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Study Evaluating the Efficacy of a Double Immunotherapy Combined With Olaparib in Patients With Solid Cancers and Carriers of Homologous Recombination Repair Genes After Olaparib Treatment

NCT04169841

Description:

The study propose to generate a clinical trial based on precision medicine to evaluate the use of immunotherapy in patients with altered homologous recombination repair genes and without progression after prior targeted therapy.

Related Conditions:
  • Breast Carcinoma
  • Clear Cell Renal Cell Carcinoma
  • Endometrial Carcinoma
  • Head and Neck Carcinoma
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Pancreatic Carcinoma
  • Prostate Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study Evaluating the Efficacy of a Double Immunotherapy Combined With Olaparib in Patients With Solid Cancers and Carriers of Homologous Recombination Repair Genes After Olaparib Treatment
  • Official Title: Precision Medicine Phase II Study Evaluating the Efficacy of a Double Immunotherapy by Durvalumab and Tremelimumab Combined With Olaparib in Patients With Solid Cancers and Carriers of Homologous Recombination Repair Genes Mutation in Response or Stable After Olaparib Treatment

Clinical Trial IDs

  • ORG STUDY ID: GUIDE2REPAIR
  • NCT ID: NCT04169841

Conditions

  • Immunotherapy

Interventions

DrugSynonymsArms
olaparib, durvalumab, tremelimumabGUIDE2REPAIR patients

Purpose

The study propose to generate a clinical trial based on precision medicine to evaluate the use of immunotherapy in patients with altered homologous recombination repair genes and without progression after prior targeted therapy.

Detailed Description

      Research Hypothesis: With the development of cost effective and rapid technology of genome
      sequencing, precision medicine becomes a new way to think oncology. Current targets involve
      mainly tyrosine kinase, but DNA repair machinery could also be targetable. Some of DNA repair
      aberrations have been associated with sensitivity to platinum and poly (adenosine diphosphate
      [ADP]-ribose) polymerase (PARP) inhibitors like Olaparib (Lynparza, AstraZeneca), suggesting
      that treatment with a PARP inhibitor may exploit a synthetic lethal interaction when we
      observed the presence of alteration of the homologous repair pathway1-4. PARP is involved in
      multiple aspects of DNA repair, and the PARP inhibitor Olaparib has recently been approved
      for treating ovarian cancers with BRCA1/2 mutations1. In addition, a recent report in the New
      England Journal of Medicine showed that using a high-throughput, next-generation sequencing
      assay in prostate cancer, detection of genomic alteration in genes involved in homologous
      repair pathway BRCA2, ATM, BRCA1, PALB2, CHEK2, FANCA, and HDAC2, is associated with response
      to olaparib3. Thus demonstrating the clinical validation of the usage of precision medicine
      to position PARP inhibitor like olaparib in different cancer types based on molecular
      analysis.

      Preclinical studies showed DNA damage promotes neoantigen expression5. It is possible that
      increased DNA damage by PARPi would yield greater mutational burden and expand neoantigen
      expression, leading to greater immune recognition of the tumor. PARPi is also associated with
      immunomodulation. The PARPi talazoparib increases the number of peritoneal CD8+ T cells and
      natural killer cells and increases production of interferon (IFN)-γ and tumor necrosis
      factor-α in a BRCA1-mutated ovarian cancer xenograft model6. Hence, addition of PARPi to
      immune checkpoint blockade could complement the clinical benefit of immune checkpoint
      inhibition.

      Such high level of mutation results in high number of neoantigen and antitumor immune
      response thus given the rational to use immunotherapy to target such type. A recent New
      England Journal of Medicine paper validate this strategy using the anti PD-1 pembrolizumab7
      Some case reports suggest also that other mutations that induce hypermutated tumor (POLD,
      POLE, or MYH) could gain benefit from anti PD-1 therapy8-10. Additional DNA repair machinery
      dysfunction may lead to accumulation of mutations. And such level of mutations could induce
      better response to immunotherapy. In the lung non-small cell setting high mutation rate were
      associated with better efficacy of both nivolumab and pembrolizumab.
    

Trial Arms

NameTypeDescriptionInterventions
GUIDE2REPAIR patientsExperimentalolaparib + immunotherapy (durvalumab + tremelimumab) during 4 months followed by durvalumab alone as maintenance in patients with solid cancer and in response or stable after prior molecular target therapy by olaparib based on molecular sequencing.
  • olaparib, durvalumab, tremelimumab

Eligibility Criteria

        Inclusion Criteria:

        Inclusion Criteria from STEP 1:

          1. Capable of giving signed informed consent

          2. Exome sequencing of tumor and constitutive DNA should have been already performed

          3. Patients must be diagnosed with a solid malignancy with the following cancer
             histologically confirmed with specified inclusion for each cohort:

             Metastatic breast cancer:

             • In second line

             • third line and after

             Metastatic lung cancer:

               -  Non-small cell lung cancer

               -  Must have progressed after at least a first line with platinum based therapy

             Metastatic head and Neck cancer

             • Must have progressed after at least a first line with platinum based therapy

             Metastatic endometrial cancer • Progression after 1 prior systemic, platinum-based
             chemotherapy regimen for EC. Participants may have received up to 1 additional line of
             platinum-based chemotherapy if given in the neoadjuvant or adjuvant treatment setting.
             There is no restriction regarding prior hormonal therapy

             Metastatic clear cell renal cancer

             • Must have progressed after at least a line with anti-angiogenic agent. Metastatic
             pancreatic cancer

             • Must have progressed after at least a line with FOLFIRINOX regimen and/or Gemcitabin
             based chemotherapy

             Locally advanced or metastatic ovarian cancer

             • Must have received at least one and no more than two lines of prior
             platinum-containing therapy and progressed after the most recent platinum therapy in a
             platinum-sensitive timeframe (more than 6 months from the last dose of platinum before
             randomization)

             Metastatic urothelial cancer • From the second line and regardless previous treatment
             (except immunotherapy)

             Metastatic prostate cancer

               -  Documented evidence of metastatic castration resistant prostate cancer (mCRPC)

               -  Ongoing therapy with LHRH analog or bilateral orchiectomy

               -  Must have progressed on prior new hormonal agent (enzalutamine or abiraterone)
                  and taxane chemotherapy

          4. Presence of mutation in homologous repair gene

          5. Age >18 years

          6. Performance status ECOG of 0 or 1.

          7. Life expectancy ≥ 6 months.

          8. At least one lesion measurable as defined by standard imaging criteria for the
             patient's tumor type (RECIST v1.1)

          9. Body weight >30 kg.

         10. 10. Patients must have normal organ and bone marrow function measured within 28 days
             prior to administration of study treatment

         11. Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential

         12. Male patients must use a condom during treatment of STEP1 (olaparib) and STEP2
             (durvalumab and tremelimumab) and for 180 days after the last dose when having sexual
             intercourse with a pregnant woman or with a woman of childbearing potential. Female
             partners of male patients should also use a highly effective form of contraception if
             they are of childbearing potential

         13. Patient is willing and able to comply with the protocol for the duration of the study.

         14. For all oral medications patients must be able to comfortably swallow capsules;

        Inclusion criteria STEP 2

        16. CT Scan evaluation after 6 weeks of olaparib should present response or stable disease
        as defined by RECIST v1.1 criteria.

        Exclusion Criteria:

        Exclusion criteria of STEP 1

          1. Involvement in the planning and/or conduct of the study

          2. Patient with mBRCA1 / 2 that are eligible for current marketing authorization for
             olaparib (ovarian cancer),and patient eligible for AstraZeneca registration clinical
             trials, particularly for the prostate cohort

          3. Specific exclusion criteria each cohort:

             Metastatic breast cancer:

             • Only for patient second line : patient with mBRCA1 / 2 that are eligible for current
             marketing authorization for Olaparib (ovarian cancer) and patient eligible for
             AstraZeneca registration clinical trials).

             Metastatic lung cancer

               -  Small cell cancer

               -  oncogenic addiction : EGFR mutation or BRAF mutation or ALK rearrangement or ROS1
                  mutation Locally advanced or metastatic ovarian cancer

               -  Patient with mBRCA1 / 2 that are eligible for current marketing authorization for
                  Olaparib (ovarian cancer) and patient eligible for AstraZeneca registration
                  clinical trials.

             Metastatic prostate cancer

             • Untreated or first line patients

             Metastatic head and Neck cancer, Metastatic endometrial cancer, Metastatic clear cell
             renal cancer, Metastatic pancreatic cancer & Metastatic urothelial cancer:

             • None

          4. Participation in another clinical study with an investigational product during within
             2 months of first administration of Olaparib.

          5. Concurrent enrolment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study

          6. Receipt of the last dose of anticancer therapy ≤21 days prior to the first dose of
             olaparib or 5 times its half-life, whichever is less.

          7. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, ototoxicity, vitiligo, and the laboratory values defined in the
             inclusion criteria

          8. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
             Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
             replacement therapy) is acceptable.

          9. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
             radiation within 4 weeks of the first dose of study drug. Radiotherapy
             (non-palliative) within 21 days prior the first dose of study drug or within 6 weeks
             for therapeutic doses of MIBG or craniospinal irradiation. Palliative RT (which would
             be <30% of the bone marrow) to non-target lesions is allowed.

         10. Major surgical procedure within 28 days prior to the first dose of olaparib and
             patients must have recovered from any effects of any major surgery.

         11. Patients unable to swallow orally administered medication and patients with Impairment
             of gastrointestinal (GI) function or GI disease that may significantly alter drug
             absorption of oral drugs

         12. History of allogenic organ, bone marrow or double umbilical cord blood
             transplantation.

         13. Active or prior documented autoimmune or inflammatory disorders

         14. Uncontrolled intercurrent illness or patient considered a poor medical risk due to a
             serious, uncontrolled medical disorder, including but not limited to, ongoing or
             active infection, symptomatic congestive heart failure

         15. Currently taking medications with known risk of prolonging the QT interval or inducing
             Torsades de Pointes.

         16. Concomitant use of known strong or moderate CYP3A inducers.

         17. Resting ECG indicating uncontrolled, potentially reversible cardiac conditions or
             patients with congenital long QT syndrome

         18. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
             suggestive of MDS/AML.

         19. History of another primary malignancy

         20. History of leptomeningeal carcinomatosis

         21. Patient with symptomatic central nervous system (CNS) metastases who are
             neurologically unstable or require increasing doses of corticosteroids or local
             CNS-directed therapy to control their CNS disease.

         22. History of active primary immunodeficiency

         23. Immunocompromised patients

         24. Active infection including tuberculosis, hepatitis B, hepatitis C, or human
             immunodeficiency virus. Patients with a past or resolved HBV infection are eligible.
             Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
             reaction is negative for HCV RNA.

         25. Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab or tremelimumab.

         26. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.

         27. Female patients who are pregnant or breastfeeding or male or female patients of
             reproductive potential

         28. Prior treatment with any PARP inhibitor including olaparib or immunotherapy.

         29. Concomitant use of known strong or moderate cytochrome CYP3A inhibitors and
             concomitant use of known strong or moderate CYP3A inducers.

             Exclusion criteria of STEP 2

             Patients should not enter the study if any of the exclusion criteria from STEP 1 and
             the following criteria for STEP 2 are fulfilled:

         30. Patient with progression observed on CT scan performed after 6 weeks of olaparib (STEP
             1).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety Assessments: progression free survival
Time Frame:6 months after the initiation of immunotherapy for all cohorts excepted for ovarian cohort where PFS will be evaluated at 12 months.
Safety Issue:
Description:progression free survival

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Centre Georges Francois Leclerc

Trial Keywords

  • immunotherapy
  • olaparib
  • durvalumab
  • tremelimumab
  • genes mutation

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