Rucaparib Camsylate and Irinotecan Hydrochloride in Treating Patients with Advanced Solid Tumors with Mutations in DNA Repair
This phase I trial studies the side effects and best dose of rucaparib camsylate and irinotecan hydrochloride in treating patients with solid tumors with mutations in deoxyribonucleic acid (DNA) repair that have spread to other places in the body (advanced). Rucaparib camsylate and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Inclusion Criteria
- INCLUSION CRITERIA FOR DOSE ESCALATION COHORT
- 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
- Solid tumors with one or more of the following DNA repair defects: * 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 Clinical Laboratory Improvement Act [CLIA] approved lab); this testing should occur prior to study consent or enrollment
- Presence of at least one lesion with measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria for response assessment
- Advanced solid tumor malignancy without curative options
- Eastern Cooperative Oncology Group (ECOG) performance status of =< 1
- Absolute neutrophil count (ANC) >= 1.5 X 10^9/L
- Hemoglobin (Hgb) >= 9 g/dL; (last transfusion cannot be within 7 days of trial initiation)
- Platelets (plt) >= 100 x 10^9/L
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit normal (ULN), < 5 x in patients with known liver metastases
- Serum total bilirubin =< 1.5 x ULN
- Creatinine < 1.5 x ULN or estimated glomerular filtration rate (GFR) >= 50 ml/min by Cockcroft-Gault
- The effects of rucaparib on the developing fetus are unknown. Therefore: * 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: ** Is considered to be permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. ** 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. * 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: ** Ongoing use of injectable or implantable progesterone ** Placement of an intrauterine device or intrauterine system ** Bilateral tubal occlusion ** Complete (as opposed to periodic) abstinence ** Male sterilization, with appropriate post-vasectomy documentation of absence of sperm in ejaculate
- ADDITIONAL INCLUSION CRITERIA FOR DOSE EXPANSION COHORT
- Mandatory biopsy on study entry, if the lesion can be biopsied with acceptable clinical risk (as judged by the investigator)
- PARPi naive or prior exposure to PARPi therapy (varies depending on Arm 1 and Arm 2) * Patients in Arm 1 (single agent rucaparib followed by combination upon progression) must be PARPi naive; prior irinotecan is allowed * Patients in Arm 2 (combination) must have been treated with and progressed on a PARPi previously; prior irinotecan is allowed
Exclusion Criteria
- EXCLUSION CRITERIA FOR DOSE ESCALATION COHORT
- 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
- Allergic reaction to single-agent rucaparib or irinotecan
- Myelodysplastic features on peripheral blood smear
- Prior allergic reaction or known intolerance to irinotecan
- Known Gilbert’s disease
- Poorly controlled or symptomatic central nervous system (CNS) metastases or carcinomatous meningitis
- Note: Patients with previously treated brain metastases may participate, 2 weeks after gamma knife (or equivalent) or 4 weeks after whole brain radiotherapy (WBRT), provided they are stable (without evidence of progression by imaging and have not been using steroids for at least 7 days prior to study treatment
- Pregnancy and breast feeding
- Inability to comply with study procedures or willingness to use adequate birth control
- ADDITIONAL EXCLUSION CRITERIA FOR DOSE EXPANSION COHORT
- PARPi naive or prior exposure to PARPi therapy * Patients in Arm 1 of the Dose Expansion cohort cannot have prior exposure to PARPi therapy * Patients in Arm 2 of the Dose Expansion cohort cannot be PARPi naive
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03318445.
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) and recommended phase II dose of rucaparib camsylate (rucaparib) with irinotecan hydrochloride (irinotecan) combination therapy.
II. To assess safety and toxicities of rucaparib and irinotecan combination.
SECONDARY OBJECTIVES:
I. To determine the preliminary efficacy of rucaparib as a single agent and the efficacy of the combination after progression on PARP inhibitors.
II. To evaluate the pharmacokinetics of rucaparib and irinotecan when given in combination.
III. To evaluate biomarkers that correlate with benefits to rucaparib in combination with irinotecan.
IV. To evaluate the steady-state trough concentration of rucaparib.
EXPLORATORY OBJECTIVES, OTHER ASSESSMENTS:
I. To assess the genomic profile of tumors with Foundation Medicine next-generation sequencing and their HRD (homologous recombination deficient) signature.
II. To evaluate DNA mutational analysis with cell free DNA assays.
III. To generate mouse avatars, where feasible, on pre and post treatment tumor biopsies.
IV. To study reversion mutations in patients with initial response and subsequent progression.
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 arms.
ARM I: Patients who are PARPi naive receive rucaparib camsylate orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients who have received prior PARPi therapy receive rucaparib camsylate PO BID on days 1-7 and 15-21 (days 1-7 only if irinotecan hydrochloride not tolerated on 28-day cycle), and irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1 and 15 (day 1 only if not tolerated on 28-day cycle). Cycles repeat every 28 days (every 21 days if irinotecan hydrochloride not tolerated on 28-day cycle) in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed for 30 days.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationUniversity of California San Francisco
Principal InvestigatorPamela N. Munster
- Primary ID169521
- Secondary IDsNCI-2017-02294, 17-22565
- ClinicalTrials.gov IDNCT03318445