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Phase I safety and pharmacokinetic (PK) study of veliparib in combination with whole brain radiation therapy (WBRT) in patients (pts) with brain metastases.
J Clin Oncol 30, 2012 (suppl; abstr 2013)
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: Veliparib is an oral PARP-1 and -2 inhibitor that enhances the antitumor activity of DNA damaging agents including radiation therapy in vivo. In pre-clinical models, veliparib crosses the blood-brain barrier. This ongoing phase I dose-escalation study evaluates the safety, PK, and provides preliminary antitumor activity of veliparib in combination with WBRT in pts with brain metastases. Methods: Pts with brain metastases from non-CNS primary solid malignancy, adequate organ function, RPA Class 2, and KPS ≥70 were treated with WBRT (37.5 Gy in 15 fractions or 30 Gy in 10 fractions) QD with veliparib BID with every fraction of WBRT in escalating doses of 10, 20, 30, 50, 100, 150, and 200 mg; the final WBRT fraction was followed by 1 extra day of veliparib. Safety, PK, and tumor response by RECIST were assessed. Results: At the time of reporting 59 pts (M/F, 21/38; median age 57 y) had been treated. Baseline KPS was 70, 80, 90, and 100 in 6.8, 32.2, 40.7, and 20.3% pts, respectively; primary tumor types were breast (n=20), NSCLC (n=20), melanoma (n=9), colorectal (n=2), and others (n=8); 71.2% pts had multiple lesions; and 18.6% had prior brain SRS. Grade 3/4 treatment-emergent adverse events (TEAEs; ≥5%) were fatigue (6.8%), anemia (5.1%), hyponatraemia (5.1%), and thrombocytopenia (5.1%); other TEAEs (≥20%) were fatigue (57.6%), headache (42.4%), nausea (40.7%), alopecia (28.8%), vomiting (22%), radiation skin reactions (22%), and decreased appetite (22%). PK of veliparib were approximately dose-proportional, with oral clearance of 21.6 ± 14.2 L/h (mean ± SD, n=45), minimal drug accumulation at day 15, and no significant effect of food on bioavailability. Tumor response was evaluable in 48 pts. Best tumor response and median survival were 37.5% and 10 months (m) for NSCLC, and 52.9% and 12.5 m for breast cancer (excluding pts with leptomeningeal disease). Conclusions: Addition of veliparib up to 200 mg BID was well tolerated with concurrent WBRT and dose escalation ongoing. The PK of veliparib was dose proportional with no food effect. Preliminary antitumor activity is encouraging and informative for the design of more definitive trials.
Abstracts by Minesh P. Mehta:
Phase II study of arsenic trioxide and temozolomide in combination with radiation therapy in patients with malignant gliomas.
Phase III study of radiation therapy (RT) with or without procarbazine, CCNU, and vincristine (PCV) in low-grade glioma: RTOG 9802 with Alliance, ECOG, and SWOG.
RTOG 1119: Phase II randomized study of whole brain radiotherapy with concurrent lapatinib in patients with brain metastasis from HER2-positive breast cancer—A collaborative study of RTOG and KROG (NCT01622868).Category: Breast Cancer - HER2/ER - HER2+
Educational Book Articles by Minesh P. Mehta:
Presentations by Minesh P. Mehta:
Meeting: 2011 ASCO Annual Meeting
Session: Inclusion of Patients with Brain Metastases in Clinical Trials (Education Session)
Meeting: 2010 ASCO Annual Meeting
Session: Supportive Care for Patients with Non-small Cell Lung Cancer (Education Session)