Clinical Trials /

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

NCT03085225

Description:

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

Related Conditions:
  • Ovarian Carcinoma
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: IB2016-02
  • NCT ID: NCT03085225

Conditions

  • Ovarian Carcinoma
  • Soft Tissue Sarcoma

Interventions

DrugSynonymsArms
Combination of trabectedin with durvalumabCombination of trabectedin with durvalumab

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Combination of trabectedin with durvalumabExperimentalTrabectedin 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.
  • Combination of trabectedin with durvalumab

Eligibility Criteria

        Inclusion Criteria:

          1. 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),

          2. or ovarian carcinoma without known g/s BRCA mutation and:

               -  platinum sensitive ovarian carcinoma relapses (> 12 months) non suitable for
                  platinum rechallenging treatment,

               -  or intermediate platinum sensitive ovarian carcinoma relapses (6-12 months).

          3. Metastatic or unresectable locally advanced disease,

          4. Age ≥ 18 years,

          5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1,

          6. Life expectancy > 3 months,

          7. 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.

          8. Documented disease progression according to RECIST v1.1 before study entry,

          9. Patient must comply with the collection of tumor biopsies,

         10. At least 1 line of chemotherapy in the palliative setting with use of Anthracyclines
             (for STS), or platinum containing regimen (for ovarian carcinoma),

         11. At least three weeks since last chemotherapy, immunotherapy or any other
             pharmacological treatment and/or radiotherapy,

         12. 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
                  109/l, and platelet count ≥ 100 x 109/l.

               2. 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.

               3. Total bilirubin ≤ ULN.

               4. Albumin ≥ 25 g/l.

               5. Calculated creatinine clearance (CrCl) > 40 ml/min (according to Cockroft Gault
                  formula).

               6. Thyroid function within normal laboratory ranges (TSH, free T3, free T4).

         13. 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. Acceptable methods of
             contraception are described in protocol section 7.6.1.1,

         14. 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,

         15. 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),

         16. Voluntarily signed and dated written informed consent prior to any study specific
             procedure,

         17. Patients with a social security in compliance with the French law relating to
             biomedical research (Article 1121-11 of French Public Health Code).

        Exclusion Criteria:

          1. Previous treatment with Trabectedin or an anti-PD-1, anti-PD-L1, anti-PD-L2, including
             durvalumab

          2. 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

          3. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis),

          4. 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,

          5. Has evidence of active non-infectious pneumonitis,

          6. Has an active infection requiring systemic therapy,

          7. Currently active bacterial or fungus infection (> grade 2 CTC [CTCAE] HIV1, HIV2,
             hepatitis A or hepatitis B or hepatitis C infections,

          8. Known central nervous system malignancy (CNS),

          9. 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,

         10. Previous enrolment in the present study,

         11. Patient unable to follow and comply with the study procedures because of any
             geographical, social or psychological reasons,

         12. 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.

         13. Known hypersensitivity to any involved study drug or any of its formulation
             components,

         14. Tumors not accessible for biopsy,

         15. Known history of active tuberculosis
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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

Secondary Outcome Measures

Measure:Recommended phase II dose (RP2D) of the association of Trabectedin and given in combination with Durvalumab
Time Frame:Throughout the treatment period, on average of 6 months
Safety Issue:
Description:
Measure:Dose Limiting Toxicities (DLT) of Trabectedin given in combination with Durvalumab
Time Frame:During the first cycle (21 days)]
Safety Issue:
Description:
Measure:Toxicity graded using the common toxicity criteria from the NCI v4.0
Time Frame:Throughout the treatment period, on average of 6 months
Safety Issue:
Description:
Measure: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
Time Frame:Throughout the treatment period, an average of 6 months
Safety Issue:
Description:
Measure: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
Time Frame:6 months
Safety Issue:
Description:
Measure: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
Time Frame:Throughout the treatment period, an average of 6 months
Safety Issue:
Description:
Measure: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
Time Frame:6-months
Safety Issue:
Description:
Measure: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
Time Frame:1 year
Safety Issue:
Description:
Measure: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
Time Frame:1-year
Safety Issue:
Description:
Measure:Predictive biomarkers analysis (blood cytokines levels
Time Frame:Day 1
Safety Issue:
Description:
Measure:Predictive biomarkers analysis (blood cytokines levels)
Time Frame:Day 21
Safety Issue:
Description:
Measure:Predictive biomarkers analysis (circulating immune cells levels)
Time Frame:Day 1
Safety Issue:
Description:
Measure:Predictive biomarkers analysis (circulating immune cells levels)
Time Frame:Day 21
Safety Issue:
Description:
Measure:Number of participants with circulating DNA available (Identification and monitoring of mutations observed at the level of the circulating tumor cells (liquid biopsies concept).
Time Frame:Day 1 of each cycle (Each cycle is 21 days)]
Safety Issue:
Description:
Measure:Number of participants with exploratory biomarkers available (Markers analyzed for Hematoxylin and eosin staining (H&E) on tumor samples)
Time Frame:Baseline
Safety Issue:
Description:
Measure:Number of participants with exploratory biomarkers available (Markers analyzed for Hematoxylin and eosin staining (H&E) on tumor samples).,
Time Frame:cycle 2 Day 8
Safety Issue:
Description:
Measure:Number of participants with exploratory biomarkers available (Markers analyzed for Immunohistochemistry (IHC) on tumor samples)
Time Frame:Baseline
Safety Issue:
Description:
Measure:Number of participants with exploratory biomarkers available (Markers analyzed for Immunohistochemistry (IHC) on tumor samples.).
Time Frame:cycle 2 Day 8
Safety Issue:
Description:
Measure:Exploratory analysis of predictive signature in responders (genomics and transcriptomics analysis).
Time Frame:Baseline
Safety Issue:
Description:Identification of predictive signature in responders by sequencing tumor sample
Measure:Exploratory analysis of predictive signature in responders (genomics and transcriptomics analysis).
Time Frame:cycle 2 Day 8
Safety Issue:
Description:Identification of predictive signature in responders by sequencing tumor sample
Measure:Exploration of mechanisms of resistance in non-responders (genomics and transcriptomics analysis)
Time Frame:Baseline
Safety Issue:
Description:Identification of predictive signature in responders by sequencing tumor sample
Measure:Exploration of mechanisms of resistance in non-responders (genomics and transcriptomics analysis).
Time Frame:cycle 2 Day 8
Safety Issue:
Description:Identification of predictive signature in responders by sequencing tumor sample

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Institut Bergonié

Trial Keywords

  • Advanced tumor
  • Pretreated tumor
  • Soft Tissue Sarcomas
  • Ovarian Carcinomas
  • Phase Ib
  • Circulating DNA

Last Updated