ProTarget: a Danish Nationwide Clinical Trial on Targeted Cancer Treatment based on genomic profiling – a national, phase 2, prospective, multi-drug, non-randomized, open-label basket trial

Abstract

Background An increasing number of trials indicate that treatment outcomes in cancer patients with metastatic disease are improved when targeted treatments are matched with druggable genomic alterations in individual patients (pts). An estimated 30–80% of advanced solid tumors harbor actionable genomic alterations. However, the efficacy of personalized cancer treatment is still scarcely investigated in larger, controlled trials due to the low frequency and heterogenous distribution of druggable alterations among different histologic tumor types. Therefore, the overall effect of targeted cancer treatment on clinical outcomes still needs investigation. Study design/methods ProTarget is a national, non-randomized, multi-drug, open-label, pan-cancer phase 2 trial aiming to investigate the anti-tumor activity and toxicity of currently 13 commercially available, EMA-approved targeted therapies outside the labeled indication for treatment of advanced malignant diseases, harboring specific actionable genomic alterations. The trial involves the Danish National Molecular Tumor Board for confirmation of drug-variant matches. Key inclusion criteria include a) measurable disease (RECIST v.1.1), b) ECOG performance status 0–2, and c) an actionable genomic alteration matching one of the study drugs. Key exclusion criteria include a) cancer type within the EMA-approved label of the selected drug, and b) genomic alterations known to confer drug resistance. Initial drug dose, schedule and dose modifications are according to the EMA-approved label. The primary endpoint is objective response or stable disease at 16 weeks. Pts are assigned to cohorts defined by the selected drug, genomic alteration, and tumor histology type. Cohorts are monitored according to a Simon’s two-stage-based design. Response is assessed every 8 weeks for the first 24 weeks, then every 12 weeks. The trial is designed similar to the Dutch DRUP and the ASCO TAPUR trials and is a partner in the Nordic Precision Cancer Medicine Trial Network. In ProTarget, serial fresh tumor and liquid biopsies are mandatory and collected for extensive translational research including whole genome sequencing, array analysis, and RNA sequencing. Discussion The ProTarget trial will identify new predictive biomarkers for targeted treatments and provide new data and essential insights in molecular pathways involved in e.g., resistance mechanisms and thereby potentially evolve and expand the personalized cancer treatment strategy. Protocol version: 16, 09-MAY-2022. Trial registration ClinicalTrials.gov Identifier: NCT04341181. Secondary Identifying No: ML41742. EudraCT No: 2019–004771-40.

The Neurogenome study: Comprehensive molecular profiling to optimize treatment for Danish glioblastoma patients

“…The neurospheres will be cultured until they are ready for drug screening. Thirty-two drugs have been chosen based upon BBB penetrance, biomarkers, phase 2 drugs from the Protarget study 35 and hypothesis-generating drugs. The majority is approved for clinical use and the rest are experimental drugs.…”

“…At the Department of Oncology, Rigshospitalet, Copenhagen, we have been performing whole exome sequencing (WES) in tumor tissue since 2016 and whole genome sequencing (WGS) since 2020 with the aim of offering experimental treatment to GBM patients in clinical trials. 34 , 35 …”

Precision cancer medicine: Concepts, current practice, and future developments

“…The DN‐MTB also plays a pivotal role in ProTarget, which is a Danish nationwide, interventional, multidrug, open‐label, pan‐cancer, non‐randomized, prospective phase 2 basket trial investigating the efficacy and safety of targeted anticancer drugs when used off‐label in patients with a malignant disease harboring actionable genomic alterations [159]. The trial aims to include 100 patients annually.…”

“…The DN-MTB reviews approximately 1200 genomic profiles annually, mainly WGS/WES and large NGS panels. Thus, the DN-MTB ensures thorough and multidisciplinary prescreening of each candidate before inclusion in available trials.The DN-MTB also plays a pivotal role in ProTarget, which is a Danish nationwide, interventional, multidrug, open-label, pan-cancer, non-randomized, prospective phase 2 basket trial investigating the efficacy and safety of targeted anticancer drugs when used off-label in patients with a malignant disease harboring actionable genomic alterations[159]. The trial aims to include 100 patients annually.…”

PCM4EU and PRIME-ROSE: Collaboration for implementation of precision cancer medicine in Europe

“…PCM4EU (Personalized Cancer Medicine for all EU citizens) (http://www.pcm4eu.eu/) and The success of the original DRUP-trial from the Netherlands, showing high inclusion rate and clinical benefit (CB), inspired similar trials in other countries [4]. All involved national trials are based on or aligned with DRUP (PIs Emile Voest, Hans Gelderblom, Henk Verheul) [5,6], while being independently organised, governed and financed (Table 1). Such trials are ongoing or soon to be initiated in 11 European countries (Figure 2A), with more countries preparing to launch DLCTs.…”