Combination Therapy in Cancers With Mutations in DNA Repair Genes

Inclusion Criteria:

1. Individuals 18 years of age or older.

2. Ability to understand and willingness to voluntarily sign a written informed consentdocument prior to any study-related assessments or procedures are conducted; andwilling and able to adhere to the study visit schedule and other protocolrequirements.

3. Solid tumors where topoisomerase I inhibitors have shown efficacy, includinggastrointestinal tumors (e.g., colon, pancreatic, gastric cancer andcholangiocarcinoma), breast cancer, and ovarian cancer (prostate cancer isexcluded), with one or more of the following DNA repair defects: a. BRCA1, BRCA2, ATM, and/or PALB2 (based upon archival tumor tissue or germ linetesting from any Clinical Laboratory Improvement Amendments (CLIA) approved lab).This testing must occur prior to study enrollment.

4. Presence of at least one lesion with measurable disease as defined by RECIST 1.1criteria for response assessment

5. Advanced solid tumor malignancy without curative options

6. At least 5 half-lives or 3 weeks (whichever is shorter) must have passed since lastanticancer therapy

7. The washout period for investigational agents without published half-lives should be 3 weeks since last therapy, and all treatment related toxicities must have recoveredto less than grade 2.

8. Eastern Cooperative Oncology Group (ECOG) Performance Status of <=1 (Karnofsky > 60%; Appendix 1).

9. Adequate organ function:

10. Absolute neutrophil count (ANC) >= 1.5 X 109/L (no growth factors allowedwithin 14 days of enrollment)

11. Hemoglobin (Hgb) ≥10 g/dL (no transfusion allowed within 7 days of enrollment)

12. Platelets (plt) >= 100 x 109/L

13. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5 xUpper Limit Normal (ULN), or AST and ALT <5 x ULN in patients with known livermetastases or known primary liver tumor(s)

14. Serum total bilirubin <= 1.5 x ULN

15. Creatinine <1.5 x ULN, or Estimated Glomerular filtration rate (GFR) >= 50ml/min by Cockcroft-Gault (http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation/)

16. Must have recovered to less than Grade 2 (CTCAE v5.0) in terms of toxicity fromprior treatments (excluding neuropathy which can be ≤ Grade 2, alopecia, nailchanges/nail loss or other chronic minor grade 2 AEs).

17. Must be able to take oral medications.

18. Based on its mechanism of action and pre-clinical findings, irinotecan can causefetal harm when administered to a pregnant woman. Additionally, the effects ofniraparib on the developing fetus are unknown. Therefore: a. Females of childbearing potential and their male partners are advised to practicea highly effective method of contraception during treatment with niraparib and/oririnotecan and for 180 days following the last dose for females and 90 daysfollowing the last dose for males. A woman is considered to be of childbearingpotential unless one of the following applies: i. Is considered to be permanently sterile. Permanent sterilization methods includehysterectomy, bilateral salpingectomy and bilateral oophorectomy. ii. Is postmenopausal, defined as no menses for 12 months without an alternativemedical cause. A high follicle-stimulating hormone (FSH) level consistently in thepostmenopausal range (30 milli-international units per millilitre (mIU/mL) orhigher) may be used to confirm a postmenopausal state in women not using hormonalcontraception or hormonal replacement therapy; however, in the absence of 12 monthsof amenorrhea, a single FSH measurement is insufficient to confirm a postmenopausalstate. b. A male participant of reproductive potential is eligible to participate if heagrees to the following starting with the first dose of study treatment through atleast 90 days (a spermatogenesis cycle) after the last dose of study treatment: i. refrain from donating sperm. ii. 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). c. Highly effective contraception is considered to be a method with a < 1% per yearfailure rate. Recommendations for highly effective contraception while takingniraparib include: i. Ongoing use of injectable or implantable progesterone. ii. Placement of an intrauterine device or intrauterine system. iii. Bilateral tubal occlusion. iv. Complete (as opposed to periodic) abstinence

. v. Male sterilization, with appropriate post-vasectomy documentation of absence ofsperm in ejaculate.

13. Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial.

14. For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

15. Individuals with a history of hepatitis C virus (HCV) infection must have beentreated and cured. For individuals with HCV infection who are currently ontreatment, they are eligible if they have an undetectable HCV viral load.

Exclusion Criteria:

1. Any significant medical condition, laboratory abnormalities, which places thesubject at unacceptable risk if he/she were to participate in the study atclinician's discretion and not otherwise stated below.

2. Prior allergic reaction to PARP inhibitor or irinotecan or their excipients. PriorPARP inhibitor or irinotecan (or topoisomerase 1 inhibitors) use is allowed.

3. Individuals with known toxicity to irinotecan (e.g., grade 3 or 4 neutropenia) orsuspected sensitivity.

4. Individuals with homozygous or compound heterozygous UGT1A1 polymorphisms (e.g.,alleles *28/*28, *6/*6, or *6/*28) predicted to be associated with medium-to-highrisk of irinotecan-related toxicity

5. Individuals receiving any other investigational agents concurrently with the studydrugs within 3 weeks or 5 half-lives, whichever is shorter, of the first dose oftherapy preceding the study.

6. Participants with unstable brain metastases are excluded. Patients with a history ofbrain metastases (>1cm) are permitted to enroll if they have been treated and havebeen stable for a minimum of one month on imaging. Patients may not currentlyreceive steroids for their brain metastases. Patients with small, asymptomatic brainmetastases (<1cm) may enroll.

7. Individuals with a second primary malignancy

8. Individuals with a prior history of posterior reversible encephalopathy syndrome (PRES)

9. Individuals with systolic blood pressure >140 mmHg or diastolic blood pressure >90mmHg that has not been adequately treated or controlled

10. History of a malabsorption syndrome or uncontrolled nausea, vomiting, or diarrheathat may interfere with the absorption of oral study medication in the opinion ofthe investigator.

11. Known or suspected diagnosis of Myelodysplastic syndromes (MDS) or Acute myeloidleukemia (AML).

12. Known Gilbert's disease

13. Individuals who are pregnant and/or breast feeding, or expecting to conceivechildren while receiving study treatment and/or for up to 180 days after the lastdose of study treatment.

14. Inability to comply with study procedures or unwilling to use adequate highlyeffective contraception