Phase II Trial of the PARP Inhibitor Niraparib and PD-1 Inhibitor Dostarlimab in Patients With Advanced Cancers With Active Progressing Brain Metastases (STARLET)

Inclusion Criteria:

1. Age ≥ 18 years old. 2. Participant must have brain metastasis and either

2. Advanced BRCA1/2m cancer 2. Advanced HRR-aberrant, non-BRCA1/2m cancer 3. Advancedsmall cell lung cancer 4. Advanced non-small cell lung cancer 5. Advanced TripleNegative Breast Cancer 3. In cohorts 1 and 2, subjects will be eligible for thisstudy based on the presence of actionable aberrations in one or more of thefollowing HRR genes: BRCA1/2, ATM; BRIP1; CDK12; CHEK1; CHEK2; FANCL; PALB2; RAD51;RAD51B; RAD51C; RAD51D; RAD52; RAD54L, or other related genes at the discretion ofthe principal investigator in consultation with the MD Anderson Cancer CenterInstitute for Personalized Cancer Therapy Precision Oncology Decision Support (PODS)group. Variant interpretation for actionability will be performed by PODS.

3. Any prior SRS to brain lesions or prior excision must have occurred ≥1 week beforethe start of dosing for this study. Lesions situated in a previously irradiated areaare considered measurable if progression has been demonstrated in such lesions.

4. Patients must have had at least one prior line of systemic therapy directed at theirmalignancy.

5. Participant must have an Eastern Cooperative Oncology Group (ECOG) performancestatus of ≤ 2.

6. Adequate organ function as described below: (Note: CBC test should be obtainedwithout transfusion or receipt of colony-stimulating factors in the 2 weeks beforeobtaining).

Hematological • Absolute neutrophil count (ANC) ≥1,500 /mcL

• Platelets ≥ 100,000 / mcL

• Hemoglobin ≥ 9.0 g/dL

• Serum creatinine ≤1.5xULN OR Measured or calculated creatinine clearance ≥50 mL/min for participants.

Hepatic

• Serum total bilirubin ≤1.5xULN OR Direct bilirubin ≤1 x ULN for subjects with totalbilirubin levels ≥1.5xULN ) (if associated with liver metastases or Gilbert'sdisease, ≤2.5 x ULN)

• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 x ULN (ifassociated with liver metastases, ≤5 x ULN) Coagulation

• International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated PartialThromboplastin Time (aPTT) ≤1.5xULN, unless subject is receiving anticoagulanttherapy.

8. Participant must have at least one measurable brain metastasis (tumor diameterof 0.5-3 cm by mRECIST on magnetic resonance imaging [MRI]) for which all ofthe following criteria have to be met: asymptomatic (no neurologic signs orsymptoms), unirradiated, not requiring immediate local intervention (surgery orradiosurgery), and not requiring systemic glucocorticoid therapy within 10 daysprior to study treatment initiation. Patient may have other metastatic lesionswhich can have had irradiation.

9. Patients must have archival systemic tumor tissue available at screening.Patients who do not have tissue specimens available may undergo a biopsy duringthe screening period. Acceptable samples include core-needle biopsies for deepsystemic tumor tissue or excisional, incisional, punch, or forceps biopsies forcutaneous, subcutaneous, or mucosal lesions. Representative formalin-fixedparaffin-embedded (FFPE) tumor specimens in paraffin blocks (blocks arepreferred) OR at least 4 unstained slides, with an associated pathology report,for testing of tumor PD-L1 expression. Tumor tissue should be of good qualitybased on total and viable tumor content.

10. Female participant has a negative serum pregnancy test within 3 days prior totaking study treatment if of childbearing potential and agrees use a highlyeffective method of contraception (< 1% failure rate with low user dependency)from screening through 180 days after the last dose of study treatment or is ofnonchildbearing potential. Nonchildbearing potential is defined as follows (byother than medical reasons):

• Patients who are ≥45 years of age and who have not had menses for >1 year or havebeen amenorrhoeic for <2 years without history of a hysterectomy and oophorectomymust have a follicle stimulating hormone value in the postmenopausal range uponscreening evaluation

• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documentedhysterectomy or oophorectomy must be confirmed with medical records of the actualprocedure or confirmed by an ultrasound. Tubal ligation must be confirmed withmedical records of the actual procedure, otherwise the patient must be willing touse an adequate barrier method throughout the study, starting with the screeningvisit through 180 days after the last dose of study treatment. See Section 4.4 for alist of acceptable birth control methods. Information must be captured appropriatelywithin the site's source documents. Note: Abstinence is acceptable if this is theestablished and preferred contraception for the patient.

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

11. Male participants are eligible to participate if they agree to the followingduring the treatment period and for at least 180 days after the last dose ofstudy treatment:

• Refrain from donating sperm plus, either:

• Be abstinent from sexual activity as their preferred and usual lifestyle (abstinenton a long-term and persistent basis) and agree to remain abstinent or

• Must agree to use a male condom (and should also be advised of the benefit for afemale partner to use a highly effective method of contraception as a condom maybreak or leak) 12. Participant must have signed and dated an IRB/IEC approvedwritten informed consent form in accordance with regulatory and institutionalguidelines. This must be obtained before the performance of any protocol relatedprocedures that are not part of normal subject care. Hence, participants must havethe ability to understand and the willingness to sign the approved written informedconsent document.

13. Participant must be willing and able to comply with scheduled visits, treatmentschedule, laboratory testing, and other requirements of the study.

Exclusion Criteria:

1. Participant must not be simultaneously receiving interventional anticancertreatment.

2. Participant must not have contraindications to MRI (implanted metal device orforeign bodies) or MRI contrast (insufficient renal function or allergy).

3. A history of / or suffers from claustrophobia or subject feels unable to lie flatand still on their back for the required period of time in an MRI or PET/CT scanner.

4. Participant must not have symptomatic or untreated spinal cord compression.

5. Participant must not have evidence of leptomeningeal disease.

6. Participant must not have previously received a combination of PARP inhibitor andPD-1/L1inhibitor. Participant must not have previously received equivalent of fulldose single agent PARPi. Prior therapy with PD-1/L1-inhibitor is permitted.

7. For participants choosing optional CSF collection via lumbar puncture: no medicalcontraindication to lumbar puncture may be present (including severe coagulopathy,radiographic concern for impending herniation or obstructive hydrocephalus, or softtissue infection at puncture site, as outlined in MD Anderson institutional policy).LP may be deferred if at any time the treating physician determines that it would beunsafe to perform this procedure due to the characteristics of the brain metastases (eg. size, associated edema, etc).

8. Participant must not have had major surgery ≤ 3 weeks prior to initiating protocoltherapy and participant must have recovered from any surgical effects.

9. Participant must not have received systemic anticancer therapy ≤2 weeks prior toinitiating protocol therapy.

10. Previous systemic radiation therapy encompassing >20% of the bone marrow (but notencompassing the CNS) within 2 weeks

11. Previous stereotactic or highly conformal radiotherapy within 1 week before thestart of dosing for this study, whole brain radiotherapy within 2 weeks.

12. Participant must not have a known hypersensitivity to niraparib and dostarlimabcomponents or excipients.

13. Participants with an inactive, known or suspected autoimmune disease. Subjects withtype I diabetes mellitus, hypothyroidism only requiring hormone replacement, skindisorders (such as vitiligo, psoriasis, or alopecia) not requiring systemictreatment, or conditions not expected to recur in the absence of an external triggerare permitted to enroll.

14. Participant must not have a history of interstitial lung disease.

15. Participants with a major medical, neurologic or psychiatric condition who arejudged as unable to fully comply with study therapy or assessments should not beenrolled.

16. Participant has a history of a second malignancy, unless potentially curativetreatment has been completed with no evidence of malignancy for 2 years.

17. Patients with prostate cancer are excluded from this trial.

18. Participant has a known history of active hepatitis B or hepatitis C. Prior treatedhepatitis B or C with undetectable viral load may be enrolled.

19. Participants who have a known history of HIV positive and are on effectiveanti-retroviral therapy with documented undetectable viral load and CD4 count ≥350within 6 months of the first dose of study treatment are eligible.

20. Participants unable to undergo contrast enhanced brain MRI.

21. Participants unable to swallow pills or have significant gastrointestinal diseasewhich would preclude the adequate oral absorption of medications.

22. Patients who have received live vaccines within 30 days of study entrance.

23. Patients with uncontrolled high blood pressure (HTN >140/90).

24. Patients with prior diagnosis of MDS or AML.