David E Kozono1, Thomas E Stinchcombe2, Joseph K Salama3, Jeffrey Bogart4, W Jeffrey Petty5, Michael J Guarino6, Lyudmila Bazhenova7, James M Larner8, Jared Weiss9, Thomas A DiPetrillo10, Steven J Feigenberg11, Xin Chen12, Zhaowen Sun13, Silpa Nuthalapati14, Lindsey Rosenwinkel15, Eric F Johnson16, Bruce A Bach17, Yan Luo18, Everett E Vokes19. 1. Department of Radiation Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address: dkozono@bwh.harvard.edu. 2. Duke Cancer Institute, Durham, 2 Seeley Mudd, 10 Bryan Searle Drive, Durham, NC 27710, USA. Electronic address: thomas.stinchcombe@duke.edu. 3. Duke Cancer Institute, Durham, 2 Seeley Mudd, 10 Bryan Searle Drive, Durham, NC 27710, USA. Electronic address: joseph.salama@duke.edu. 4. Department of Radiation Oncology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. Electronic address: bogartj@upstate.edu. 5. Department of Hematology and Oncology, Wake Forest School of Medicine, Bowman Gray Center for Medical Education, 475 Vine Street, Winston-Salem, NC 27101, USA. Electronic address: wpetty@wakehealth.edu. 6. Christiana Care Health System, Helen F Graham Cancer Center, 4701 Ogletown Stanton Road, Suite 3400, Newark, DE 19713, USA. Electronic address: Michael.Guarino@usoncology.com. 7. Department of Medicine, Moores Cancer Center, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: lbazhenova@ucsd.edu. 8. University of Virginia, Emily Couric Clinical Cancer Center, 1240 Lee Street, Charlottesville, VA 22903, USA. Electronic address: JML2P@hscmail.mcc.virginia.edu. 9. Lineberger Comprehensive Cancer Center at the University of North Carolina, Cancer Hospital, 101 Manning Drive, Chapel Hill, NC 27514, USA. Electronic address: jared_weiss@med.unc.edu. 10. Department of Radiation Oncology, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA. Electronic address: TDiPetrillo@Lifespan.org. 11. Greenebaum Comprehensive Cancer Center, University of Maryland, 22 South Greene Street, Baltimore, MD 21201, USA. 12. Data and Statistical Sciences, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA. Electronic address: xin.chen@abbvie.com. 13. Data and Statistical Sciences, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA. Electronic address: zhaowen.sun@abbvie.com. 14. Clinical Pharmacology and Pharmacometrics, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA. Electronic address: silpa.nuthalapati@Abbvie.com. 15. Global Pharmaceutical R&D, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA. Electronic address: lindsey.rosenwinkel@abbvie.com. 16. Oncology Early Development, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA. Electronic address: eric.f.johnson@abbvie.com. 17. Oncology Development, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA. Electronic address: bruce.bach@abbvie.com. 18. Oncology Development, AbbVie Inc, 1 N. Waukegan Road, North Chicago, IL 60064, USA. Electronic address: yan.luo@abbvie.com. 19. Department of Medicine, University of Chicago, 5801 South Ellis Avenue, Chicago, IL 60637, USA. Electronic address: evokes@medicine.bsd.uchicago.edu.
Abstract
OBJECTIVES: Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients received veliparib orally twice daily (BID) in escalating doses (60-240 mg, Day -3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m2), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120-240 mg BID, Days -2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m2, Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. RESULTS: Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7-32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0-not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0-not reached). CONCLUSIONS: When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.
OBJECTIVES: Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients received veliparib orally twice daily (BID) in escalating doses (60-240 mg, Day -3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m2), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120-240 mg BID, Days -2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m2, Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. RESULTS: Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7-32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0-not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0-not reached). CONCLUSIONS: When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.