The Drug Rediscovery Protocol (DRUP).

Abstract

2547 Background: Bringing precision medicine to cancer patients remains a challenge. For many cancers, the relative contribution of tumor type, mutations or CNV to drug sensitivity remains unknown. In addition, drug access is generally limited to the labeled indication, bypassing rarer disease subgroups for which large trials are not feasible. An innovative trial that facilitates drug access, whilst systematically analyzing treatment outcomes and biomarkers, could help overcome these challenges. Methods: We designed a prospective, non randomized clinical trial in which patients with advanced cancer are treated with targeted or immunotherapy matched to their tumor profile, defined by genetic aberration, microsatellite instability (MSI) or high mutational load (HML). Upon a mandatory pre-treatment tumor biopsy for biomarker research, patients are enrolled in multiple parallel cohorts, each defined by study drug, histologic tumor type and molecular tumor profile. Efficacy is analyzed per cohort, enrolling 8 patients in stage I and 16 more in stage II if ≥1 response is observed in stage I. Study endpoints include objective tumor response (CR or PR), stable disease (SD) at 16 weeks and grade≥3 adverse events. The DRUP is registered at ClinicalTrials.gov (NCT02925234). Results: Since start of recruitment in Sep 2016, 76 patients have been submitted for review (mean per month 15, range 8-17) and 16 (21%) have started treatment in 10 different cohorts, directed at either ATM (n = 1; breast cancer), BRAF (n = 2; salivary duct carcinoma and ACUP), BRCA (n = 1; breast cancer), ERBB2 (n = 2; CRC), HML (n = 2; prostate and CRC), MSI (n = 5; CRC, GBM and urothelial carcinoma), RET (n = 1; NSCLC) or RAS-RAFwt (n = 2; SCC and sarcoma). Out of the 7 patients for whom response evaluation is available, PR (n = 2) or SD at 16 weeks (n = 1) was observed in 3 (43%). Thirteen study drugs (supplied by 6 pharmaceutical companies) are currently available, 6 more are expected soon. Conclusions: Execution of a nationwide multidrug precision oncology trial is feasible. It contributes to oncologists’ education on molecularly targeted therapies and to identification of early signs of activity in rare cancer subsets. Data sharing with similar studies such as TAPUR and CAPTUR will help to enlarge cohorts and affirm conclusions. Clinical trial information: NCT02925234.

Relevance and Effectiveness of Molecular Tumor Board Recommendations for Patients With Non–Small-Cell Lung Cancer With Rare or Complex Mutational Profiles

“…39,40 However, the proportion of cases discussed by the UMCG-MTB that were finally enrolled in a trial was low (19%), similar to previously published MTBs (range, 7%-34%). 12,16,17 This could be due to limited availability of slots; strict inclusion criteria for these trials, such as a good performance score; and additional sample requirements (eg, the DRUP trial requires a fresh frozen tumor biopsy sample, which is not always available 42 ).…”

“…Frequently, a drug is available within the Dutch Drug Rediscovery Protocol (DRUP). [40][41][42] Alternatively, available trials in the Netherlands and neighboring countries Belgium and Germany are listed in the MTB app available for Android (Google, Mountain View, CA) and iOS (Apple, Cupertino, CA). This app is linked to ClinicalTrials.gov and allows one to search for trials on the basis of tumor type and molecular alteration.…”