Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter phase II trial

Abstract

Background: Approvals 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 methods: Continuous 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.

Conclusions: CRAFT was activated in October 2021 and will recruit at 10 centers in Germany.

Trial registration numbers: EudraCT: 2019-003192-18; ClinicalTrials.gov: NCT04551521.

Keywords: clinical trial in progress; immunotherapy; precision oncology; target therapy.

Conflict of interest statement

Disclosure AV reports speaker, consultancy, and advisory role for Amgen, Roche, Bayer, Sanofi, BMS, Lilly, Novartis, EISAI, AstraZeneca, Merck, Incyte, Ipsen, Pierre Fabre, MSD, Sirtex, BTG, Servier, Terumo, and GSK. AD reports consulting for or advisory board membership with Bayer, Roche, BMS, MSD, Takeda, Janssen-Cilag; as well as travel or accommodation expenses from Celgene. GB reports consulting for or advisory board membership with AstraZeneca, BMS, MSD, Novartis, Roche, and Pfizer; research associations with Roche and MSD; and travel funds from BMS, MSD, and Roche. AS reports sitting on the Advisory Board/Speaker’s Bureau of Aignostics, Amgen, Astra Zeneca, AGCT, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, and Thermo Fisher; Research funding from Bayer, BMS, Chugai, and Incyte. KS reports honorary, partly with travel expenses, from Adviva, Audi, Pierre Fabre, Preventon, Swiss Group for Clinical Research, and Takeda. DJ reports consulting or advisory role for Roche/Genentech, Bristol Myers Squibb, BioNTech AG, and Amgen. CH reports consulting for or advisory board membership with Boehringer Ingelheim; honoraria from Roche and Novartis; and research funding from Boehringer Ingelheim. SF: reports consulting for or advisory board membership with Bayer, Illumina, and Roche; honoraria from Amgen, Eli Lilly, PharmaMar, and Roche; research funding from AstraZeneca, Pfizer, PharmaMar, and Roche; travel or accommodation expenses from Amgen, Eli Lilly, Illumina, PharmaMar, and Roche. RFS reports consulting for or advisory board membership with Daiichi Sankyo, Pfizer, Astellas, and Novartis; research funding from PharmaMar, AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, and Daiichi Sankyo; travel, accommodations, and expenses covered by Daiichi Sankyo. All others have declared no conflicts of interest.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Pathways and study arms of the CRAFT trial. Molecular eligibility is determined by the DKFZ/NCT/DKTK MTB. Representative examples of eligible molecular alterations include BRAF V600E/K mutations (Arm 1/BRAF); ERBB2 amplification and/or overexpression, activating ERBB2 mutations (Arm 2/ERBB2); ALK rearrangements, activating ALK mutations, alternative ALK transcription initiation, RET rearrangements (Arm 3/ALK); activating PIK3CA mutations, activating AKT mutations, other alterations predicting increased PI3K–AKT pathway activity, for example, PTEN loss, AKT amplification (Arms 4 and 5); alterations other than BRAF V600E/K predicting increased RAF–MEK–ERK pathway activity, for example, BRAF rearrangements, activating MEK mutations (Arm 6/MAPK); high tumor mutational burden, alterations predicting sensitivity to PD-L1 inhibition, for example, DNA mismatch repair deficiency, PD-L1 amplification, PD-L1 overexpression (Arm 7/Immune evasion). CRAFT, Continuous ReAssessment with Flexible ExTension in Rare Malignancies; DKFZ, German Cancer Research Center; DKTK, German Cancer Consortium; MASTER, Molecularly Aided Stratification for Tumor Eradication Research; MTB, molecular tumor board; NCT, National Center for Tumor Diseases.