Niraparib and Dostarlimab in HRD Solid Tumors

Inclusion Criteria:

1. Metastatic, recurrent, or unresectable solid tumor with a pathogenic, or presumedpathogenic, somatic mutation of one of the following homologous recombinationdeficiency (HRD) gene mutations: • BRCA1, BRCA2, ATM, RAD51B, RAD51C, RAD54L, RAD51D, FANC/BRIP1, FANCI, FANCL,FANCN(PALB2), BARD1, CHEK1, CHEK2, CDK12, or PPP2R2A.
2. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance statusof ≤ 1
3. Participant must be ≥ 18 years of age
4. Participant must have adequate organ function, defined as follows:

• Absolute neutrophil count ≥ 1,500/µL
• Platelets ≥ 100,000/µL
• Hemoglobin ≥ 9 g/dL
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinineclearance ≥ 60mL/min using the Cockcroft-Gault equation
• Total bilirubin ≤ 1.5 x ULN (≤2.0 in patients with known Gilberts syndrome) ORdirect bilirubin ≤ 1 x ULN
• Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless livermetastases are present, in which case they must be ≤ 5 x ULN
• International normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN unlesspatient is receiving anticoagulant therapy as long as PT or partialthromboplastin (PTT) is within therapeutic range of intended use ofanticoagulants. Activated partial thromboplastin time (aPTT) ≤1.5× ULN unlesspatient is receiving anticoagulant therapy as long as PT or PTT is withintherapeutic range of intended use of anticoagulants

5. Participant must agree to not donate blood during the study or for 90 days after thelast dose of study treatment.
6. Female participant has a negative serum pregnancy test within 72 hours prior to takingstudy treatment if of childbearing potential and agrees to use a highly effectivemethod of contraception from screening through 180 days after the last dose of studytreatment, or is of non-childbearing potential. Non-childbearing potential is definedas follows (by other than medical reasons):

• ≥45 years of age and has not had menses for >1 year
• Patients who have been amenorrhoeic for <2 years without history of ahysterectomy and oophorectomy must have a follicle stimulating hormone value inthe postmenopausal range upon screening evaluation
• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation.Documented hysterectomy or oophorectomy must be confirmed with medical records ofthe actual procedure or confirmed by an ultrasound. Tubal ligation must beconfirmed with medical records of the actual procedure, otherwise the patientmust be willing to use an adequate barrier method throughout the study, startingwith the screening visit through 180 days after the last dose of study treatment.See Section 5.4 for a list of acceptable birth control methods. Information mustbe captured appropriately within the site's source documents. Note: Abstinence isacceptable if this is the established and preferred contraception for thepatient.

h. Male participant agrees to use a highly effective method of contraception (see Section 5.4 for a list of acceptable birth control methods) starting with the first dose of studytreatment through 180 days after the last dose of study treatment. Note: Abstinence isacceptable if this is the established and preferred contraception for the patient. i. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with documented undetectable viral load and CD 4 count of >350 within 6 months ofthe first dose of study treatment are eligible for this trial.

j. If an appropriate archival tumor tissue sample is not available, patient is willing toundergo a pre-treatment tumor biopsy.

k. Participant must be able to understand the study procedures and agree to participate inthe study by providing written informed consent

Exclusion Criteria:

1. Participant must not be simultaneously enrolled in any interventional clinical trial
2. Patients with the following malignancies will be excluded:

• Prostate cancer
• Ovarian, breast, and pancreatic patients with known germline BRCA1 or BRCA2mutation
• Platinum sensitive ovarian cancer (defined as recurrence > 6 months from lastplatinum agent), unless platinum intolerant.

3. Participant must not have had major surgery ≤ 3 weeks prior to initiating protocoltherapy and participant must have recovered from any surgical effects.
4. Participant must not have received investigational therapy ≤ 4 weeks, or within a timeinterval less than at least 5 half-lives of the investigational agent, whichever isshorter, prior to initiating protocol therapy.
5. Participant has had radiation therapy encompassing >20% of the bone marrow within 2weeks; or any radiation therapy within 1 week prior to Day 1 of protocol therapy.
6. Participant must not have a known hypersensitivity to niraparib and dostarlimabcomponents or excipients.
7. Participant must not have received a transfusion (platelets or red blood cells) ≤ 4weeks prior to initiating protocol therapy.
8. Participant must not have received colony stimulating factors (eg, granulocytecolony-stimulating factor, granulocyte macrophage colony stimulating factor, orrecombinant erythropoietin) within 4 weeks prior initiating protocol therapy.
9. Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia dueto prior chemotherapy that persisted > 4 weeks and was related to the most recenttreatment.
10. Participant must not have any known history of myelodysplastic syndrome (MDS) or acutemyeloid leukemia (AML)
11. Participant must not have a serious, uncontrolled medical disorder, nonmalignantsystemic disease, or active, uncontrolled infection. Examples include, but are notlimited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardialinfarction, uncontrolled major seizure disorder, unstable spinal cord compression,superior vena cava syndrome, or any psychiatric disorder that prohibits obtaininginformed consent
12. Participant must not have had diagnosis, detection, or treatment of another type ofcancer ≤ 2 years prior to initiating protocol therapy (except basal or squamous cellcarcinoma of the skin and cervical cancer that has been definitively treated)
13. Participant must not have known leptomeningeal disease, carcinomatous meningitis,symptomatic brain metastases, or radiologic signs of CNS hemorrhage. • Patients with a history of brain metastases may be enrolled if the metastases arefully treated with either resection or irradiation, the patient is asymptomatic for 4weeks, and the patient is off steroids.
14. Patient experienced ≥ Grade 3 immune-related AE with prior immunotherapy, with theexception of non-clinically significant lab abnormalities.
15. Participant has a diagnosis of immunodeficiency or has received systemic steroidtherapy at a dose of >10 prednisone or its equivalent or any other form ofimmunosuppressive therapy within 7 days prior to initiating protocol therapy.
16. Participant has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg]reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [qualitative]is detected).
17. Participant has an active autoimmune disease that has required systemic treatment inthe past 2 years (ie, with use of disease-modifying agents, corticosteroids, orimmunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologiccorticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) isnot considered a form of systemic treatment.
18. Participant must not have a history of interstitial lung disease.
19. Participant has received a live vaccine within 14 days of initiating protocol therapy.