A Phase I Study of ABT-888 in Combination With Temozolomide in Cancer Patients

A Phase 1, multicenter, dose-escalation study evaluating the safety and tolerability of the PARP inhibitor ABT-888 in combination with Temozolomide (TMZ) in subjects with non-hematologic malignancies (NHM), including metastatic melanoma (MM), BRCA deficient breast, ovarian, primary peritoneal, or fallopian tube cancer, and hepatocellular carcinoma (HCC).

Inclusion criteria

Dose escalation and expanded safety cohorts

• Evaluable disease, histologically confirmed malignancy (metastatic or unresectable) and standard curative measures or other therapy that may provide clinical benefit do not exist or are no longer effective
• ECOG Performance Score less than or equal to 2
• Adequate hematologic, renal and hepatic function
• Normal sodium, calcium and magnesium levels
• Voluntarily signed informed consent

Expanded Safety Cohorts Only

• Population:
• Metastatic melanoma (MM)
• Hepatocellular carcinoma (HCC) Child Pugh Category A and B classification only
• BRCA deficient tumor status*: advanced breast cancer (with soft tissue disease), or advanced ovarian cancer, or advanced primary peritoneal cancer, or advanced fallopian tube cancer*

*Patients must have histologically or cytologically confirmed solid tumors with a positive genetic test result documenting BRCA 1 or BRCA 2 mutation status, to be considered eligible.

• Serial tumor biopsies: Required for all subjects enrolled in one of the Expanded Low Dose Safety Cohorts.

Exclusion criteria

Dose Escalation and Expanded Safety Cohorts

• Known central nervous system (CNS) metastases or CNS primary cancer.
• Previous or current malignancies at other sites, except: adequately treated in situ carcinoma of cervix uteri; basal/squamous cell carcinoma of skin; previous malignancy considered cured.
• Previous history or current seizure disorder.
• Clinically significant and uncontrolled major medical condition(s) or any medical condition that places the subject at an unacceptably high risk for toxicities.
• Transplant recipients and patients receiving combination anti-retroviral therapy for HIV due to the use of immunosuppressant therapies.
• Lactating or pregnant female.
• Chemotherapy, immunotherapy, radiotherapy, biologic or any investigational therapy will not be allowed within either 4 weeks, or 5 half lives of a targeted therapy prior to study drug administration (Study Day 1).
• Prior therapy with regimens containing dacarbazine (DTIC) or TMZ is not permitted.
• Anti-cancer therapy is not permitted during the treatment portion of the study.
• Hormone therapy, bisphosphonates or LHRH-agonists for prostate cancer are permitted prior to and during the study.
• Significant adverse event or toxicity due to previous anti-cancer treatment that has not recovered to within one grade level (not to exceed Grade 2) of baseline.

Expanded Safety Cohorts Only:

• MM Only: Prior treatment with DNA damaging agents or cytotoxic chemotherapy including carboplatin, cisplatin, fotemustine, paclitaxel, vincristine, TMZ and DTIC.
• Prior therapy with biologic agents (including IL-2, interferon, bevacizumab, vaccines and immunostimulants) and signal transduction inhibitors (including sorafenib, erlotinib, sutent and elesclomol) are allowed.

Lower Dose Expanded Safety Cohorts Only

• Anti-coagulant restrictions for subjects that have tumor biopsies.