Research Article

A novel Phase I/IIa design for early phase oncology studies and its application in the evaluation of MK-0752 in pancreatic cancer

  1. John Whitehead1,*,
  2. Helene Thygesen1,
  3. Thomas Jaki1,
  4. Scot Davies2,
  5. Sarah Halford2,
  6. Helen Turner2,
  7. Natalie Cook3,
  8. Duncan Jodrell3,4

Article first published online: 11 APR 2012

DOI: 10.1002/sim.5331

Issue

Statistics in Medicine

Statistics in Medicine

Volume 31, Issue 18, pages 1931–1943, 15 August 2012

Additional Information

How to Cite

Whitehead, J., Thygesen, H., Jaki, T., Davies, S., Halford, S., Turner, H., Cook, N. and Jodrell, D. (2012), A novel Phase I/IIa design for early phase oncology studies and its application in the evaluation of MK-0752 in pancreatic cancer. Statist. Med., 31: 1931–1943. doi: 10.1002/sim.5331

Author Information

  1. 1

    Medical and Pharmaceutical Statistics Research Unit, Lancaster University, U.K.

  2. 2

    Cancer Research UK, London, U.K.

  3. 3

    Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, U.K.

  4. 4

    University of Cambridge Department of Oncology, Addenbrookes Hospital, Cambridge, U.K.

*John Whitehead, MPS Research Unit, Fylde College, Lancaster University, Lancaster LA1 4YF, U.K.
E-mail: j.whitehead@lancaster.ac.uk

Publication History

  1. Issue published online: 16 JUL 2012
  2. Article first published online: 11 APR 2012
  3. Manuscript Accepted: 25 DEC 2011
  4. Manuscript Received: 8 JUL 2011

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Keywords:

  • adaptive design;
  • Bayesian procedure;
  • combination therapies;
  • dose finding;
  • pancreatic cancer;
  • phase I/II design

The Cancer Research UK study CR0720-11 is a trial to determine the tolerability and effect on survival of using two agents in combination in patients with advanced pancreatic cancer. In particular, the trial is designed first to identify the most suitable combination of doses of the two agents in terms of the incidence of dose-limiting toxicities. Then, the survival of all patients who have received that dose combination in the study so far, together with additional patients assigned to that dose combination to ensure that the total number is sufficient, will be analysed. If the survival outcomes show promise, then a definitive randomised study of that dose combination will be recommended. The first two patients in the trial will be treated with the lowest doses of each agent in combination. An adaptive Bayesian procedure based only on monotonicity constraints concerning the risks of toxicity at different dose levels will then be used to suggest dose combinations for subsequent patients. The survival analysis will concern only patients who received the chosen dose combination, and will compare observed mortality with that expected from an exponential model based on the known survival rates associated with current treatment. In this paper, the Bayesian dose-finding procedure is described and illustrated, and its properties are evaluated through simulation. Computation of the appropriate sample size for the survival investigation is also discussed. Copyright © 2012 John Wiley & Sons, Ltd.

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