectedine, CP and trabectedine concentration peak: from samples collected on Days 1 and 15 of cycle 1 -Blood samples markers levels (pharmacodynamics st | — |
Countries
France
Contacts
Public ContactPauline BEAUFRERE
INSTITUT BERGONIE
Outcome results
None listed