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Rationale and design of the CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) multicenter
C E Heilig1, P Horak1, S Kreutzfeldt1
1Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
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.
Insights
The Continuous ReAssessment with Flexible ExTension in Rare Malignancies (CRAFT) trial uses molecular profiling to match rare cancer patients with targeted therapies. This approach aims to improve treatment selection and outcomes for patients with limited options.
Area of Science:
- Oncology
- Genomics
- Clinical Trials
Background:
- Cancer drug approvals are typically disease-specific, limiting treatment options for rare cancers or subtypes.
- Molecular diagnostics identify actionable alterations in rare cancers, but corresponding treatments are often unavailable due to trial eligibility criteria.
- Systematic collection of risk-benefit data is lacking for experimental cancer therapies in rare malignancies.
Purpose of the Study:
- To evaluate the efficacy of targeted therapies and PD-L1 inhibition in patients with rare solid tumors.
- To establish an optimized patient selection strategy based on comprehensive molecular characterization.
- To translate experimental treatments into standard care for rare cancer populations.
Main Methods:
- The Continuous ReAssessment with Flexible ExTension in Rare Malignancies (CRAFT) is an open-label, phase II trial for pretreated, advanced solid tumors.
- Patients are assigned to seven study arms based on molecular profiling, receiving combinations of targeted agents and a PD-L1 antagonist.
- The primary endpoint is disease control rate (DCR) at week 16, using a two-stage Simon's optimal design for patient accrual.
Main Results:
- The study is ongoing, with patient accrual and treatment allocation based on molecular tumor board evaluations.
- The primary endpoint, disease control rate at week 16, will determine the success of each study arm.
- Secondary endpoints include progression-free survival, overall survival, and patient-reported outcomes.
Conclusions:
- The CRAFT trial, activated in October 2021, is recruiting patients across 10 centers in Germany.
- This trial addresses the unmet need for effective treatments in rare malignancies through molecularly guided therapy.
- The findings will contribute to optimizing patient selection and validating novel therapeutic strategies in rare cancers.
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