Targeted Treatments for Hereditary Breast or Ovarian Cancer (including PARP Inhibitors)
Novel Targeted Therapies for BRCA-associated Cancer
BRCA deficiency in tumor cells is associated with genomic instability due in part to impaired homologous recombination repair (HRR). Inhibitors of poly (ADP-ribose) polymerase (PARP), a therapeutic target that functions in base excision repair that is complementary to HRR, have shown promising results in pre-clinical models and early phase clinical trials. Recently completed Phase II multi-center studies to assess the efficacy and safety of KU-0059436 given orally to patients with advanced BRCA1- or BRCA2-associated breast or ovarian cancer showed promising results. We demonstrated pre-clinical activity of a novel PARP inhibitor (ABT-888) obtained from NCI/CTEP in BRCA-deficient breast cancer cell lines, and a multi-center randomized phase II trial (ABT-888 +/- carboplatinum) in advanced BRCA-associated breast cancer is now open to accrual. An NCI R21 grant is enabling prospective study of molecular mechanisms of resistance. Drs. Weitzel and O’Connor are developing a translational therapeutics program targeted to hereditary cancers, to bring other DNA repair targeted agents from the bench to the bedside. These clinical trials constitute a paradigm shift and proof of principle that complementary DNA repair pathways can be inhibited by the study drug, resulting in specific tumor killing and a very mild toxicity profile.
Protocol #07211 Principal Investigator: Jeffrey Weitzel, M.D.
Title: PHII-96 NCI #8264: Phase II Trial of Single Agent ABT-888 with Post-Progression Therapy of ABT-888 in Combination with Carboplatin in Patients with Stage IV BRCA-associated Breast Cancer
The purpose of this study is to find the most effective and well-tolerated dose-level of ABT-888 when used with carboplatin and to evaluate the effectiveness of ABT-888 alone and in combination with carboplatin in treating BRCA1- or BRCA2-associated advanced breast cancer.
Cells contain a type of molecule called deoxyribonucleic acid (DNA). DNA carries the genetic information for the development of cells. If DNA becomes damaged, chemicals inside the cell try to repair it. One such chemical is the protein PARP-1. ABT-888 is an inhibitor of PARP-1. This means ABT-888 stops PARP-1 from repairing DNA. Functioning BRCA genes in normal cells can repair DNA damage even if PARP-1 is inhibited. However, cells with abnormal BRCA, such as BRCA1 and BRCA2 cancer cells, cannot. ABT-888 is in an early phase of development so there is limited information about the use of ABT-888 in human subjects. In previous studies, ABT-888 has been well-tolerated and has caused less side effects than conventional chemotherapies. ABT-888 has not yet been approved for use by the Food and Drug Administration (FDA) except in research studies.
In laboratory and animal experiments, ABT-888 was found to enhance the anti-tumor activity of carboplatin. This study will evaluate whether ABT-888 and/or ABT-888 with carboplatin can prevent the survival of BCRA1- and BCRA2-associated breast cancer cells.
Protocol #09158 Principal Investigator: Mihaela Cristea, M.D.
Title: A Phase 1 Study of ABT-888 in Combination with Carboplatin and Gemcitabine in Subjects with Advanced Solid Tumors
Protocol #08240 Principal Investigator: Robert Morgan, M.D.
Title: PHI-63 NCI #8282: A Phase I Study of Chronically-Dosed, Single Agent ABT-888 in patients with Either BRCA 1/2-Mutated Cancer: Platinum Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer; or Basal Like Breast Cancer
Protocol #07242 Principal Investigator: Karen Reckamp, M.D.
Title: PHI-61 NCI#7967: A Phase I Study of ABT-888 in Combination with Carboplatin and Paclitaxel in Advanced Solid Malignancies
For more detailed information on each of the above studies, please call 1-877-482-HOPE(4673) or visit http://clinicaltrials.coh.org. Please note, that clinical trials are occasionally on hold, so if you are unable to find a particular trial, please check back later. In all cases, patients must be under the care of a City of Hope physician in order to be eligible.
Cancer Prevention Trials and Other Studies for Postmenopausal Women
03178 - Grape seed as an aromatase inhibitor for breast cancer risk reduction – The goal of this project is to determine whether grape seed extract (GSE) significantly suppresses serum estrogens in normal postmenopausal women and to determine if there is a dose effect between GSE and suppression of estrogen biosynthesis.
Principal Investigator: Melanie Palomares, M.D., M.S.
For more detailed information on this study, please call 1-877-482-HOPE(4673) or visit http://clinicaltrials.coh.org. Please note, that clinical trials are occasionally on hold, so if you are unable to find a particular trial, please check back later. In all cases, patients must be under the care of a City of Hope physician in order to be eligible.