Dataset Information

A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints.

ABSTRACT: There is growing interest in integrated Phase I/II oncology clinical trials involving molecularly targeted agents (MTA). One of the main challenges of these trials are nontrivial dose-efficacy relationships and administration of MTAs in combination with other agents. While some designs were recently proposed for such Phase I/II trials, the majority of them consider the case of binary toxicity and efficacy endpoints only. At the same time, a continuous efficacy endpoint can carry more information about the agent's mechanism of action, but corresponding designs have received very limited attention in the literature. In this work, an extension of a recently developed information-theoretic design for the case of a continuous efficacy endpoint is proposed. The design transforms the continuous outcome using the logistic transformation and uses an information-theoretic argument to govern selection during the trial. The performance of the design is investigated in settings of single-agent and dual-agent trials. It is found that the novel design leads to substantial improvements in operating characteristics compared to a model-based alternative under scenarios with nonmonotonic dose/combination-efficacy relationships. The robustness of the design to missing/delayed efficacy responses and to the correlation in toxicity and efficacy endpoints is also investigated.

SUBMITTER: Mozgunov P

PROVIDER: S-EPMC6899762 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints.

Mozgunov Pavel P Jaki Thomas T

Biometrical journal. Biometrische Zeitschrift 20190712 6

There is growing interest in integrated Phase I/II oncology clinical trials involving molecularly targeted agents (MTA). One of the main challenges of these trials are nontrivial dose-efficacy relationships and administration of MTAs in combination with other agents. While some designs were recently proposed for such Phase I/II trials, the majority of them consider the case of binary toxicity and efficacy endpoints only. At the same time, a continuous efficacy endpoint can carry more information ...[more]

PMID: 31298770

Similar Datasets

Project description:BackgroundApprovals of cancer therapeutics are primarily disease entity specific. Current molecular diagnostic approaches frequently identify actionable alterations in rare cancers or rare subtypes of common cancers for which the corresponding treatments are not approved and unavailable within clinical trials due to entity-related eligibility criteria. Access may be negotiated with health insurances. However, approval rates vary, and critical information required for a scientific evaluation of treatment-associated risks and benefits is not systematically collected. Thus clinical trials with optimized patient selection and comprehensive molecular characterization are essential for translating experimental treatments into standard care.Patients and methodsContinuous ReAssessment with Flexible ExTension in Rare Malignancies (CRAFT) is an open-label phase II trial for adults with pretreated, locally advanced, or metastatic solid tumors. Based on the evaluation by a molecular tumor board, patients are assigned to combinations of six molecularly targeted agents and a programmed death-ligand 1 (PD-L1) antagonist within seven study arms focusing on (i) BRAF V600 mutations; (ii) ERBB2 amplification and/or overexpression, activating ERBB2 mutations; (iii) ALK rearrangements, activating ALK mutations; (iv and v) activating PIK3CA and AKT mutations, other aberrations predicting increased PI3K-AKT pathway activity; (vi) aberrations predicting increased RAF-MEK-ERK pathway activity; (vii) high tumor mutational burden and other alterations predicting sensitivity to PD-L1 inhibition. The primary endpoint is the disease control rate (DCR) at week 16; secondary and exploratory endpoints include the progression-free survival ratio, overall survival, and patient-reported outcomes. Using Simon's optimal two-stage design, 14 patients are accrued for each study arm. If three or fewer patients achieve disease control, the study arm is stopped. Otherwise, 11 additional patients are accrued. If the DCR exceeds 7 of 25 patients, the null hypothesis is rejected for the respective study arm.ConclusionsCRAFT was activated in October 2021 and will recruit at 10 centers in Germany.Trial registration numbersEudraCT: 2019-003192-18; ClinicalTrials.gov: NCT04551521.

Dataset Information

A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints.

Publications

A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets