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