Basket Trial Exploring the Efficacy and Safety of the Combination of Niraparib and Dostarlimab

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Brief Title

Basket Trial Exploring the Efficacy and Safety of the Combination of Niraparib and Dostarlimab

Official Title

An Open Label Phase II Basket Trial Exploring the Efficacy and Safety of the Combination of Niraparib and Dostarlimab in Patients With DNA Repair-deficient or Platinum-sensitive Solid Tumors

Brief Summary

      Treatment will consist of a PARP inhibitor (niraparib) monotherapy priming period (cycle 0;
      21 days); an anti-PD-1 antibody (Dostarlimab ; TSR-042) will then be added from C1D1 every 21
      days in combination for the first 4 cycles, and then every 42 days. Disease will be assessed
      every 2 cycles (6 weeks) from C3D1 by CT-scan (or MRI or bone scan, if relevant). Patients
      still under treatment after 1 year may have tumor evaluation spaced out every 3 cycles
    


Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Overall Response Rate (ORR)


Condition

Urothelial Bladder Cancer

Intervention

Dostarlimab

Study Arms / Comparison Groups

 1.A - Urothelial Bladder Cancer
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

112

Start Date

March 2021

Completion Date

March 2027

Primary Completion Date

March 2024

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 18 years.

          -  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 physician investigator.

          -  Evidence of disease progression prior to trial entry.

          -  To be enrolled in this study, only the tumor types and settings described below are
             allowed:

        4.1 - Cohorts 1 A-E: DNA repair deficiency, defined as bi-allelic loss-of-function
        alteration (mutation and/or deletion) in at least one of the following genes: ARID1A,
        ARID2, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, IDH1, IDH2, NBN, PALB2, PBRM1,
        RAD51C, RAD51D, FANCA, NBN, RAD51, RAD54L, SMARCA4.

        4.1.1 - Cohort 1A: Urothelial Bladder Cancer

          -  Patients must have received at least one line of prior platinum - based systemic
             therapy. No more than 3 lines of previous systemic therapy for metastatic disease are
             allowed.

               -  Relapse within 6 months of completion of adjuvant/neoadjuvant chemotherapy
                  containing platinum-based regimen is considered as first-line therapy.

               -  Previous adjuvant/neoadjuvant chemotherapy is allowed, if completed more than 6
                  months prior to starting the first-line therapy.

               -  Patients must have platinum-sensitive disease defined as disease which reaches at
                  least partial response after the last platinum chemotherapy line and the patient
                  must have progressed at least 3 months after the last cycle of chemotherapy.

          -  Previous exposure to one line of anti-PD-1 or anti-PD-L1 is allowed, unless
             hyperprogression (Appendix 6) occurred on immunotherapy 4.1.2- Cohort 1B: Gastric or
             gastro-esophageal junction adenocarcinoma

          -  Metastatic or recurrent gastric or gastro-esophageal junction adenocarcinoma that has
             progressed following at least 1 and maximum 2 prior therapies, by imaging modalities.

          -  Relapse within 6 months of completion of adjuvant/neoadjuvant chemotherapy is
             considered as first-line therapy.

          -  Previous adjuvant/neoadjuvant chemotherapy is allowed, if completed more than 6 months
             prior to starting the first-line therapy.

          -  HER2-positive and -negative amplified patients are both eligible for entry into this
             study.

          -  Patients with HER2-positive gastric cancer must have received trastuzumab-containing
             regimen prior to study entry.

          -  Previous exposure to anti-PD-1 or anti-PD-L1 is not allowed 4.1.3- Cohort 1C: Head and
             Neck Cancer

          -  Histologically or cytologically confirmed carcinoma of the head and neck.

          -  Subjects are eligible regardless of HPV status

          -  Relapse within 6 months of completion of adjuvant/neoadjuvant chemotherapy or
             chemo-radiotherapy regimen is considered as first-line therapy

          -  In case of previous platinum-based therapy, tumor progression or recurrence within 6
             months of last dose of platinum-based therapy is not allowed.

          -  Previous exposure to one line of anti-PD-1 or anti-PD-L1 is allowed, unless
             hyperprogression (Appendix 6) occurred on immunotherapy

          -  Patients must have received at last one prior line of therapy in the advanced /
             metastatic setting

          -  No more than 2 lines of previous systemic therapy for metastatic disease are allowed.

        4.1.4- Cohort 1D: Biliary Tract Cancer

          -  Histologically or cytologically confirmed carcinoma of the biliary tract that has
             progressed following at least 1 and maximum 2 prior therapies, by imaging modalities.

          -  Previous exposure to anti-PD-1 or anti-PD-L1 is not allowed 4.1.5- Cohort 1E Others

          -  Any histology, excepted breast cancer, prostate cancer or serous ovarian cancer
             (Appendix 7).

          -  Previous exposure to one line of anti-PD-1 or anti-PD-L1 is allowed, unless
             hyperprogression (Appendix 6) occurred on immunotherapy 4.2 - Cohorts 2:
             Platinum-sensitive urothelial bladder cancer

          -  Patients must have received at least one line of prior platinum - based systemic
             therapy. No more than 3 lines of previous systemic therapy for metastatic disease are
             allowed.

          -  Platinum-sensitive disease is defined as disease which reached at least partial
             response after the last platinum chemotherapy line and progressed at least 3 months
             after the last cycle of chemotherapy

          -  Relapse within 6 months of completion of adjuvant/neoadjuvant chemotherapy containing
             platinum-based regimen is considered as first-line therapy.

          -  Previous adjuvant/neoadjuvant chemotherapy is allowed, if completed more than 6 months
             prior to starting the first-line therapy.

          -  Previous exposure to one line of anti-PD-1 or anti-PD-L1 is allowed, unless
             hyperprogression (Appendix 6) occurred on immnotherapy 4.3 - Cohort 3: Clear cell
             Renal Cell Carcinoma

          -  Patients must have received at least one line of previous therapy. No more than 4
             previous lines of therapy are allowed.

          -  Patients must have received anti-PD-1 (or anti-PD-L1) in combination with an
             anti-CTLA-4 or an anti-angiogenic agent, and an antiangiogenic agent.

          -  Previous exposure to one line of anti-PD-1 or anti-PD-L1 is allowed unless
             hyperprogression (Appendix 6) occurred on immunotherapy

          -  Representative archival formalin-fixed paraffin-embedded (FFPE) tumor specimens in
             paraffin blocks (preferred) or 20 (ideally) freshly cut and unstained slides, with an
             associated pathology report, for ancillary studies and/or central testing. If less
             than 20 slides are available, inclusion must be discussed with the Coordinating
             Investigator. In all cases, recovery of the most recent tumor block or biopsy is
             encouraged.

        For Cohorts 1A-E:

          -  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 no archival tissue available
             feasibility of a fresh tumor biopsy at baseline should be ensured and mutation
             confirmed on that tissue. 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.

          -  For patients whose tissue will be evaluated by the Gustave Roussy DNA repair gene
             panel, original or more recent tumor blocks can be used.

               -  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.

               -  Patients must have progressed following standard of care or not eligible to
                  effective standard therapy

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

               -  Estimated life expectancy of greater than 12 weeks.

               -  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).

               -  Lymphocyte count ≥ 500/μL.

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

               -  Hemoglobin ≥ 9g/dL (patients are not allowed to be transfused with RBC 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 involvement.

               -  Albumin ≥ 28g/L.

               -  Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 40 mL/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.

               -  Women of childbearing potential must have a negative serum β-HCG pregnancy test
                  within 14 days prior to the administration of the first study treatment.

               -  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 180 days after the last
                  study treatment administration.

               -  Participant must agree to not breastfeed during the study or for 180 days after
                  the last dose of study treatment.

               -  Participant must agree to not donate blood during the study or for 90 days after
                  the last dose of study treatment.

               -  Sexually active males patients must agree to use condom during the study and for
                  at least 180 days after the last study treatment administration. Also, it is
                  recommended their women of childbearing potential partner use a highly effective
                  method of contraception for the same duration.

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

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

               -  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 simultaneously
             and/or during the last 4 weeks (excepting observational or non-interventional clinical
             studies).

          2. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
             endocrine therapy, 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. Participant has had radiation therapy encompassing >20% of the bone marrow within 2
             weeks prior to Cycle 0 Day 1; or any radiation therapy within 1 week 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:

             o 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. Participant must not have received a platelet transfusion ≤ 4 weeks prior to Cycle 0
             Day 1.

          9. Participants must not have received colony stimulating factors (eg, granulocyte
             colony-stimulating factor, granulocyte macrophage colony stimulating factor, or
             recombinant erythropoietin) within 4 weeks prior to Cycle 0 Day 1.

         10. Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due
             to prior chemotherapy that persisted > 4 weeks and was related to the most recent
             treatment.

         11. Participant must not have any known history of myelodysplastic syndrome (MDS) or acute
             myeloid leukemia (AML).

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

         13. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
             ovary cells or to any component of the TSR-042 formulation, or to niraparib or its
             components.

         14. History of autoimmune disease, including but not limited to myasthenia gravis,
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
             inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid
             syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,
             multiple sclerosis, vasculitis or glomerulonephritis.

               -  Patients with autoimmune hypothyroidism on a stable dose of thyroid replacement
                  hormone are eligible.

               -  Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are
                  eligible.

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

         16. History of interstitial lung disease, idiopathic pulmonary fibrosis, drug-induced
             pneumonitis, organizing pneumonia or evidence of active pneumonitis on screening chest
             CT scan.

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

         18. 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, superior vena cava syndrome,
                  uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia,
                  pericardial effusion, myocardial infarction within 90 days.

               -  active peptic ulcer disease or gastritis.

               -  active bleeding diatheses.

               -  major seizure disorder

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

         20. 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.

         21. Known positive test for HIV.

         22. 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.

         23. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase
             chain reaction (PCR) is negative for HCV RNA.

         24. Active tuberculosis.

         25. Administration of attenuated or live vaccine within 4 weeks prior to Cycle 0 Day 1 or
             anticipation that such a live attenuated vaccine will be required during the study.

         26. Major surgical procedure within 20 days prior ty Cycle 0 Day 1 or anticipation of need
             for a major surgical procedure during the course of the study.

         27. 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 enrolment.

         28. 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.

         29. 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.

               -  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.

               -  Patients who are receiving denosumab prior to enrollment must be willing and
                  eligible to receive a bisphosphonate instead while on study.

         30. 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.

         31. Previous treatment with PARP inhibitors.

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

         33. Patients with rare hereditary problems of galactose intolerance, the lapp lactase
             deficiency or glucose galactose malabsorption

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

         35. Patient under guardianship or deprived of his liberty by a judicial or administrative
             decision or incapable of giving its consent.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

, 0142114211, [email protected]



Administrative Informations


NCT ID

NCT04779151

Organization ID

2020-002766-14

Secondary IDs

2020/3093

Responsible Party

Sponsor

Study Sponsor

Gustave Roussy, Cancer Campus, Grand Paris


Study Sponsor

, , 


Verification Date

February 2021