Bench to Bedside: From Laboratory to Pharmacy
A phase I dose-escalation study of ABT-888 (veliparib) in combination with carboplatin in HER2-negative metastatic breast cancer
Hypothesis: Combining a DNA-damaging agent such as carboplatin with the PARP inhibitor veliparib will improve outcomes in patients with triple-negative breast cancer and patients with ER/PR-positive breast cancer that has defects in Fanconi Anemia DNA-repair pathway. Also that higher doses of veliparib will be tolerated when combined with single agent carboplatin alone, and that FLT-PET uptake will reliably predict antitumor responses, and that higher induction of γH2AX in CTCs will be observed with higher doses of veliparib.
Rationale: More than 1 million new breast-cancer cases occur annually worldwide. In general, 70 percent of early and about 50 percent of metastatic breast-cancer patients respond to initial therapies. However, the disease recurs in a significant number of patients, either because tumor cells have acquired drug resistance, or possibly because cancer-initiating stem cells that are inherently therapy resistant lead to eventual disease progression. Targeted therapies such as tamoxifen and trastuzumab have been highly successful as adjuvant therapies, yet a considerable number of patients still develop metastatic disease.
This protocol primarily focuses on pathways that could result in treatment resistance. The trial investigates the use of the PARP inhibitor veliparib to enhance the sensitivity of cancer cells to chemotherapies to gain maximum benefit and improve outcomes for breast-cancer patients. If our hypothesis is confirmed, it could have a significant impact on clinical outcomes.
Veliparib is an oral small-molecule inhibitor of poly (ADPribose) polymerase (PARP). PARP is an essential nuclear enzyme that recognizes DNA damage and facilitates DNA repair. Expression of PARP is higher in tumor cells compared with normal cells. This overexpression has been linked to drug resistance and the ability of tumor cells to withstand nontoxic stress. We therefore anticipate that inhibiting PARP will enhance the effects of DNA damage and will function as sensitizing agents for chemotherapy and radiation therapy that are designed to cause DNA damage, in this case by carboplatin.
This multi-center, open-label, multi-dose single-arm, phase I, dose-escalation study targets two groups of patients with HER2- negative metastatic breast cancer: 1. ER/PR negative (triple negative) and 2. ER and/or PR positive with defect in Fanconi Anemia repair pathway as tested by the FATSI immunofluorescence screening test.
The study has three key objectives:
- Determine the recommended phase II dose, toxicity and preliminary efficacy of veliparib in combination with carboplatin.
- Evaluate pharmacodynamic markers possibly associated with PARP inhibition in tumor cells. These include changes measurable by positron emission tomography (specifically, FLT-PET) and the induction of the histone variant gamma H2AX in circulating tumor cells.
- Evaluate biomarkers in primary tumor that could predict antitumor response following PARP inhibitor treatment such as BRCA-1 and 2, FANCD2 nuclear foci formation and expression of miR-155.
At a Glance
OSU-10080: A phase I dose-escalation study of ABT-888 (veliparib) in combination with carboplatin in HER2-negative metastatic breast cancer
Eligibility: Patients with triple negative metastatic breast cancer or ER/PR-positive HER2 negative metastatic breast cancer with defects in Fanconi anemia pathway. Patients with known BRCA1/2 germline mutations will also be eligible irrespective of their ER/PR status. Study allows up to three prior lines of chemotherapy for metastatic breast cancer, which could include carboplatin and will allow any number of prior hormonal agents.