Expanding the use of approved drugs: The CPCT’s Drug Rediscovery Protocol (DRUP)
Authors: D. van der Velden, L. Hoes, H. van der Wijngaart, H. Bloemendal, K. Grunberg, A. Huitema, E. Lugtenburg, F. De Vos, C.M.L. Herpen, D.J. de Groot, P. Hamberg, E. Smit, E. Cuppen, N. Steeghs, S. Sleijfer, H.M. Verheul, H. Gelderblom, E. Voest
Journal: Annals of Oncology (2017)

Background: Once regulatory drug approval is obtained, patients and pharma would greatly benefit from identifying signals of activity in cancer subsets outside the approved indication. In the Netherlands' precision oncology-network (), Whole Genome Sequencing (WGS) is offered to systemically treated cancer patients. This allows us to identify a spectrum of potentially actionable genetic aberrations in all types of cancer. The DRUP provides patients with such aberrations access to genetically matched treatment upon central review of the tumor profile. Methods: Adult patients with solid tumors, glioblastoma, lymphoma or multiple myeloma, with no standard treatment options, are eligible. Patients are enrolled in multiple parallel cohorts, each defined by 1 tumor type, 1 tumor profile and 1 treatment. Efficacy is analyzed per cohort using a Simon-2-stage approach, aimed at ≥ 1 clinical benefit (CR, PR or SD ≥ 16 weeks)/8 patients in stage I, and ≥5/24 in stage II (85% power, α error rate 7.8%). A fresh tumor biopsy for biomarker research is mandatory. There are currently 23 participating hospitals and 19 study drugs, supplied by 10 pharmaceutical companies. Results: Since study launch Sep 2016, ∼250 cases were submitted for review and about 1/3 of these patients have started study treatment. Clinical benefit was observed in 37% (6% CR, 14% PR, 17% SD ≥ 16 weeks; all CRs and 2/3 of PRs were ongoing at the time of writing and awaiting ≥30 days confirmation). About 2/3 of case submissions were rejected, due to a general protocol ineligibility (18%), b current unavailability of matching study drugs (17%), c no actionable target detected (15%), d negative evidence for target-drug-match (13%), e eligible for standard treatment (12%), f eligible for competing trials (11%), g loss to follow up (10%) or h genetic tumor profile not yet assessed (4%). Conclusions: Execution of a national multi-drug and multi-tumor precision oncology trial is feasible. By performing WGS in many different cancer types, subgroups are identified who may benefit from existing drugs outside of their registered indication. This study hereby accelerates translation of new findings to the clinic and increases the yield of existing therapies. Clinical trial identification: NCT02925234 (release date: 26-Aug-2016) EudraCT 2015-004398-33 (release date: 01-Oct-2015) Legal entity responsible for the study: • Governance: Stichting Het Nederlands Kanker Instituut – Antoni van Leeuwenhoek Ziekenhuis, whose registered office is at Plesmanlaan 121, 1066CX, Amsterdam, lawfully represented by Prof. R. Medema, Head of the Board representing the CPCT. • Coordination and running of the study: Prof. E.E. Voest, Netherlands Cancer Institute, division of Molecular Oncology, Amsterdam, the Netherlands. Funding: • Barcode for Life Foundation (BFL): funding • Dutch Cancer Society (KWF): funding • Hartwig Medical Foundation (HMF): sequencing • Pharmaceutical partners (Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Novartis, Roche): funding and study drugs Disclosure: F. De Vos: 1. Direct research support to the responsible project lead (Principle Investigator): see 2 2. Novartis, BMS, Roche/Genetech, GSK, Array, AstraZeneca, Merus, Merck E. Cuppen: Board of Directors Hartwig Medical Foundation (not for profit) N. Steeghs: 1. Consulting or Advisory role - Lilly 2. Research Funding - AB Science; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol MS All other authors have declared no conflicts of interest.