A Study of Oral Rucaparib in Patients With gBRCA Mutation Breast or Ovarian Cancer, or Other Solid Tumor

• Incidence of Grade 3 or 4 adverse events and clinical lab abnormalities defined as DLTs (Part 1) [ Time Frame: Cycle 1 Days 1, 8, 15 and 22 ] [ Designated as safety issue: Yes ]
• PK Profile for Single Dose and at Steady State [ Time Frame: Days 1 and 15 of Cycle 1 ] [ Designated as safety issue: No ]
  AUC - area under curve from time zero to time t or infinity; Cmax - max concentration; Tmax - time to max concentration; t1/2 - elimination half-life; kel - elimination rate constant; Vss/F - volume of distribution at steady state after nonintravenous administration; Cl/F - total plasma clearance
• Overall Response Rate per RECIST version 1.1 (Part 2) [ Time Frame: Every 2 - 3 cycles of treatment ] [ Designated as safety issue: No ]

• PK profile (fasted and fed) (Part 1 only) [ Time Frame: Day -7 and Day 1 of Cycle 1 ] [ Designated as safety issue: No ]
  AUC and Cmax
• Change from baseline in QT/QTc interval (ECG) (Part 1 only) [ Time Frame: Every week (Cycle 1); q3wks (Cycles 2+) ] [ Designated as safety issue: Yes ]
• Incidence of AEs, clinical laboratory abnormalities, and ECG abnormalities [ Time Frame: Every 1-2 weeks (Cycle 1); q3wks (Cycles 2+) ] [ Designated as safety issue: Yes ]
• Duration of response per RECIST version 1.1 (Part 2 only) [ Time Frame: Every 2-3 cycles of treatment ] [ Designated as safety issue: No ]
• Response per RECIST version 1.1 (Part 1 only) [ Time Frame: Every 2-3 cycles of treatment ] [ Designated as safety issue: No ]

• PK profile (fasted and fed) (Part 1 only) [ Time Frame: Day -7 and Day 1 of Cycle 1 ] [ Designated as safety issue: No ]
  AUC and Cmax
• Change from baseline in QT/QTc interval (ECG) (Part 1 only) [ Time Frame: Every week (Cycle 1); q3wks (Cycles 2+) ] [ Designated as safety issue: Yes ]
• Incidence of AEs, clinical laboratory abnormalities, and ECG abnormalities [ Time Frame: Every 1-2 weeks (Cycle 1); q3wks (Cycles 2+) ] [ Designated as safety issue: Yes ]
• Duration of response per RECIST version 1.1 (Part 2 only) [ Time Frame: Every 2-3 cycles of treatment ] [ Designated as safety issue: No ]

The purpose of the first part of the study is to evaluate the safety of different doses and dosing regimens of oral rucaparib administered daily to patients with solid tumors.

The purpose of the second part of the study is to determine the safety and clinical activity of oral rucaparib administered daily to patients with a gBRCA mutation and locally advanced or metastatic breast cancer or platinum-sensitive relapsed ovarian cancer.

Rucaparib (CO-338; formerly known as PF 01367338 and AG 14699) is a small molecule inhibitor of poly-adenosine disphosphate (ADP) ribose polymerase(PARP) being developed for antitumor therapy as monotherapy and in combination with a variety of chemotherapeutic agents as a chemosensitizer. The safety and efficacy of IV rucaparib administered in combination with chemotherapy has been evaluated in several Phase I and Phase II studies.

An oral formulation is the focus of current development efforts. Rucaparib is currently being investigated as monotherapy in patients with cancer associated with BRCA1 or BRCA2 mutations, and in combination with carboplatin in patients with advanced solid tumors. For this study, it is anticipated that rucaparib will promote cell death in the BRCA-deficient tumor cells of breast and ovarian cancer patients with evidence of a germline mutation, thereby limiting tumor progression and providing therapeutic benefit.

• Metastatic Solid Tumor
• Breast Cancer
• Ovarian Cancer

• Experimental: Rucaparib (Breast Cancer)
  Oral rucaparib monotherapy (Part 2 only)
  Intervention: Drug: Rucaparib
• Experimental: Rucaparib (Ovarian Cancer)
  Oral rucaparib monotherapy (Part 2 only)
  Intervention: Drug: Rucaparib

Inclusion Criteria:

(PART 1)

• All cohorts (Dose Escalation and R2PD expansion): Adequate bone marrow, hepatic (liver), renal, and cardiac function.
• All cohorts: Locally recurrent or metastatic solid tumor (includes lymphoma, all types of breast cancer) that has progressed on standard treatment.
• R2PD Expansion cohort only: Documented deleterious gBRCA mutation.

OR

(PART 2)

• Locally advanced or metastatic breast cancer associated with a gBRCA mutation that has relapsed following prior treatment, is not HER2+, and is measurable. One to three regimens in locally advanced/metastatic setting permitted.
• Ovarian cancer associated with a gBRCA mutation that has relapsed >6 months following platinum-based prior treatment and is measurable. Two to four prior treatment regimens permitted.

Exclusion Criteria:

(ALL)

• History of prior cancer except for non-melanoma skin cancer, curatively treated solid tumor (>5 years ago without evidence of recurrence), and synchronous endometrial cancer (Stage 1A) with ovarian cancer.
• Prior treatment with any PARP inhibitor, including rucaparib. Patients who received prior iniparib are eligible.
• Untreated or symptomatic central nervous system metastases.
• Impaired cardiac function or clinically significant cardiac disease.
• Prior gastrectomy or upper bowel removal or any gastrointestinal disorder that would interfere with the absorption of rucaparib.