Rucaparib and Irinotecan in Cancers With Mutations in DNA Repair

Open to people ages 18 years and up

for Dose Escalation Cohort:

1. Men and women, 18 years or older
2. Understand and voluntarily sign informed consent prior to any study-related assessments or procedures are conducted and are able adhere to the study visit schedule and other protocol requirements.
3. Solid tumors with one or more of the following DNA repair defects:
4. BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L (validated from archival tumor tissue or germ line testing from any CLIA approved lab). This testing should occur prior to study consent or enrollment.
5. Presence of at least one lesion with measurable disease as defined by RECIST 1.1 criteria for response assessment
6. Advanced solid tumor malignancy without curative options
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1.
8. Adequate organ function:
9. Absolute neutrophil count (ANC) ≥ 1.5 X 109/L
10. Hemoglobin (Hgb) ≥9g/dL; (last transfusion cannot be within 7 days of trial initiation)
11. Platelets (plt) ≥ 100 x 109/L
12. AST and ALT ≤2.5 x Upper Limit Normal (ULN), <5x in patients with known liver metastases
13. Serum total bilirubin ≤ 1.5 x ULN
14. Creatinine<1.5 x ULN or estimated GFR ≥ 50ml/min by Cockroft-Gault (http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation/)
15. The effects of rucaparib on the developing fetus are unknown. Therefore
16. Given the results of the embryo-fetal development study, in which rucaparib was embryotoxic at all doses administered, females of childbearing potential and their male partners are advised to practice a highly effective method of contraception during treatment with rucaparib and for 1 month following the last dose for females and 4 months following the last dose for males. A woman is considered to be of childbearing potential unless one of the following applies: i. Is considered to be permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

ii. Is postmenopausal, defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level consistently in the postmenopausal range (30 mIU/mL or higher) may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy; however, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to confirm a postmenopausal state.

1. Highly effective contraception is considered to be a method with a < 1% per year failure rate. Recommendations for highly effective contraception while taking rucaparib 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 of sperm in ejaculate

Additional Inclusion Criteria for Dose Expansion Cohort

1. Mandatory biopsy on study entry, if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator)
2. . PARPi naïve or prior exposure to PARPi therapy (varies depending on Arm 1 and Arm 2)
3. Patients in Arm 1 (single agent rucaparib followed by combination upon progression) must be PARPi naïve. Prior irinotecan is allowed
4. Patients in Arm 2 (combination) must have been treated with and progressed on a PARPi previously. Prior irinotecan is allowed.