A new pragmatic design for dose escalation in phase 1 clinical trials using an adaptive continual reassessment method

Abstract

Background: A key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Traditional rule-based designs require temporarily stopping recruitment whilst waiting to see whether enrolled patients develop toxicity. This can be both inefficient and introduces logistic challenges to recruitment in the clinic. We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible.

Methods: The STARPAC design uses rule-based design until the first patient has a dose limiting toxicity (DLT) and then switches to a modified CRM, with rules to handle patient recruitment during follow-up of earlier patients. STARPAC design is compared via simulations with the TITE-CRM and 3 + 3 methods in various toxicity estimate (T1-5), rate of recruitment (R1-2), and DLT events timing (DT1-4), scenarios using several metrics: accuracy of maximum tolerated dose (MTD), numbers of DLTs, number of patients enrolled and those missed; duration of trial; and proportion of patients treated at the therapeutic dose or MTD.

Results: The simulations suggest that STARPAC design performed well in MTD estimation and in treating patients at the highest possible therapeutic levels. STARPAC and TITE-CRM were comparable in the number of patients required and DLTs incurred. The 3 + 3 design often had fewer patients and DLTs although this is due to its low escalation rate leading to poor MTD estimation. For the numbers of declined patients and MTD estimation 3 + 3 is uniformly worse, with STARPAC being better in those metrics for high toxicity scenarios and TITE-CRM better with low toxicity. In situations including doses with toxicities both above and below 30%, the STARPAC design outperformed TITE-CRM with respect to every metric.

Conclusion: When considering doses with toxicities both above and below the target of 30% toxicities, the two-stage STARPAC dose escalation design provides a more efficient phase I trial design than either the traditional 3 + 3 or the TITE-CRM design. Trialists should model various designs via simulation to adopt the most efficient design for their clinical scenario.

Trial registration: Clinical Trials NCT03307148 (11 October 2017).

Keywords: 3 + 3 design; Adaptive design; Bayesian adaptive; CRM; Dose-finding; Maximal tolerated dose; Model-based design; Rule-based design; Simulation.

Conflict of interest statement

HMK received funding for Investigator Initiated trial from Celgene Sarl (AX-CL-Panc-PI-003922).

Figures

Fig. 1

Flowchart of STARPAC design

Fig. 2

Schematic of recruitment of patients in STARPAC, 3 + 3 and TITE-CRM designs of a hypothetical scenario where the true toxicity is T1, recruitment rate is R1 and DLT timings are DT4. Missed patients are with dashed boxes, recruited patients are with solid boxes and patients with DLT (which may happen anytime between days 7 to 21 as for DT4) are shown in grey boxes