Clinical Trials /

Efficacy and Safety of the Combination of Rucaparib (PARP Inhibitor) and Atezolizumab (Anti-PD-L1 Antibody) in Patients With DNA Repair-deficient or Platinum-sensitive Solid Tumors

NCT04276376

Description:

The primary objective of the trial is to evaluate the antitumor activity of atezolizumab and rucaparib in patients with selected advanced solid tumors as measured by the Overall Response Rate

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Bladder Urothelial Carcinoma
  • Clear Cell Renal Cell Carcinoma
  • Gastric Adenocarcinoma
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Efficacy and Safety of the Combination of Rucaparib (PARP Inhibitor) and Atezolizumab (Anti-PD-L1 Antibody) in Patients With DNA Repair-deficient or Platinum-sensitive Solid Tumors
  • Official Title: A Multicenter, Open Label, Phase II Basket Trial Exploring the Efficacy and Safety of the Combination of Rucaparib (PARP Inhibitor) and Atezolizumab (Anti-PD-L1 Antibody) in Patients With DNA Repair-deficient or Platinum-sensitive Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: 2018-001744-62
  • SECONDARY ID: 2018/2727
  • NCT ID: NCT04276376

Conditions

  • Solid Tumor

Interventions

DrugSynonymsArms
AtezolizumabCohort 1A-D
RucaparibCohort 1A-D

Purpose

The primary objective of the trial is to evaluate the antitumor activity of atezolizumab and rucaparib in patients with selected advanced solid tumors as measured by the Overall Response Rate

Trial Arms

NameTypeDescriptionInterventions
Cohort 1A-DExperimentalMolecularly selected cohorts that harbor DNA repair deficiency, defined as bi-allelic loss-of-function alteration (mutation and/or deletion) in at least one of the following genes: ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, PALB2, RAD51C, RAD51D, FANCA, NBN, RAD51, RAD54L. 1.A - Non-Small Cell Lung Cancer 1.B - Urothelial Bladder Cancer 1.C - metastatic Castration Resistant Prostate Cancer 1.D - others: any histology, excepted breast cancer or serous ovarian cancer
  • Atezolizumab
  • Rucaparib
Cohort 2A-CExperimentalPlatinum-sensitive disease 2.A - Non-Small Cell Lung Cancer 2.B - Urothelial Bladder Cancer 2.C - Gastric or gastro-esophageal junction adenocarcinoma
  • Atezolizumab
  • Rucaparib
Cohort 3ExperimentalMetastatic Castration Resistant Prostate Cancer (mCRPC)
  • Atezolizumab
  • Rucaparib
Cohort 4ExperimentalClear Cell Renal Cell Carcinoma
  • Atezolizumab
  • Rucaparib

Eligibility Criteria

        Inclusion Criteria:

          1. Signed informed consent form.

          2. Age ≥ 18 years.

          3. Patients must have histologically or cytologically confirmed progressive metastatic or
             recurrent solid tumor (as defined below for each tumor type). Diagnosis must be stated
             in a pathology report and confirmed by the investigator.

        5. Representative archival formalin-fixed paraffin-embedded (FFPE) tumor specimens in
        paraffin blocks (preferred) or 20 freshly cut and unstained slides, with an associated
        pathology report, for ancillary studies and central testing, is mandatory for all cohorts.
        In all cases, recovery of the most recent tumor block or biopsy is encouraged and tumor
        tissue has to date back from less than 3 years ago. If tumor tissue is more than 3 years
        old, a fresh tumor biopsy is mandatory for cohorts 1, 2 and 4.

        o Specificities for Cohorts 1A-D:

          -  For patients with DNA repair gene mutation already identified by local testing,
             mutational testing must have been done less than one year prior to inclusion in the
             trial (i.e. signing of informed consent). Tumor block should correspond to the one
             that has been used for the original testing. If more recent blocks are available,
             these should be provided for ancillary studies, and the presence of the mutation of
             interest should be confirmed on these.

          -  If no archival tissue is available or if tumor tissue is more than 3 years old,
             feasibility of a fresh tumor biopsy at baseline (C0D1 pre-dose) should be ensured and
             mutation confirmed on that tissue for cohorts 1A, 1B and 1D. Only tissue from core
             needle, punch or excisional biopsy sample collection will be accepted. Other methods
             such as fine-needle aspiration, brushing, bone tissue or lavage samples are not
             acceptable.

          -  Bone biopsies are allowed for mCRPC (cohort 1C), if sufficient tumor cellularity can
             be achieved.

             o Specificity for cohort 3:

          -  If no archival tumor biopsy is available, a new fresh biopsy should be done prior to
             treatment start (C0D1 pre-dose) whenever feasible; otherwise, any archival tumor
             tissue will be accepted.

          -  Core or excisional biopsy from soft tissue or a bone biopsy is required from a site
             not previously irradiated (samples from tumors progressing in a prior site of
             radiation are allowed; other exceptions may be considered after Sponsor consultation).

             6. Measurable disease, defined as:

          -  For the non-prostate cohorts: At least one lesion, not previously irradiated,
             measurable according to RECIST v1.1 as ≥10 mm in the longest diameter (except lymph
             nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic
             resonance imaging (MRI) and suitable for repeated assessment.

          -  For prostate cohorts: At least one lesion, not previously irradiated, measurable
             according to RECIST v1.1 and / or bone scan measurable disease (Cf inclusion criteria
             4) and / or measurable disease according to Prostate Cancer Working Group Criteria 3
             (PCWG3) 7. Agreement of the patient to sign the genetic analysis consent form for
             access to plasma samples for ctDNA analysis.

             8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no
             deterioration from registration date.

             9. Estimated life expectancy of greater than 12 weeks. 10. Adequate hematologic and
             organ function, defined by the following laboratory results obtained within 3 days
             prior to the first study treatment (Cycle 0 Day 1):

               -  Absolute neutrophil count (ANC) ≥ 1500 cells/μL (without granulocyte
                  colony-stimulating factor support within 2 weeks before cycle 0 day 1).

               -  Platelet count ≥ 100.000/μL (without transfusion within 2 weeks before Cycle 0
                  Day 1).

               -  Hemoglobin ≥ 9g/dL (patients may be transfused or receive erythropoietic
                  treatment to meet this criterion).

               -  Total bilirubin ≤ 1.5 ULN (subjects with documented/suspected Gilbert's disease
                  or liver metastases may be enrolled with bilirubin ≤ 3 × ULN).

               -  Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≤ 2.5 x upper
                  normal limit (ULN) or ≤ 5 × ULN in case of liver metastases.

               -  Albumin ≥ 28g/L.

               -  Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40mL/min (according to
                  Cockroft and Gault formula).

               -  International normalized ratio (INR) and activated partial thromboplastin time
                  (aPTT) ≤ 1.5 x ULN. This applies only to patients who do not receive therapeutic
                  anticoagulation; patients receiving therapeutic anticoagulation (such as
                  low-molecular weight heparin or warfarin) should be on stable dose.

                  11. Women of childbearing potential must have a negative serum β-HCG pregnancy
                  test within 7 days prior to the administration of the first study treatment 12.
                  Sexually active women of childbearing potential must agree to use a highly
                  effective method of contraception << supplemented by a barrier method >>, or to
                  abstain from sexual activity during the study and for at least 6 months after the
                  last study treatment administration.

                  13. Sexually active males patients must agree to use condom during the study and
                  for at least 6 months after the last study treatment administration. Also, it is
                  recommended their women of childbearing potential partner use a highly effective
                  method of contraception.

        A woman is considered of childbearing potential following menarche and until becoming
        post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) unless permanently sterile.
        Permanent sterilization methods include hysterectomy, bilateral oophorectomy and bilateral
        salpingectomy. A highly effective birth control method is a one which can achieve a failure
        rate of less than 1% per year when used consistently and correctly. Such methods include:
        combined (estrogen and progesterone containing) hormonal contraception; progestogen-only
        hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD);
        intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized
        partner (on the understanding that this is the only one partner during the whole study
        duration), and sexual abstinence during the entire period of risk associated with study
        treatment. To prevent the risk of interaction between the study drug and hormonal
        contraceptives, hormonal contraceptives should be supplemented with a barrier method
        (preferably male condom). Following methods are considered as unacceptable methods
        (non-exhaustive list): periodic abstinence (calendar, symptothermal, post-ovulation
        methods) and withdrawal (coitus interruptus).

        14. Patient should understand, sign, and date the written informed consent form prior to
        any protocol-specific procedures performed.

        15. Patient should be able and willing to comply with study visits and procedures as per
        protocol.

        16. Patients must be affiliated to a social security system or beneficiary of an equivalent
        system.

        Exclusion Criteria:

          1. Participation in another clinical study with an investigational product during the
             last 4 weeks (excepting non-interventional clinical studies) and while on study
             treatment.

          2. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
             endocrine therapy (excepted androgen deprivation therapy by LHRH agonists for prostate
             cancer patients), targeted therapy, biologic therapy, tumor embolization, monoclonal
             antibodies, other investigational agent) 28 days prior to the first dose of study
             drug, or five half lives of the previous agent, whichever is the shorter.

          3. Prior radiation therapy within 2 weeks prior to Cycle 0 Day 1.

          4. History of another primary malignancy within 5 years prior to Cycle 0 Day 1 except
             for:

               -  Malignancy treated with curative intent and with no known active disease ≥5 years
                  before the first dose of study drug and of low potential risk for recurrence.

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease.

               -  Adequately treated carcinoma in situ without evidence of disease (eg, carcinoma
                  in situ of the cervix, localized prostate cancer treated surgically with curative
                  intent, ductal carcinoma in situ treated surgically with curative intent).

          5. Treatment with systemic corticosteroids or other immunosuppressive medications
             (including but not limited to prednisone, dexamethasone, cyclophosphamide,
             azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents) within
             2 weeks prior to Cycle 0 Day 1, or anticipated requirements for systemic
             immunosuppressive medications during the trial:

             . The use of inhaled corticosteroids for chronic obstructive pulmonary disease,
             mineralocorticoids for patients with orthostatic hypotension, low-dose supplemental
             corticosteroids for adrenocortical insufficiency and topical steroids for cutaneous
             diseases are allowed.

          6. Acute toxicities from previous therapies that have not resolved to Grade ≤ 1, with the
             exception of alopecia.

          7. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
             immunotherapy agent, or any unresolved irAE > Grade 1.

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

          9. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or to any component of the atezolizumab formulation.

         10. History of autoimmune/immune mediated inflammatory disease, including but not limited
             to colitis, pneumonitis, hepatitis, hypophysitis, nephritis, hyperthyroidism, systemic
             lupus erythematous, rheumatoid arthritis, inflammatory bowel disease, Wegener's
             granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, vasculitis, or
             glomerulonephritis excepted stable hypothyroidism or stable Type 1 diabetes mellitus.

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

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

         13. History of allogeneic organ transplant or prior bone marrow transplantation of double
             umbilical cord blood transplantation.

         14. Uncontrolled intercurrent illness including, but not limited to:

               -  ongoing or active infection or severe infection requiring hospitalization or IV
                  antibiotics within 2 weeks of starting treatment (with the exception of
                  prophylactic antibiotics).

               -  symptomatic congestive heart failure > NYHA II, uncontrolled hypertension,
                  unstable angina pectoris, cardiac arrhythmia, pericardial effusion.

               -  active peptic ulcer disease or gastritis.

               -  active bleeding diatheses.

         15. Psychiatric illness/social situations that would limit compliance with study
             requirements or compromise the ability of the subject to give written informed
             consent.

         16. Patients with known left ventricular ejection fraction (LVEF) < 40%; patients with
             known coronary artery disease, congestive heart failure not meeting the above
             criteria, or LVEF < 50% must be on a stable cardiologic treatment.

         17. Known positive test for HIV.

         18. Patients with active hepatitis B (defined as positive HBsAg test at screening) or
             hepatitis C (HCV). 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) are eligible. Patients positive for hepatitis C
             virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative
             for HCV RNA.

         19. Active tuberculosis.

         20. 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 vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1,
             Day 1 or at any time during the study treatment or within 5 months after the last dose
             of atezolizumab.

         21. Major surgical procedure within 28 days prior to Cycle 0 Day 1 or anticipation of need
             for a major surgical procedure during the course of the study.

         22. Uncontrolled tumor-related pain: patients requiring pain medication must be on a
             stable regimen at study entry and symptomatic lesions amenable to palliative
             radiotherapy should be treated prior to enrollment.

         23. Uncontrolled effusion (pleural, pericardial or ascites) requiring recurrent drainage
             procedures (once a month or more frequently); patients with indwelling catheters (e.g.
             PleurX) are allowed.

         24. Uncontrolled hypercalcemia (>1.5mmol/L ionized calcium or Ca > 12mg/dL or corrected
             serum calcium >ULN) or symptomatic hypercalcemia requiring continued use of
             bisphosphonate therapy or denosumab.

         25. Patients who are receiving bisphosphonate therapy or denosumab specifically to prevent
             skeletal events and who do not have a history or clinically significant hypercalcemia
             are eligible

         26. History of leptomeningeal disease

               -  Symptomatic CNS metastasis or uncontrolled CNS metastasis, requiring increasing
                  doses of steroids or stable dose of steroids > 10mg prednisone qd.

               -  Spinal cord compression without evidence that disease has been clinically stable
                  for ≥ 2 weeks prior to Cycle 0 Day 1.

         27. Female subjects who are pregnant, breast-feeding or male or female patients of
             reproductive potential who are not employing an effective method of birth control.

         28. Previous treatment with PARP inhibitors.

         29. Concomitant use of strong inhibitors or inducers of CYP3A4

         30. Treatment with systemic immunostimulatory agents (e.g. INF-a and IL-2) within 4 weeks
             prior to Cycle 0 Day 1.

         31. Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study result.

         32. Patient under guardianship or deprived of his liberty by a judicial or administrative
             decision or incapable of giving its consent.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:at 12 weeks
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Gustave Roussy, Cancer Campus, Grand Paris

Last Updated

February 17, 2020