scholarly journals Practical modifications to the time-to-event continual reassessment method for phase I cancer trials with fast patient accrual and late-onset toxicities

2011 ◽  
Vol 30 (17) ◽  
pp. 2130-2143 ◽  
Author(s):  
Mei-Yin C. Polley
Keyword(s):  
Phase I ◽  
Late Onset ◽  
Time To Event ◽  
Continual Reassessment Method ◽  
Continual Reassessment ◽  
Cancer Trials ◽  
Patient Accrual

Designing Dose-Escalation Trials With Late-Onset Toxicities Using the Time-to-Event Continual Reassessment Method

2006 ◽  
Vol 24 (27) ◽  
pp. 4426-4433 ◽  
Author(s):  
Daniel Normolle ◽  
Theodore Lawrence
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Late Onset ◽  
Maximum Tolerated Dose ◽  
Phase I Trials ◽  
Operating Characteristics ◽  
Time To Event ◽  
Continual Reassessment Method ◽  
Standard Design ◽  
Continual Reassessment

Purpose The standard design for phase I trials of combined chemotherapy and radiation, which enters either three or six patients per dose level, has little statistical basis and is subject to opening and closing because of delayed toxicities that disrupt patient accrual. We compared the operating characteristics of this standard design and the time-to-event continual reassessment method (TITE-CRM) for dose-escalation trials of combination chemotherapy and radiation. Methods The operating characteristics were determined by Monte Carlo simulation of 60,000 phase I trials. Results Compared with the standard trial design, in studies with delayed toxicity (ie, where four or more patients are expected to enter onto the study during a single previously enrolled patient's observation for toxicity), TITE-CRM trials are significantly shorter when toxicity observation times are long, treat more patients at or above the maximum-tolerated dose, identify the maximum-tolerated dose (MTD) more accurately, and provide phase II information, but do not expose patients to significant additional risk. Estimation precision and overdose control of TITE-CRM increase as the design assumptions more closely resemble the true state of nature, but are reduced if, for instance, the toxicity of treatment has been grossly underestimated. Conclusion Compared with the standard design, if there is any prior knowledge concerning the toxicity profile of a treatment, TITE-CRM can leverage it to produce more accurate estimates of the MTD and does not expose patients to significant excess risk, but requires timely communication between clinical investigators, data managers, and study statisticians.

Phase I Trial Using a Time-to-Event Continual Reassessment Strategy for Dose Escalation of Cisplatin Combined With Gemcitabine and Radiation Therapy in Pancreatic Cancer

2004 ◽  
Vol 22 (2) ◽  
pp. 238-243 ◽  
Author(s):  
Jeffrey H. Muler ◽  
Cornelius J. McGinn ◽  
Daniel Normolle ◽  
Theodore Lawrence ◽  
Diane Brown ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Radiation Therapy ◽  
Phase I ◽  
Dose Level ◽  
Maximum Tolerated Dose ◽  
Time To Event ◽  
Continual Reassessment Method ◽  
Full Dose ◽  
Continual Reassessment ◽  
Dose Limiting Toxicity

Purpose The primary objective of this study was to determine the maximum-tolerated dose of cisplatin that could be added to full-dose gemcitabine and radiation therapy (RT) in patients with pancreatic cancer. Patients and Methods Nineteen patients were treated. Gemcitabine 1,000 mg/m2 was administered over 30 minutes on days 1, 8, and 15 of a 28-day cycle. Cisplatin followed gemcitabine on days 1 and 15. The initial dose level of cisplatin was 30 mg/m2, escalated to a targeted dose of 50 mg/m2 using Time-to-Event Continual Reassessment Method. RT was initiated on cycle 1, day 1, in 2.4 Gy fractions to a total dose of 36 Gy. A second cycle of chemotherapy was planned following a 1-week rest. Results Four of eight patients experienced acute dose limiting toxicity at the 50 mg/m2 cisplatin dose level. Patients treated at 30 and 40 mg/m2 cisplatin dose level tolerated therapy without dose-limiting toxicity. Median survival was 10.7 months (95% CI, 5.4 to 18.2) for all patients, and 12.9 months (95% CI, 7.4 to 21.2) for those without metastasis. Conclusion Cisplatin at doses up to 40 mg/m2 may be safely added to full-dose gemcitabine and conformal RT. The Time-to-Event Continual Reassessment Method trial design allowed rapid completion of the study and confidence in the conclusion about the maximum tolerated dose, but accrued more patients to a dose level above the maximum tolerated dose than the typical phase I design. Local and systemic disease control and survival in this study cohort supports further investigation of gemcitabine-based RT and combination chemotherapy in this disease.

scholarly journals Phase I cancer clinical trials†

2016 ◽  
Vol 4 (1) ◽  
pp. 67-72 ◽  
Author(s):  
Juan R. Cabrera ◽  
Jennie W. Taylor ◽  
Annette M. Molinaro
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Phase Ii Trial ◽  
Maximum Tolerated Dose ◽  
Cancer Clinical Trials ◽  
Dose Estimation ◽  
Time To Event ◽  
Timely Manner ◽  
Continual Reassessment Method ◽  
Continual Reassessment

Abstract An efficient phase I trial is a crucial step in developing a new drug in a safe and timely manner. The main objective of a phase I trial is to determine the maximum tolerated dose in order to recommend the dose for a phase II trial. There are many designs that are implemented in phase I trials. Rule-based designs such as the traditional 3 + 3 method and rolling six design are easy to implement and assess for safety using a conservative approach. Model-based designs such as the continual reassessment method and the time-to-event continual reassessment method use mathematical models to increase the precision of dose estimation. The advantages and shortcomings of these designs, along with other designs, are reviewed.

scholarly journals A Bayesian dose-finding design for outcomes evaluated with uncertainty

2021 ◽  
pp. 174077452110015
Author(s):  
Matthew J Schipper ◽  
Ying Yuan ◽  
Jeremy MG Taylor ◽  
Randall K Ten Haken ◽  
Christina Tsien ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Data Augmentation ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Number Of Patients ◽  
Continual Reassessment ◽  
Partially Observed ◽  
Dose Limiting Toxicity

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

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