P1.03Analysis of Biomarkers and PK Modeling of ABT-767 in Patients With BRCA1/BRCA2-Mutated Tumors or High Grade Serous Ovarian Cancer
| Autor: | Jonge, M. de, Herpen, C.M.L. van, Gietema, J., Timms, K., Dunbar, M., Hetman, R., Serpenti, C., Xiong, H., Zhu, M., Mittapalli, R., Ansell, P., Shepherd, S. |
|---|---|
| Rok vydání: | 2015 |
| Předmět: | |
| Zdroj: | Annals of Oncology, 26 Suppl 2, ii16 Annals of Oncology, 26 Suppl 2, pp. ii16 |
| ISSN: | 0923-7534 |
| Popis: | Item does not contain fulltext BACKGROUND: Malignancies with homologous repair deficiency (HRD) are more dependent on PARP for DNA repair than normal cells. This trial assessed safety and PK of the oral PARP-1 and -2 inhibitor, ABT-767. Here we present biomarker and PK modeling results in patients (pts) with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer or solid tumors with germline (g) BRCA1 or BRCA2 mutation. MATERIALS AND METHODS: In this Phase I, single-agent, dose escalation study, pts received ABT-767 20mg QD to 500mg BID on days 1-28 on a 28-day cycle to assess safety and PK. Tumor BRCA1 and BRCA2 mutation screening and HRD score analyses were performed using a next generation sequencing assay. Dose, BRCA mutation, platinum sensitivity, baseline CA125 level (if relevant), and age were examined as potential predictive variables for efficacy and safety responses. RESULTS: As of Nov 10, 2014, 93 pts were treated; 86% had a primary diagnosis of ovarian cancer. 45% had known gBRCA mutations. Cmax and AUC were dose-proportional from 20-500mg BID. By RECIST 1.1 and/or CA-125 criteria: 13 (14%) CR, 14 (15%) PR; median PFS 110 days. 78 pts submitted tissue for biomarker testing, and HRD status was determined for 63. 34 pts were HR-deficient; of these, 26 had deleterious BRCA mutations. Of 16 RECIST 1.1 and/or CA-125 responders tested, all were HR-deficient; 14/16 had deleterious BRCA mutations. 8 pts had high HRD without deleterious BRCA mutation (2 had CR at 400mg BID; OS > 330 and 368 days, respectively). HR-deficient pts had prolonged PFS (log rank p < 0.05). Logistical regression analyses revealed platinum sensitivity and BRCA status to be significant covariates affecting best tumor response and PFS. Pts with gBRCA mutations also experienced a higher rate of grade 3/4 anemia across dose groups. CONCLUSIONS: As reported previously, ABT-767 has an acceptable safety profile for Phase 2 studies and has single-agent activity in pts with BRCA mutations or high-grade serous ovarian cancer. BRCA mutations, HRD score and platinum sensitivity were associated with response, and gBRCA mutation carriers demonstrated a trend for increased grade 3/4 anemia that was manageable. Overall, these analyses identify pt populations who may be more sensitive to PARP inhibition by ABT-767. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|