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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.
Central Nervous System Tumors
Session Type and Session Title:
Poster Discussion Session, Central Nervous System Tumors
J Clin Oncol 30, 2012 (suppl; abstr 2013)
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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:
An independently validated nomogram for individualized estimation of survival among patients with newly diagnosed glioblastoma: NRG oncology/RTOG 0525 and 0825.Meeting: 2016 ASCO Annual Meeting | Abstract No: 2007
Comprehensive mutation analysis in NRG Oncology/RTOG 9802: A phase III study of RT vs RT + PCV in high-risk low-grade gliomas (LGGs).Meeting: 2016 ASCO Annual Meeting | Abstract No: 2017
Comprehensive mutation analysis in NRG Oncology/RTOG 9813: A phase III trial of RT + TMZ vs RT + nu for anaplastic astrocytoma and mixed anaplastic oligoastrocytoma (Astrocytoma Dominant).Meeting: 2016 ASCO Annual Meeting | Abstract No: 2016
Educational Book Articles by Minesh P. Mehta:
Presentations by Minesh P. Mehta:
Meeting: 2016 ASCO Annual Meeting
Session: Treatment of Low-Grade Gliomas in the Era of Genomic Medicine (Education Session)
Meeting: 2011 ASCO Annual Meeting
Session: Inclusion of Patients with Brain Metastases in Clinical Trials (Education Session)