Advertisement

Journal of Neuro-Oncology

, Volume 122, Issue 2, pp 409–417 | Cite as

Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study

  • Minesh P. MehtaEmail author
  • Ding Wang
  • Fen Wang
  • Lawrence Kleinberg
  • Anthony Brade
  • H. Ian Robins
  • Aruna Turaka
  • Terri Leahy
  • Diane Medina
  • Hao Xiong
  • Nael M. Mostafa
  • Martin Dunbar
  • Ming Zhu
  • Jane Qian
  • Kyle Holen
  • Vincent Giranda
  • Walter J. Curran
Clinical Study

Abstract

Veliparib, a potent, oral PARP inhibitor, potentiates the antitumor activity of radiation therapy and crosses the blood–brain barrier. This was a phase 1 dose-escalation study evaluating the safety, and secondarily the antitumor activity of veliparib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases, in order to power future trials. Patients with brain metastases from primary solid tumors were treated with WBRT (30.0 or 37.5 Gy in 10 or 15 fractions) and veliparib (escalating doses of 10–300 mg, orally BID). Safety and tumor response were assessed. Observed survival was compared to predicted survival based on a published nomogram. Eighty-one patients (median age 58 years) were treated. The most common primary tumor types were non-small cell lung (NSCLC; n = 34) and breast cancer (n = 25). The most common AEs deemed possibly related to veliparib (AEs, ≥15 %) were fatigue (30 %), nausea (22 %), and decreased appetite (15 %). Fatigue (5 %), hypokalemia and hyponatremia (3 % each) were the only Grade 3/4 AEs deemed possibly related to veliparib observed in ≥2 patients. Although this was an uncontrolled study, preliminary efficacy results were better than predicted: the median survival time (MST, 95 % CI) for the NSCLC subgroup was 10.0 mo (3.9–13.5) and for the breast cancer subgroup was 7.7 mo (2.8–15.0) compared to a nomogram-model-predicted MST of 3.5 mo (3.3–3.8) and 4.9 mo (4.2–5.5). The addition of veliparib to WBRT did not identify new toxicities when compared to WBRT alone. Based on encouraging safety and preliminary efficacy results, a randomized, controlled phase 2b study is ongoing.

Keywords

Phase 1 clinical trial Veliparib PARP inhibitor Whole brain radiation therapy Brain metastases 

Notes

Acknowledgements

Medical writing support was provided by Jacqueline Nielsen and Jaimee Glasgow, employees of AbbVie.

Conflict of interest

MMehta has served as a consultant for AbbVie, Elekta, Merck, BMS, Novelos, Novocure, and Roche. He serves on the Board of Directors for Pharmacyclics; owns stocks with Pharmacyclics, and Accuray. W Curran is a consultant for BMS and receives research funding from AbbVie. L Kleinberg receives research funding from AbbVie. HI Robins has been a consultant for AbbVie. A Turaka, D Wang, F Wang and A Brade have no conflicts of interest to declare. J Qian, M Zhu, TL Leahy, D Median, H Xiong, N Mostafa, M Dunbar, K Holen, and VL Giranda are AbbVie employees and may own stock; V. L. Giranda has a pending patent application related to the subject matter in the manuscript.

Funding

AbbVie provided financial support for this study and participated in the design, study conduct, analysis and interpretation of the data as well as the writing, review, and approval of this manuscript.

Human rights

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.

References

  1. 1.
    Gavrilovic IT, Posner JB (2005) Brain metastases: epidemiology and pathophysiology. J Neurooncol 75:5–14CrossRefPubMedGoogle Scholar
  2. 2.
    Barnholtz-Sloan JS, Sloan AE, Davis FG, Vigneau FD, Lai P, Sawaya RE (2004) Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan detroit cancer surveillance system. J Clin Oncol 22:2865–2872CrossRefPubMedGoogle Scholar
  3. 3.
    Zhang X, Zhang W, Cao W-D, Cheng G, Liu B, Cheng J (2012) A review of current management of brain metastases. Ann Surg Oncol 19:1043–1050CrossRefPubMedGoogle Scholar
  4. 4.
    Ranjan T, Abrey LE (2009) Current management of metastatic brain disease. Neurotherapeutics 6:598–603CrossRefPubMedGoogle Scholar
  5. 5.
    Smalley SR, Schray MF, Laws ER Jr, O’Fallon JR (1987) Adjuvant radiation therapy after surgical resection of solitary brain metastasis: association with pattern of failure and survival. Int J Radiat Oncol Biol Phys 13:1611–1616CrossRefPubMedGoogle Scholar
  6. 6.
    Tsao MN, Lloyd N, Wong R, Chow E, Rakovitch E, Laperriere N (2006) Whole brain radiotherapy for the treatment of multiple brain metastases. Cochrane Database Syst Rev 4:CD003869Google Scholar
  7. 7.
    Kocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Collette S, Collette L, Mueller RP (2011) Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the eortc 22952-26001 study. J Clin Oncol 29:134–141CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Mehta MP, Khuntia D (2005) Current strategies in whole-brain radiation therapy for brain metastases. Neurosurgery 57:S33–S44; discusssion S31–S34Google Scholar
  9. 9.
    Abe E, Aoyama H (2012) The role of whole brain radiation therapy for the management of brain metastases in the era of stereotactic radiosurgery. Curr Oncol Rep 14:79–84CrossRefPubMedGoogle Scholar
  10. 10.
    Khalsa SS, Chinn M, Krucoff M, Sherman JH (2013)The role of stereotactic radiosurgery for multiple brain metastases in stable systemic disease: a review of the literature. Acta Neurochir (Wien) 155:1321–1327; discussion 1327–1328Google Scholar
  11. 11.
    Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, Werner-Wasik M, Demas W, Ryu J, Bahary JP, Souhami L, Rotman M, Mehta MP, Curran WJ Jr (2004) Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase iii results of the rtog 9508 randomised trial. Lancet 363:1665–1672CrossRefPubMedGoogle Scholar
  12. 12.
    Siegal T, Zylber-Katz E (2002) Strategies for increasing drug delivery to the brain: focus on brain lymphoma. Clin Pharmacokinet 41:171–186CrossRefPubMedGoogle Scholar
  13. 13.
    Rebucci M, Michiels C (2013) Molecular aspects of cancer cell resistance to chemotherapy. Biochem Pharmacol 85:1219–1226CrossRefPubMedGoogle Scholar
  14. 14.
    Vollebergh MA, Jonkers J, Linn SC (2012) Genomic instability in breast and ovarian cancers: translation into clinical predictive biomarkers. Cell Mol Life Sci 69:223–245CrossRefPubMedGoogle Scholar
  15. 15.
    Curtin NJ (2012) DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 12:801–817CrossRefPubMedGoogle Scholar
  16. 16.
    Barckhausen C, Roos WP, Naumann SC, Kaina B (2014) Malignant melanoma cells acquire resistance to DNA interstrand cross-linking chemotherapeutics by p53-triggered upregulation of ddb2/xpc-mediated DNA repair. Oncogene 33:1964–1974CrossRefPubMedGoogle Scholar
  17. 17.
    Mladenov E, Magin S, Soni A, Iliakis G (2013) DNA double-strand break repair as determinant of cellular radiosensitivity to killing and target in radiation therapy. Front Oncol 3:113CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Hirai K, Ueda K, Hayaishi O (1983) Aberration of poly(adenosine diphosphate-ribose) metabolism in human colon adenomatous polyps and cancers. Cancer Res 43:3441–3446PubMedGoogle Scholar
  19. 19.
    Tomoda T, Kurashige T, Moriki T, Yamamoto H, Fujimoto S, Taniguchi T (1991) Enhanced expression of poly(adp-ribose) synthetase gene in malignant lymphoma. Am J Hematol 37:223–227CrossRefPubMedGoogle Scholar
  20. 20.
    Shiobara M, Miyazaki M, Ito H, Togawa A, Nakajima N, Nomura F, Morinaga N, Noda M (2001) Enhanced polyadenosine diphosphate-ribosylation in cirrhotic liver and carcinoma tissues in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 16:338–344CrossRefPubMedGoogle Scholar
  21. 21.
    Donawho CK, Luo Y, Penning TD, Bauch JL, Bouska JJ, Bontcheva-Diaz VD, Cox BF, DeWeese TL, Dillehay LE, Ferguson DC, Ghoreishi-Haack NS, Grimm DR, Guan R, Han EK, Holley-Shanks RR, Hristov B, Idler KB, Jarvis K, Johnson EF, Kleinberg LR, Klinghofer V, Lasko LM, Liu X, Marsh KC, McGonigal TP, Meulbroek JA, Olson AM, Palma JP, Rodriguez LE, Shi Y, Stavropoulos JA, Tsurutani AC, Zhu GD, Rosenberg SH, Giranda VL, Frost DJ (2007) Abt-888, an orally active poly(adp-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 13:2728–2737CrossRefPubMedGoogle Scholar
  22. 22.
    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 27:2705–2711CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Albert JM, Cao C, Kim KW, Willey CD, Geng L, Xiao D, Wang H, Sandler A, Johnson DH, Colevas AD, Low J, Rothenberg ML, Lu B (2007) Inhibition of poly(adp-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin Cancer Res 13:3033–3042CrossRefPubMedGoogle Scholar
  24. 24.
    Barnholtz-Sloan JS, Yu C, Sloan AE, Vengoechea J, Wang M, Dignam JJ, Vogelbaum MA, Sperduto PW, Mehta MP, Machtay M, Kattan MW (2012) A nomogram for individualized estimation of survival among patients with brain metastasis. Neuro Oncol 14:910–918CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Iasonos A, Schrag D, Raj GV, Panageas KS (2008) How to build and interpret a nomogram for cancer prognosis. J Clin Oncol 26:1364–1370CrossRefPubMedGoogle Scholar
  26. 26.
    Kattan MW (2003) Nomograms are superior to staging and risk grouping systems for identifying high-risk patients: preoperative application in prostate cancer. Curr Opin Urol 13:111–116CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Minesh P. Mehta
    • 1
    Email author
  • Ding Wang
    • 2
  • Fen Wang
    • 3
  • Lawrence Kleinberg
    • 4
  • Anthony Brade
    • 5
  • H. Ian Robins
    • 6
  • Aruna Turaka
    • 7
  • Terri Leahy
    • 8
  • Diane Medina
    • 8
  • Hao Xiong
    • 8
  • Nael M. Mostafa
    • 8
  • Martin Dunbar
    • 8
  • Ming Zhu
    • 8
  • Jane Qian
    • 8
  • Kyle Holen
    • 8
  • Vincent Giranda
    • 8
  • Walter J. Curran
    • 9
  1. 1.Department of Radiation OncologyUniversity of Maryland School of MedicineBaltimoreUSA
  2. 2.Henry Ford HospitalDetroitUSA
  3. 3.The University of Kansas Medical CenterKansas CityUSA
  4. 4.Johns Hopkins UniversityBaltimoreUSA
  5. 5.Princess Margaret HospitalTorontoCanada
  6. 6.University of WisconsinMadisonUSA
  7. 7.Fox Chase Cancer CenterPhiladelphiaUSA
  8. 8.AbbVie, Inc.North ChicagoUSA
  9. 9.Winship Cancer Institute of Emory UniversityAtlantaUSA

Personalised recommendations