Expanded Access With ABT-888 (Veliparib) to Treat Metastatic Breast Cancer
Metastatic Breast Cancer With BRCA 1 or BRCA 2 Genetic Mutation
Triple-Negative Breast Cancer
|Study Type:||Expanded Access What is Expanded Access?|
|Official Title:||Expanded Access Protocol With ABT-888 (Veliparib) in Patients With Metastatic BRCA-Mutation Associated or Triple Negative Breast Cancer|
Patients will start veliparib at 300 mg po BID days 1 through 21 of the first 21 day cycle, then increase to 400 mg po BID days 1 through 21 of each subsequent cycle, as tolerated by the patient.
At the treating investigator's discretion, and with principal investigator approval, veliparib may be used in combination with cisplatin and/or vinorelbine. Veliparib (300mg) will be dosed po BID on Days 1 through 14 of each 21-day cycle.
The patient will receive therapy as long as there is therapeutic benefit
ABT-888 (Veliparib) or Poly(ADP-ribose)-polymerase (PARP) is a nuclear enzyme that recognizes deoxyribonucleic acid (DNA) damage and facilitates DNA repair. Inactive PARPs 1 and 2 bind to damaged DNA, which leads to their auto-activation. The resulting activated PARP then poly(ADP-ribosyl)ates many nuclear target proteins, including those that facilitate DNA repair of both single-stranded or double-stranded DNA breaks. Thus, PARP inhibition will result in less efficient DNA repair following a DNA damage insult.
Since cancer cells are genetically unstable, often exhibiting complex karyotypes that include large deletions, insertions, and unbalanced translocations of chromosomal fragment, these cells are more susceptible than normal tissues to cytotoxicity induced by DNA-damaging agents.Of these, deficiencies in mismatch repair and homologous recombination are associated with the largest number of malignancies, including many sporadic TNBCs. These deficiencies render cells more dependent on PARP for DNA repair and, hence, are more prone to cytotoxicity induced by PARP inhibition. In particular, tumor cells with BRCA1 or BRCA2 deficiencies are exquisitely sensitive to PARP inhibition, even in the absence of any other insults. Identification of sporadic TNBC with defects in homologous recombination and mismatch repair independent of germline mutation of BRCA 1 and 2 is an active area of research interest.
PARP-enabled DNA repair may also compensate for the loss of other repair pathways. Higher expression of PARP in cancer cells compared to normal cells has been linked to drug resistance and the overall ability of cancer cells to sustain genotoxic stress.
The combination of platinum based chemotherapy and PARP inhibition may be most effective in TNBC, and particularly in subsets of TNBC. This combination may also be active in tumors with a germline BRCA1-deficiency and/or basal phenotype, since a defect in the DNA double-strand break repair pathway should increase sensitivity to these agents. The addition of a PARP inhibitor to platinum based chemotherapy may induce a "double hit" to tumor cells lacking homologous recombination without causing excess toxicity to normal cells. ABT-888 may be used in combination with the DNA damaging agent, cisplatin, to potentiate its cytotoxic effect and with vinorelbine to enhance tumor response rate. Safety and preliminary efficacy of veliparib in combination with cisplatin and vinorelbine in patients with advanced triple negative and BRCA-associated breast cancer has been reported.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02985658
|Contact: Jennifer Specht, MD||206-288-6329|
|United States, Washington|
|Seattle Cancer Care Allliance|
|Seattle, Washington, United States, 98109|
|Contact: Jennifer Specht, MD 206-288-6329|