A simulation study of approaches for handling disease progression in dose-finding clinical trials

ABSTRACT

In traditional dose-finding studies, dose-limiting toxicity (DLT) is determined within a fixed time observation window where DLT is often defined as a binary outcome. In the setting of oncology dose-finding trials, often patients in advanced stage of diseases are enrolled. Therefore, disease progression may occur within the DLT observation window leading to treatment discontinuation and rendering the patient unevaluable for DLT assessment. As a result, additional patients have to be enrolled, increasing the sample size. We propose and compare several practical approaches for handling disease progression which occurs within the DLT observation window, while in the framework of the time-to-event continual reassessment method (TITE-CRM) which allows using partial observations. The approaches differ on the way they define an evaluable patient and in the way incomplete observations are included. The practical approaches, which we call strategies A, B and C, are illustrated and contrasted in the context of a single simulated trial, and compared via simulations under various scenarios of dose-progression relationship, in the setting of advanced soft-tissue sarcoma.

KEYWORDS:

• Dose-finding
• disease progression
• late-onset toxicity
• molecularly-targeted agent
• immunotherapy

Abbreviations

CRM: Continual reassessment method; DLT: Dose-Limiting Toxicity; MTAs: Molecularly targeted agents; MTD: Maximum tolerated dose; OBD: Optimal biological dose; PCS: Probability of correct dose selection; POS: Probability of overdose selection; TITE-CRM: Time-to-event continual reassessment method.

Declaration of interests

The authors declare that they have no competing interests.

Supplementary material

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Additional information

Funding

Shing M. Lee was supported by the American Cancer Society [grant number MRSG-13-146-01-CPHPS].