Trabectedin Combined With Durvalumab in Patients With Advanced Pretreated Soft-tissue Sarcomas and Ovarian Carcinomas.

Study Overview
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Brief Summary
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A phase Ib trial study of trabectedin when prescribed in combination with durvalumab in locally advanced/unresectable soft-tissue sarcoma and ovarian carcinomas.

Detailed Description
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This is a multicenter, prospective phase Ib trial based on a dose escalation study design (3+3 traditional design) assessing three dose levels of Trabectedin given with durvalumab, followed by two expansion cohorts once the MTD is established.

Official Title
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Trabectedin Combined With Durvalumab (MEDI4736) in Patients With Advanced Pretreated Soft-tissue Sarcomas and Ovarian Carcinomas. A Phase Ib Study.

Conditions
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Ovarian Carcinoma, Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Combination of trabectedin with durvalumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histology : Soft-tissue sarcoma histologically confirmed. In care outside a center of the RRePS Network, a central review is necessary (Pr. Coindre team), histologically confirmed ovarian carcinoma (carcinosarcoma included), or ovarian carcinoma without known g/s BRCA mutation Ovarian carcinoma must have received at least one line of platinum-containing regimen Metastatic or unresectable locally advanced disease, not amenable to curative therapy Age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1, Life expectancy > 3 months, Patients must have measurable disease (lesion in previously irradiated filed can be considered as measurable if progressive at inclusion according to RECIST 1.1) defined as per RECIST v1.1 with at least one lesion that can be measured in at least one dimension (longest diameter to be recorded) as > 10 mm with spiral CT scan. Documented disease progression according to RECIST v1.1 before study entry, Patient must comply with the collection of tumor biopsies, At least 1 line of chemotherapy in the palliative setting with use of Anthracyclines (for STS), 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 109/l, and platelet count ≥ 100 x 109/l. 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. Total bilirubin ≤ ULN. Albumin ≥ 25 g/l. Calculated creatinine clearance (CrCl) > 60 ml/min (according to Cockroft Gault formula). Thyroid function within normal laboratory ranges (TSH, free T3, free T4). Creatine Phosphokinase (CPK) ≤ 2.5 x ULN Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of trial medication. Both women and men must agree to use a highly effective method of contraception throughout the treatment period and for six months after discontinuation of treatment. 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), Voluntarily signed and dated written informed consent prior to any study specific procedure, Patients with a social security in compliance with the French law . Exclusion Criteria: Previous treatment with Trabectedin or an anti-PD-1, anti-PD-L1, anti-PD-L2, including durvalumab Current or prior use of immunosuppressive medication medication including any use of oral glucocorticoids, within 21 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis), Has an active autoimmune disease requiring systemic treatment within the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insuddiciency) is not considered a form of systemic treatment, Has evidence of active non-infectious pneumonitis, Has an active infection requiring systemic therapy, Currently active bacterial or fungus infection (> grade 2 CTC [CTCAE] HIV1, HIV2, hepatitis A or hepatitis B or hepatitis C infections, 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, Previous enrolment in the present study, Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons, Has received a live vaccine within 30 days prior to the first dose of trial treatment. Note: the killed virus vaccines used for seasonal influenza vaccines for injection are allowed; however intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. Known hypersensitivity to any involved study drug or any of its formulation components, Tumors not accessible for biopsy, Known history of active tuberculosis Person under judicial protection or deprived of liberty, Cardiac dysfunction: LVEF < 40% at Baseline or clinically symptomatic cardiac dysfunction (any % of LVEF at Baseline) Concomitant use of strong inhibitor or inductors of cytochrome CYP3A4 taken within 21 days prior to the first dose of study drug

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
Intervention Model: Single Group Assignment
Interventional Model Description: This is a multicenter, prospective open-labeled phase Ib trial based on a dose escalation study design (3+3 traditional design) assessing three dose levels of trabectedin when prescribed in combination with durvalumab followed by two expansion cohorts (Soft-tissue sarcomas and ovarian carcinomas) once the MTD is established
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination of trabectedin with durvalumab<br>Trabectedin will be administered intraveinously, on day 1 of each cycle, every three weeks, as appropriate for assigned dose level. Durvalumab will be administered intraveinously, at fixed doses of 1120 mg (equivalent to 15 mg/kg), on day 2 of each cycle, every three weeks. | Drug: Combination of trabectedin with durvalumab<br>* Dose Escalation : 3 doses of trabectedin given in combination with durvalumab (fixed dose) will be investigated. A treatment cycle consists of 3 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.). Expansion cohorts: Once the Maximum Tolerated Dose (MTD) has been defined, the expansion cohorts will be opened. All patients will be treated at the MTD of Trabectedin (as defined in the dose escalation part of the trial) given in association with Durvalumab with the same schedule as in the dose escalation part of the trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D21) of Trabectedin when administered in association with Durvalumab |  | During the first cycle (21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended phase II dose (RP2D) of the association of Trabectedin and given in combination with Durvalumab |  | Throughout the treatment period, on average of 6 months | 
| Dose Limiting Toxicities (DLT) of Trabectedin given in combination with Durvalumab |  | During the first cycle (21 days)] | 
| Toxicity graded using the common toxicity criteria from the NCI v4.0 |  | Throughout the treatment period, on average of 6 months | 
| Preliminary signs of antitumor activity of Trabectedin given in combination with Durvalumab in terms of objective response (OR) under treatment defined as CR or PR as per RECIST 1.1 |  | Throughout the treatment period, an average of 6 months | 
| Preliminary signs of antitumor activity of Trabectedin given in combination with Durvalumab in terms of objective response (OR) at 6 months defined as CR or PR as per RECIST 1.1 |  | 6 months | 
| Preliminary signs of antitumor activity of Trabectedin given in combination with Durvalumab in terms of best overall response under treatment as per RECIST 1.1 |  | Throughout the treatment period, an average of 6 months | 
| Preliminary signs of antitumor activity of Trabectedin given in combination with Durvalumab in terms of 6-month non-progression (NP) defined as CR, PR, and SD as per RECIST 1.1 |  | 6-months | 
| Preliminary signs of antitumor activity of Trabectedin given in combination with Durvalumab in terms of 1-year progression-free survival (PFS) as per RECIST 1.1 |  | 1 year | 
| Preliminary signs of antitumor activity of Trabectedin given in combination with Durvalumab in terms of 1-year Overall Survival (OS) as per RECIST 1.1 |  | 1-year | 
| Predictive biomarkers analysis (blood cytokines levels |  | Day 1 | 
| Predictive biomarkers analysis (blood cytokines levels) |  | Day 21 | 
| Predictive biomarkers analysis (circulating immune cells levels) |  | Day 1 | 
| Predictive biomarkers analysis (circulating immune cells levels) |  | Day 21 | 
| Number of participants with circulating DNA available (Identification and monitoring of mutations observed at the level of the circulating tumor cells (liquid biopsies concept). |  | Day 1 of each cycle (Each cycle is 21 days)] | 
| Number of participants with exploratory biomarkers available (Markers analyzed for Hematoxylin and eosin staining (H&E) on tumor samples) |  | Baseline | 
| Number of participants with exploratory biomarkers available (Markers analyzed for Hematoxylin and eosin staining (H&E) on tumor samples)., |  | cycle 2 Day 8 | 
| Number of participants with exploratory biomarkers available (Markers analyzed for Immunohistochemistry (IHC) on tumor samples) |  | Baseline | 
| Number of participants with exploratory biomarkers available (Markers analyzed for Immunohistochemistry (IHC) on tumor samples.). |  | cycle 2 Day 8 | 
| Exploratory analysis of predictive signature in responders (genomics and transcriptomics analysis). | Identification of predictive signature in responders by sequencing tumor sample | Baseline | 
| Exploratory analysis of predictive signature in responders (genomics and transcriptomics analysis). | Identification of predictive signature in responders by sequencing tumor sample | cycle 2 Day 8 | 
| Exploration of mechanisms of resistance in non-responders (genomics and transcriptomics analysis) | Identification of predictive signature in responders by sequencing tumor sample | Baseline | 
| Exploration of mechanisms of resistance in non-responders (genomics and transcriptomics analysis). | Identification of predictive signature in responders by sequencing tumor sample | cycle 2 Day 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced tumor, Pretreated tumor, Soft Tissue Sarcomas, Ovarian Carcinomas, Phase Ib, Circulating DNA