Combination Therapy in Cancers With Mutations in DNA Repair Genes

Eligibility Criteria

• 1. Individuals 18 years of age or older.
• 2. Ability to understand and willingness to voluntarily sign a written informed consent document prior to any study-related assessments or procedures are conducted; and willing and able to adhere to the study visit schedule and other protocol requirements.
• 3. Solid tumors where topoisomerase I inhibitors have shown efficacy, including gastrointestinal tumors (e.g., colon, pancreatic, gastric cancer and cholangiocarcinoma), breast cancer, and ovarian cancer (prostate cancer is excluded), with one or more of the following DNA repair defects:
• 4. Presence of at least one lesion with measurable disease as defined by RECIST 1.1 criteria 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 last anticancer 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 recovered to less than grade 2.
• 8. Eastern Cooperative Oncology Group (ECOG) Performance Status of \<=1 (Karnofsky \> 60%; Appendix 1).
• 9. Adequate organ function:
• 1. Absolute neutrophil count (ANC) \>= 1.5 X 109/L (no growth factors allowed within 14 days of enrollment)
• 2. Hemoglobin (Hgb) ≥10 g/dL (no transfusion allowed within 7 days of enrollment)
• 3. Platelets (plt) \>= 100 x 109/L
• 4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<=2.5 x Upper Limit Normal (ULN), or AST and ALT \<5 x ULN in patients with known liver metastases or known primary liver tumor(s)
• 5. Serum total bilirubin \<= 1.5 x ULN
• 6. 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/)
• 10. Must have recovered to less than Grade 2 (CTCAE v5.0) in terms of toxicity from prior treatments (excluding neuropathy which can be ≤ Grade 2, alopecia, nail changes/nail loss or other chronic minor grade 2 AEs).
• 11. Must be able to take oral medications.
• 12. Based on its mechanism of action and pre-clinical findings, irinotecan can cause fetal harm when administered to a pregnant woman. Additionally, the effects of niraparib on the developing fetus are unknown. Therefore:
• 13. Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy 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 HBV viral load must be undetectable on suppressive therapy, if indicated.
• 15. Individuals with a history of hepatitis C virus (HCV) infection must have been treated and cured. For individuals with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• 1. Any significant medical condition, laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study at clinician's discretion and not otherwise stated below.
• 2. Prior allergic reaction to PARP inhibitor or irinotecan or their excipients. Prior PARP inhibitor or irinotecan (or topoisomerase 1 inhibitors) use is allowed.
• 3. Individuals with known toxicity to irinotecan (e.g., grade 3 or 4 neutropenia) or suspected 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-high risk of irinotecan-related toxicity
• 5. Individuals receiving any other investigational agents concurrently with the study drugs within 3 weeks or 5 half-lives, whichever is shorter, of the first dose of therapy preceding the study.
• 6. Participants with unstable brain metastases are excluded. Patients with a history of brain metastases (\>1cm) are permitted to enroll if they have been treated and have been stable for a minimum of one month on imaging. Patients may not currently receive steroids for their brain metastases. Patients with small, asymptomatic brain metastases (\<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 \>90 mmHg that has not been adequately treated or controlled
• 10. History of a malabsorption syndrome or uncontrolled nausea, vomiting, or diarrhea that may interfere with the absorption of oral study medication in the opinion of the investigator.
• 11. Known or suspected diagnosis of Myelodysplastic syndromes (MDS) or Acute myeloid leukemia (AML).
• 12. Known Gilbert's disease
• 13. Individuals who are pregnant and/or breast feeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment.
• 14. Inability to comply with study procedures or unwilling to use adequate highly effective contraception