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

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A novel phase I/IIa design for early phase oncology studies and its application in the evaluation of MK-0752 in pancreatic cancer. / Whitehead, John; Thygesen, Helene; Jaki, Thomas et al.

In: Statistics in Medicine, Vol. 31, No. 18, 15.08.2012, p. 1931-1943.

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Whitehead J, Thygesen H, Jaki T, Davis S, Halford S, Turner H et al. A novel phase I/IIa design for early phase oncology studies and its application in the evaluation of MK-0752 in pancreatic cancer. Statistics in Medicine. 2012 Aug 15;31(18):1931-1943. Epub 2012 Apr 11. doi: 10.1002/sim.5331

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@article{957c02350f7d4430ae16a6938440d3f8,
title = "A novel phase I/IIa design for early phase oncology studies and its application in the evaluation of MK-0752 in pancreatic cancer",
abstract = "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. ",
keywords = "adaptive design, Bayesian procedure , combination therapies , dose finding , pancreatic cancer , phase I/II design",
author = "John Whitehead and Helene Thygesen and Thomas Jaki and S. Davis and S. Halford and H. Turner and N. Cook and Duncan Jodrell",
year = "2012",
month = aug,
day = "15",
doi = "10.1002/sim.5331",
language = "English",
volume = "31",
pages = "1931--1943",
journal = "Statistics in Medicine",
issn = "0277-6715",
publisher = "John Wiley and Sons Ltd",
number = "18",

}

RIS

TY - JOUR

T1 - A novel phase I/IIa design for early phase oncology studies and its application in the evaluation of MK-0752 in pancreatic cancer

AU - Whitehead, John

AU - Thygesen, Helene

AU - Jaki, Thomas

AU - Davis, S.

AU - Halford, S.

AU - Turner, H.

AU - Cook, N.

AU - Jodrell, Duncan

PY - 2012/8/15

Y1 - 2012/8/15

N2 - 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.

AB - 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.

KW - adaptive design

KW - Bayesian procedure

KW - combination therapies

KW - dose finding

KW - pancreatic cancer

KW - phase I/II design

U2 - 10.1002/sim.5331

DO - 10.1002/sim.5331

M3 - Journal article

VL - 31

SP - 1931

EP - 1943

JO - Statistics in Medicine

JF - Statistics in Medicine

SN - 0277-6715

IS - 18

ER -