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A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study

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Abstract

This study tested the hypothesis that ABT-888 (velparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, can modulate temozolomide (TMZ) resistance in recurrent TMZ refractory glioblastoma patients. The combination regimen (TMZ/ABT-888) was tested using two randomized schedules (5 vs. 21 days), with 6-month progression free survival (PFS6) as the primary endpoint. The maximum tolerated dose (MTD) for TMZ using the 21 day of 28 TMZ schedule, in concert with 40 mg BID ABT-888 was determined in a phase I portion of this study, and previously reported to be 75 mg/m2 (arm1). The MTD for ABT-888 (40 mg BID) and the 5 of 28 day TMZ (150–200 mg/m2) schedule was known from prior trials (arm2). Two cohorts were studied: bevacizumab (BEV) naïve (n = 151), and BEV refractory (n = 74). Overall ten patients were ineligible. The incidence rate of grade 3/4 myelosuppression over all was 20.0 %. For the BEV refractory cohort, the PFS 6 was 4.4 %; for the BEV naïve cohort, PFS6 was 17 %. Overall survival was similar for both arms in both the BEV naïve [median survival time (MST) 10.3 M; 95 % CI 8.4–12] and BEV refractory cohort (MST 4.7 M; 95 %CI 3.5–5.6). The median PFS was essentially the same for both arms and both cohorts at ~2.0 M (95 % CI 1.9–2.1).

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References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330

    Article  PubMed  CAS  Google Scholar 

  2. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466. doi:10.1016/S1470-2045(09)70025-7

    Article  PubMed  CAS  Google Scholar 

  3. Stupp R, Wong E, Scott C, Taillibert S, Kanner A, Kesari S, Ram Z (2014) Interim analysis of the EF-14 trial: a prospective, multi-center trial of NovoTTF-100A together with temozolomide compared to temozolomide alone in patients with newly diagnosed GBM. Neuro-Oncology 16:v167–v167. doi:10.1093/neuonc/nou265.40 (abstr NT-140)

    Article  Google Scholar 

  4. Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, Black K, Sisti M, Brem S, Mohr G et al (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet 345:1008–1012

    Article  PubMed  CAS  Google Scholar 

  5. Magnuson W, Ian Robins H, Mohindra P, Howard S (2014) Large volume reirradiation as salvage therapy for glioblastoma after progression on bevacizumab. J Neurooncol 117:133–139. doi:10.1007/s11060-014-1363-z

    Article  PubMed  CAS  Google Scholar 

  6. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. doi:10.1056/NEJMoa043331

    Article  PubMed  CAS  Google Scholar 

  7. Tolcher AW, Gerson SL, Denis L, Geyer C, Hammond LA, Patnaik A, Goetz AD, Schwartz G, Edwards T, Reyderman L, Statkevich P, Cutler DL, Rowinsky EK (2003) Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 88:1004–1011. doi:10.1038/sj.bjc.6600827

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Tentori L, Graziani G (2005) Chemopotentiation by PARP inhibitors in cancer therapy. Pharmacol Res 52:25–33. doi:10.1016/j.phrs.2005.02.010

    Article  PubMed  CAS  Google Scholar 

  9. Tentori L, Orlando L, Lacal PM, Benincasa E, Faraoni I, Bonmassar E, D’Atri S, Graziani G (1997) Inhibition of O6-alkylguanine DNA-alkyltransferase or poly(ADP-ribose) polymerase increases susceptibility of leukemic cells to apoptosis induced by temozolomide. Mol Pharmacol 52:249–258

    PubMed  CAS  Google Scholar 

  10. Wedge SR, Porteous JK, Newlands ES (1996) 3-aminobenzamide and/or O6-benzylguanine evaluated as an adjuvant to temozolomide or BCNU treatment in cell lines of variable mismatch repair status and O6-alkylguanine-DNA alkyltransferase activity. Br J Cancer 74:1030–1036

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Lepeak LM, Leal T, Robins HI (2010) Preclinical and clinical development of Velaparib (ABT-888): a poly (ADP-ribose) polymerase inhibitor. Drugs Futur 35:815–822

    Article  CAS  Google Scholar 

  12. Kummar S, Kinders R, Gutierrez ME, Rubinstein L, Parchment RE, Phillips LR, Ji J, Monks A, Low JA, Chen A, Murgo AJ, Collins J, Steinberg SM, Eliopoulos H, Giranda VL, Gordon G, Helman L, Wiltrout R, Tomaszewski JE, Doroshow JH (2009) Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J Clin Oncol 27:2705–2711. doi:10.1200/JCO.2008.19.7681

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Robins HI, Wang M, Gilbert MR, Chakravarti A, Grimm S, Penas-Prado M, Chaudhary R, Anderson PJ, Elinzano H, Gilbert RA, Mehta M (2012) Phase I results from RTOG 0929, a randomized phase I/II study of ABT-888 (veliparib) in combination with temozolomide (TMZ) in recurrent, TMZ-resistant glioblastoma. Neuro Oncol 14:vi65 (abstr NO-14)

    Google Scholar 

  14. Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578

    PubMed  CAS  Google Scholar 

  15. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10

    Article  PubMed  CAS  Google Scholar 

  16. Lassman AB, Iwamoto FM, Gutin PH et al (2008) Patterns of relapse and prognosis after bevacizumab (BEV) failure in recurrent glioblastoma (GBM). J Clin Oncol 26:2028 (96S abstr 2028)

    Google Scholar 

  17. Wick W, Weller M, van den Bent M, Sanson M, Weiler M, von Deimling A, Plass C, Hegi M, Platten M, Reifenberger G (2014) MGMT testing–the challenges for biomarker-based glioma treatment. Nat Rev Neurol 10:372–385. doi:10.1038/nrneurol.2014.100

    Article  PubMed  CAS  Google Scholar 

  18. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740. doi:10.1200/JCO.2008.19.8721

    Article  PubMed  CAS  Google Scholar 

  19. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745. doi:10.1200/JCO.2008.16.3055

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

The authors wish to thank our senior data manager, Sandrine Geinoz PhD, CCRP for her significant contributions.

Funding

This project was supported by Grants U10CA21661, U10CA180868, U10CA180822, U10CA37422, and UG1CA189867 from the National Cancer Institute (NCI) and AbbVie.

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Authors and Affiliations

  1. Paul Carbone Comprehensive Cancer Center, University of Wisconsin, 600 Highland Avenue, Madison, WI, 53792, USA

    H. Ian Robins

  2. NRG Oncology Statistics and Data Management Center, Philadelphia, PA, USA

    Peixin Zhang

  3. National Cancer Institute at the National Institutes of Health, Bethesda, MD, USA

    Mark R. Gilbert

  4. Ohio State University Medical Center, Columbus, OH, USA

    Arnab Chakravarti & Robert Cavaliere

  5. University of Texas-MD Anderson Cancer Center, Houston, TX, USA

    John F. de Groot

  6. Candence Cancer Center, Warrenville, USA

    Sean A. Grimm

  7. University of Kansas, Kansas City, KS, USA

    Fen Wang

  8. UPMC-Shadyside Hospital, Pittsburgh, PA, USA

    Frank S. Lieberman

  9. National Cancer Institute Radiation Oncology Branch, Bethesda, MD, USA

    Andra Krauze

  10. H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Andy M. Trotti

  11. University of Rochester, Rochester, NY, USA

    Nimish Mohile

  12. Legacy Health, Portland, OR, USA

    Andrew Y. J. Kee

  13. University of Utah Health Science Center, Salt Lake City, UT, USA

    Howard Colman

  14. Departments of Neurosciences and Radiation Medicine & Applied Sciences, UC San Diego Health Sciences, La Jolla, CA, USA

    Santosh Kesari

  15. University of Chicago, Chicago, IL, USA

    Steven J. Chmura

  16. University of Maryland Medical Systems, Baltimore, MD, USA

    Minesh Mehta

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  1. H. Ian Robins
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Corresponding author

Correspondence to H. Ian Robins.

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Conflicts of Interest

H. Ian Robins reports grants and personal fees from Novocure, personal fees from AbbVie, outside the submitted work. Mark R Gilbert reports personal fees and non-financial support from Merck, personal fees from Genentech Roche, personal fees from AbbVie, personal fees from Wellcome Trust, and personal fees from Foundation Medicine, outside the submitted work. Frank S Lieberman reports grants and personal fees from Roche (Genentech), grants from Novacure, grants from Celldex, and grants from Stemline, outside the submitted work. Nimish Mohile reports personal fees from Novocure, personal fees from AbbVie, outside the submitted work. Howard Colman reports personal fees from Hoffman La Roche, personal fees from Genentech, personal fees from Sigma Tau, personal fees from Proximagen/Upsher Smith, personal fees from Foundation Medicine, personal fees from Merck, outside the submitted work. Santosh Kesari reports personal fees from Novocure, personal fees from Sigma Tau, grants from Celldex, grants from Tocagen, grants from NWBT, grants from Novartis, outside the submitted work. Minesh Mehta reports personal fees from AbbVie, personal fees from BMS, personal fees from Celldex, grants and personal fees from Novelos, personal fees from Phillips, personal fees from Roche, personal fees from Elekta, personal fees from Novartis, personal fees from Cavion, grants and personal fees from Novocure, personal fees from Pharmacyclics, outside the submitted work.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Robins, H.I., Zhang, P., Gilbert, M.R. et al. A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study. J Neurooncol 126, 309–316 (2016). https://doi.org/10.1007/s11060-015-1966-z

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