Clinical Trials /

Immunotherapy With Neo-adjuvant Chemotherapy for OVarian Cancer

NCT03249142

Description:

This is a randomized, open, comparative, multi-centre study which will recruit up to 66 patients. The objective is mainly to explore the safety and feasibility in neo-adjuvant first-line ovarian cancer (including patients with primary peritoneal or fallopian tube adenocarcinoma) of various combinations of durvalumab with chemotherapy with or without tremelimumab.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Epithelial Tumor
  • Primary Peritoneal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy With Neo-adjuvant Chemotherapy for OVarian Cancer
  • Official Title: A Multicentre Feasibility Randomized Study of Anti-PD-L1 Durvalumab (MEDI4736) With or Without Anti-CTLA-4 Tremelimumab in Patients With Ovarian, Fallopian Tube or Primary Peritoneal Adenocarcinoma, Treated With a First-line Neo-adjuvant Strategy

Clinical Trial IDs

  • ORG STUDY ID: GINECO-OV127b
  • NCT ID: NCT03249142

Conditions

  • Ovarian Cancer

Interventions

DrugSynonymsArms
ARM A Durvalumab/chemotherapy associationARM A Durvalumab/chemotherapy association
ARM B Durvalumab/Tremelimumab/chemotherapy associationARM B Durvalumab/Tremelimumab/chemotherapy association

Purpose

This is a randomized, open, comparative, multi-centre study which will recruit up to 66 patients. The objective is mainly to explore the safety and feasibility in neo-adjuvant first-line ovarian cancer (including patients with primary peritoneal or fallopian tube adenocarcinoma) of various combinations of durvalumab with chemotherapy with or without tremelimumab.

Detailed Description

      The schedule is the following:

      • In a first step a run-in phase of 6 patients will be conducted to test the safety and
      feasibility of the combination of durvalumab with standard carboplatin-paclitaxel
      chemotherapy.

      Cycle 1 : chemotherapy alone (day1) Cycle 2 : chemotherapy + durvalumab (day1) Cycle 3 :
      chemotherapy + durvalumab (day1)

      • In a second step, if first-step was found feasible, a run-in phase of 6 patients will be
      conducted to test the safety and feasibility of the combination of durvalumab plus
      tremelimumab with standard carboplatin-paclitaxel chemotherapy.

      Cycle 1 : chemotherapy alone (day1) Cycle 2 : chemotherapy + durvalumab + tremelimumab (day1)
      Cycle 3 : chemotherapy + durvalumab (day1)

        -  After the run-in phase, patients will be randomized in a ratio 1:1 between those
           included in the durvalumab-chemotherapy expansion phase (arm A) and those included in
           the durvalumab + tremelimumab-chemotherapy expansion phase (arm B).

        -  This study will also allow to explore the feasibility of a salvage therapy personalized
           according to the results of interval surgery and type of previous neo-adjuvant therapy.

             1. In those patients who achieved a complete surgical resection at interval debulking
                surgery, adjuvant treatment will include 3 cycles of durvalumab + chemotherapy and
                then a follow-up period.

             2. In patients with residual tumor at interval debulking surgery, salvage therapy will
                depend on the initial treatment arm allocated.

                  1. In arm A, the tremelimumab will be added to the durvalumab-chemotherapy
                     combination at day 1 of cycle 2 before a salvage surgery. Durvalumab (with one
                     cycle of tremelimumab post S3) will be pursued in maintenance treatment, up to
                     1 year or until disease progression, unacceptable toxicity or patient
                     withdrawn.

                  2. In arm B, the therapy will be according to the Investigator choice and managed
                     according to local practice.
    

Trial Arms

NameTypeDescriptionInterventions
ARM A Durvalumab/chemotherapy associationExperimental
  • ARM A Durvalumab/chemotherapy association
ARM B Durvalumab/Tremelimumab/chemotherapy associationExperimental
  • ARM B Durvalumab/Tremelimumab/chemotherapy association

Eligibility Criteria

        Inclusion Criteria:

        I-1 Female patients must be ≥ 18 years of age. I-2 Signed informed consent and ability to
        comply with treatment and follow-up. I-3 Patients with newly histologically confirmed
        epithelial ovarian cancer (or fallopian tube or primary peritoneal adenocarcinoma).

        I-4 Advanced FIGO stage IIIC to IV. I-5 Patients for whom primary debulking surgery has
        been denied after an evaluation through laparoscopy or laparotomy.

        I-6 Patient for whom a neo-adjuvant strategy has been planned. I-7 Interval between
        diagnosis and enrolment (informed consent signed) ≤ 8 weeks.

        I-8 Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. I-9 Geriatric
        vulnerability score (GVS) < 3 for patients ≥ 70 years. I-10 Adequate organ and bone marrow
        function. I-11 Patients not receiving anticoagulant medication who have an International
        Normalized Ratio (INR) ≤ 1.5 and an Activated ProThrombin Time (aPTT) ≤ 1.5 x ULN. The use
        of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is
        within therapeutic limits (according to site medical standard) and if the patient is on a
        stable dose of anticoagulants for at least two weeks at the time of randomization.

        I-12 As this study will include patients in France, a subject will be eligible for
        randomization in this study only if either affiliated to, or a beneficiary of, a social
        category.

        Exclusion Criteria:

        E-1 Other malignancy within the last 5 years except: adequately treated non-melanoma skin
        cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS).

        E-2 Major surgical procedure (defined by the resection of at least one organ including
        ovary) within 28 days prior to the first dose.

        E-3 Any concurrent chemotherapy, investigational product, biological, or hormonal therapy
        for cancer treatment.

        E-4 Previous treatment with immunotherapy, including, but not limited to, anti-CTLA-4,
        anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies, or therapeutic anticancer vaccine.

        E-5 Active or prior documented autoimmune or inflammatory disorders The following are
        exceptions to this criterion:

          1. Patients with vitiligo or alopecia,

          2. Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
             replacement or psoriasis not requiring systemic treatment.

        E-6 Current/prior immunosuppressive medication ≤ 14 days before first durvalumab and
        tremelimumab dose (including, but not limited to, prednisone, dexamethasone,
        cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor
        [TNF] agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for
        systemic immunosuppressive medications during the trial.

        E-7 Immunocompromised patients, e.g., patients who are known to be serologically positive
        for human immunodeficiency virus (HIV). Patients with active hepatitis B (defined as having
        a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients
        with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a
        negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody
        test) are eligible.

        E-8 Uncontrolled diabetes mellitus, uncontrolled hypothyroidism. E-9 Treatment with
        systemic immunostimulatory agents (including but not limited to interferon-alpha (IFN-α)
        and interleukin-2 (IL-2) within 4 weeks or five half- lives of the drug (whichever is
        shorter) prior to Cycle 1, Day 1.

        E-10 History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced
        pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
        pneumonia), or evidence of active pneumonitis. Radiation pneumonitis in the radiation field
        (fibrosis) detected on screening chest CT scan is permitted.

        E-11 Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1. E-12
        Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or
        anticipation that such a live attenuated vaccine will be required during the study.
        Influenza vaccination should be given during influenza season only (example approximately
        October to March in the Northern Hemisphere). Patients must not receive live, attenuated
        influenza.

        E-13 Current or recent (within 10 days prior to randomization) chronic use of aspirin > 325
        mg/day.

        E-14 Prior history of hypertensive crisis (CTC-AE grade 4) or hypertensive encephalopathy.

        E-15 Inadequately controlled HTN (defined as systolic blood pressure > 150 mmHg and/or
        diastolic blood pressure > 100 mmHg on antihypertensive medications).

        E-16 Clinically significant (e.g. active) cardiovascular disease, including:

          1. Myocardial infarction or unstable angina within ≤ 6 months of randomization,

          2. New York Heart Association (NYHA) ≥ grade 2 congestive heart failure (CHF),

          3. Poorly controlled cardiac arrhythmia despite medication (patients with rate controlled
             atrial fibrillation are eligible),

          4. Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering with
             activities of daily living [ADL] requiring repair or revision).

        E-17 Previous Cerebro-Vascular Accident (CVA), Transient Ischemic Attack (TIA) or
        Sub-Arachnoids Hemorrhage (SAH) within 6 months prior to randomization.

        E-18 History or evidence of hemorrhagic disorders within 6 months prior to randomization.

        E-19 Evidence of bleeding diathesis or significant coagulopathy (in the absence of
        coagulation).

        E-20 History or clinical suspicion of brain metastases or spinal cord compression unless
        asymptomatic, treated, and stable off steroids and anti-convulsants for at least 1 month
        prior to entry.

        E-21 History or evidence upon neurological examination of central nervous system (CNS)
        disease, unless adequately treated with standard medical therapy (e.g. uncontrolled
        seizures).

        E-22 Pre-existing motor or sensory neurotoxicity (grade > 1). E-23 Significant traumatic
        injury within 4 weeks prior to randomization. E-24 Non-healing wound, active ulcer or bone
        fracture. Patients with granulating incisions healing by secondary intention with no
        evidence of facial dehiscence or infection are eligible but require 3 weekly wound
        examinations.

        E-25 Current, clinically relevant bowel obstruction, including sub-occlusive disease,
        related to underlying disease.

        E-26 Previous allogeneic bone marrow transplant or previous solid organ transplantation.

        E-27 Patients with evidence of abdominal free air not explained by paracentesis or recent
        surgical procedure.

        E-28 Evidence of any other disease, metabolic dysfunction, physical examination finding or
        laboratory finding giving reasonable suspicion of a disease or condition that
        contraindicates the use of an investigational drug or puts the patient at high risk for
        treatment related complications.

        E-29 Female patients who are pregnant or breastfeeding or male or female patients of
        reproductive potential (< 2 years after last menstruation and not surgically sterile) who
        are not willing to employ effective birth control from screening to 180 days after the last
        dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of
        durvalumab monotherapy, whichever is the longer time period.

        E-30 History of severe allergic, anaphylactic, or other hypersensitivity reactions to
        chimeric or humanized antibodies or fusion proteins.

        E-31 Known hypersensitivity or allergy to biopharmaceuticals or to any component of the
        durvalumab or tremelimumab formulations.

        E-32 Known hypersensitivity reaction or allergy to drugs chemically related to carboplatin,
        paclitaxel, or their excipients that contraindicates the subject's participation.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Toxicity after neo-adjuvant treatment
Time Frame:At the end of cycle 3 (each cycle is 21 days)
Safety Issue:
Description:frequency of adverse events according to CTCAE v4.03 criteria

Secondary Outcome Measures

Measure:Toxicity after adjuvant treatment
Time Frame:At the end of cycle 6 (each cycle is 21 days)
Safety Issue:
Description:
Measure:Toxicity after maintenance therapy
Time Frame:Up to 18 months
Safety Issue:
Description:
Measure:Safety after interval debulking surgery
Time Frame:Up to 6 months
Safety Issue:
Description:adverse events according to the Clavien-Dindo classification
Measure:Progression Free Survival (PFS) based on investigator assessment using the RECIST version 1.1
Time Frame:From date of randomisation until the date of progression or death, which ever occurs earlier, assessed up to 36 months
Safety Issue:
Description:
Measure:Sugarbaker Peritoneal Index Score (PCI)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Time to start of first subsequent therapy or death
Time Frame:Up to 36 months
Safety Issue:
Description:
Measure:overall survival
Time Frame:from date of randomisation to death, assessed up to 36 months
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ARCAGY/ GINECO GROUP

Trial Keywords

  • Ovarian Cancer
  • Anti-PD-L1
  • Anti-CLA-4
  • Neo-adjuvant

Last Updated

May 12, 2020