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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03085225
Recruitment Status : Active, not recruiting
First Posted : March 21, 2017
Last Update Posted : February 6, 2020
Sponsor:
Collaborators:
AstraZeneca
PharmaMar
Information provided by (Responsible Party):
Institut Bergonié

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

Condition or disease Intervention/treatment Phase
Ovarian Carcinoma Soft Tissue Sarcoma Drug: Combination of trabectedin with durvalumab Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention 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)
Masking Description: Open Label
Primary Purpose: Treatment
Official Title: Trabectedin Combined With Durvalumab (MEDI4736) in Patients With Advanced Pretreated Soft-tissue Sarcomas and Ovarian Carcinomas. A Phase Ib Study.
Actual Study Start Date : May 5, 2017
Estimated Primary Completion Date : May 5, 2020
Estimated Study Completion Date : May 5, 2021


Arm Intervention/treatment
Experimental: Combination of trabectedin with durvalumab

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

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.





Primary Outcome Measures :
  1. 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) ]

Secondary Outcome Measures :
  1. 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 ]
  2. Dose Limiting Toxicities (DLT) of Trabectedin given in combination with Durvalumab [ Time Frame: During the first cycle (21 days)] ]
  3. Toxicity graded using the common toxicity criteria from the NCI v4.0 [ Time Frame: Throughout the treatment period, on average of 6 months ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. 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 ]
  9. 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 ]
  10. Predictive biomarkers analysis (blood cytokines levels [ Time Frame: Day 1 ]
  11. Predictive biomarkers analysis (blood cytokines levels) [ Time Frame: Day 21 ]
  12. Predictive biomarkers analysis (circulating immune cells levels) [ Time Frame: Day 1 ]
  13. Predictive biomarkers analysis (circulating immune cells levels) [ Time Frame: Day 21 ]
  14. 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)] ]
  15. Number of participants with exploratory biomarkers available (Markers analyzed for Hematoxylin and eosin staining (H&E) on tumor samples) [ Time Frame: Baseline ]
  16. 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 ]
  17. Number of participants with exploratory biomarkers available (Markers analyzed for Immunohistochemistry (IHC) on tumor samples) [ Time Frame: Baseline ]
  18. Number of participants with exploratory biomarkers available (Markers analyzed for Immunohistochemistry (IHC) on tumor samples.). [ Time Frame: cycle 2 Day 8 ]
  19. Exploratory analysis of predictive signature in responders (genomics and transcriptomics analysis). [ Time Frame: Baseline ]
    Identification of predictive signature in responders by sequencing tumor sample

  20. Exploratory analysis of predictive signature in responders (genomics and transcriptomics analysis). [ Time Frame: cycle 2 Day 8 ]
    Identification of predictive signature in responders by sequencing tumor sample

  21. Exploration of mechanisms of resistance in non-responders (genomics and transcriptomics analysis) [ Time Frame: Baseline ]
    Identification of predictive signature in responders by sequencing tumor sample

  22. Exploration of mechanisms of resistance in non-responders (genomics and transcriptomics analysis). [ Time Frame: cycle 2 Day 8 ]
    Identification of predictive signature in responders by sequencing tumor sample



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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), or ovarian carcinoma without known g/s BRCA mutation
  2. Ovarian carcinoma must have received at least one line of platinum-containing regimen
  3. Metastatic or unresectable locally advanced disease, not amenable to curative therapy
  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),
  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) > 60 ml/min (according to Cockroft Gault formula).
    6. Thyroid function within normal laboratory ranges (TSH, free T3, free T4).
    7. Creatine Phosphokinase (CPK) ≤ 2.5 x ULN
  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.
  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 .

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
  16. Person under judicial protection or deprived of liberty,
  17. Cardiac dysfunction: LVEF < 40% at Baseline or clinically symptomatic cardiac dysfunction (any % of LVEF at Baseline)
  18. Concomitant use of strong inhibitor or inductors of cytochrome CYP3A4 taken within 21 days prior to the first dose of study drug

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03085225


Locations
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France
Institut Bergonié
Bordeaux, France, 33076
Centre Léon Bérard
Lyon, France, 69373
Institut Gustave Roussy
Villejuif, France, 94800
Sponsors and Collaborators
Institut Bergonié
AstraZeneca
PharmaMar
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Responsible Party: Institut Bergonié
ClinicalTrials.gov Identifier: NCT03085225    
Other Study ID Numbers: IB2016-02
First Posted: March 21, 2017    Key Record Dates
Last Update Posted: February 6, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Institut Bergonié:
Advanced tumor
Pretreated tumor
Soft Tissue Sarcomas
Ovarian Carcinomas
Phase Ib
Circulating DNA
Additional relevant MeSH terms:
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Carcinoma
Sarcoma
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Connective and Soft Tissue
Endocrine Gland Neoplasms
Neoplasms by Site
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Durvalumab
Trabectedin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action