Skip to main content

Advertisement

SpringerLink
Log in

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

  • Clinical Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Gavrilovic IT, Posner JB (2005) Brain metastases: epidemiology and pathophysiology. J Neurooncol 75:5–14

    Article  PubMed  Google Scholar 

  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 22:2865–2872

    Article  PubMed  Google Scholar 

  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 19:1043–1050

    Article  PubMed  Google Scholar 

  4. Ranjan T, Abrey LE (2009) Current management of metastatic brain disease. Neurotherapeutics 6:598–603

    Article  CAS  PubMed  Google Scholar 

  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 13:1611–1616

    Article  CAS  PubMed  Google Scholar 

  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:CD003869

    Google Scholar 

  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 29:134–141

    Article  PubMed Central  PubMed  Google Scholar 

  8. Mehta MP, Khuntia D (2005) Current strategies in whole-brain radiation therapy for brain metastases. Neurosurgery 57:S33–S44; discusssion S31–S34

  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 14:79–84

    Article  CAS  PubMed  Google Scholar 

  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 1327–1328

  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 363:1665–1672

    Article  PubMed  Google Scholar 

  12. Siegal T, Zylber-Katz E (2002) Strategies for increasing drug delivery to the brain: focus on brain lymphoma. Clin Pharmacokinet 41:171–186

    Article  CAS  PubMed  Google Scholar 

  13. Rebucci M, Michiels C (2013) Molecular aspects of cancer cell resistance to chemotherapy. Biochem Pharmacol 85:1219–1226

    Article  CAS  PubMed  Google Scholar 

  14. Vollebergh MA, Jonkers J, Linn SC (2012) Genomic instability in breast and ovarian cancers: translation into clinical predictive biomarkers. Cell Mol Life Sci 69:223–245

    Article  CAS  PubMed  Google Scholar 

  15. Curtin NJ (2012) DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 12:801–817

    Article  CAS  PubMed  Google Scholar 

  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 33:1964–1974

    Article  CAS  PubMed  Google Scholar 

  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 3:113

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Hirai K, Ueda K, Hayaishi O (1983) Aberration of poly(adenosine diphosphate-ribose) metabolism in human colon adenomatous polyps and cancers. Cancer Res 43:3441–3446

    CAS  PubMed  Google Scholar 

  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 37:223–227

    Article  CAS  PubMed  Google Scholar 

  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 16:338–344

    Article  CAS  PubMed  Google Scholar 

  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 13:2728–2737

    Article  CAS  PubMed  Google Scholar 

  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 27:2705–2711

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 13:3033–3042

    Article  CAS  PubMed  Google Scholar 

  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 14:910–918

    Article  PubMed Central  PubMed  Google Scholar 

  25. Iasonos A, Schrag D, Raj GV, Panageas KS (2008) How to build and interpret a nomogram for cancer prognosis. J Clin Oncol 26:1364–1370

    Article  PubMed  Google Scholar 

  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 13:111–116

    Article  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, University of Maryland School of Medicine, 22 S. Greene Street, GGK19, Baltimore, MD, 21201, USA

    Minesh P. Mehta

  2. Henry Ford Hospital, Detroit, MI, USA

    Ding Wang

  3. The University of Kansas Medical Center, Kansas City, KS, USA

    Fen Wang

  4. Johns Hopkins University, Baltimore, MD, USA

    Lawrence Kleinberg

  5. Princess Margaret Hospital, Toronto, ON, Canada

    Anthony Brade

  6. University of Wisconsin, Madison, WI, USA

    H. Ian Robins

  7. Fox Chase Cancer Center, Philadelphia, PA, USA

    Aruna Turaka

  8. AbbVie, Inc., North Chicago, IL, USA

    Terri Leahy, Diane Medina, Hao Xiong, Nael M. Mostafa, Martin Dunbar, Ming Zhu, Jane Qian, Kyle Holen & Vincent Giranda

  9. Winship Cancer Institute of Emory University, Atlanta, GA, USA

    Walter J. Curran

Authors
  1. Minesh P. Mehta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ding Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lawrence Kleinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anthony Brade
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H. Ian Robins
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aruna Turaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Terri Leahy
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Diane Medina
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hao Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nael M. Mostafa
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martin Dunbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ming Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jane Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kyle Holen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Vincent Giranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Walter J. Curran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Minesh P. Mehta.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mehta, M.P., Wang, D., Wang, F. et al. Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study. J Neurooncol 122, 409–417 (2015). https://doi.org/10.1007/s11060-015-1733-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-015-1733-1

Keywords

Search

Navigation