2012 - Open Label Phase III Study of Arfolitixorin vs. Leucovorin in mFOLFOX-6 for First Line Treatment of Metastatic Colorectal Cancer: AGENT

Background

5-fluorouracil (5-FU) in combination with the folate Leucovorin (LV) has been the cornerstone in the treatment of colorectal cancer (CRC) for decades. All folates currently approved for use in the clinical setting need to be metabolically activated to [6R] 5,10-methylenetetrahydrofolic acid ([6R]-MTHF), which is the active thymidylate synthase co-substrate that potentiates the effect of 5-FU. Arfolitixorin does not need multi step metabolic activation like currently available folates. It is therefore hypothesized that the administration of arfolitixorin will result in higher, and less individual variability, intracellular concentrations of the active thymidylate synthase co-substrate [6R]-MTHF in all patients compared to LV administration.

Trial design

Primary endpoint ORR by Blinded Independent Central Review (BICR) Key secondary endpoints Progression Free Survival (PFS) Duration of Response (DoR) Secondary endpoints Overall Survival (OS) Quality of Life (QoL) Safety and Tolerability Patients undergoing curative metastasis resection Study Design This is a randomized, multicenter, parallel-group, Phase III study to compare the efficacy of arfolitixorin versus LV in patients with mCRC treated with 5-FU, oxaliplatin, and bevacizumab. Patients will be randomized in a 1:1 ratio to either the investigational arm or the comparator arm. The study target is to randomize 440 patients in 18 months. An adaptive study design includes the possibility to increase the sample size to 660 patients as determined by the DSMB during the interim analysis to be conducted after 330 patients have conducted their 16 weeks scan. Key inclusion criteria: Adults > 18 years of age Colorectal adenocarcinoma verified by biopsy Non-resectable mCRC No prior treatment for first line mCRC ECOG performance status 0 or 1 Key exclusion criteria: Malignant tumors other than colorectal adenocarcinomas Less than 6 months since last anti-cancer treatment DPD deficiency Clinically significant cardiovascular disease Central nervous system metastases Study Countries Australia, Austria, Canada, France, Germany, Greece, Spain, Sweden and USA FPI: December 18, 2018.

Clinical trial identification

NCT03750786; 2017-004154-41.

Editorial acknowledgement

Legal entity responsible for the study

Isofol Medical AB.

Funding

Isofol Medical AB.

Disclosure

J. Tabernero: Advisory / Consultancy: Array Biopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Chugai; Advisory / Consultancy: Genetech Inc; Advisory / Consultancy: Genemab A/S; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Imugene Limited; Advisory / Consultancy: Inflection Biosciences Limited; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Kura Oncology; Advisory / Consultancy: Lilly; Advisory / Consultancy: MSD; Advisory / Consultancy: Menarini; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Merus; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: Novartis. G. Prager: Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Lilly; Advisory / Consultancy: Servier; Advisory / Consultancy: Taiho; Advisory / Consultancy: Bayer; Advisory / Consultancy: Halozyme; Advisory / Consultancy: BMS; Advisory / Consultancy: Cellgene; Advisory / Consultancy: Shire. S. Stintzing: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy: Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Taiho; Advisory / Consultancy: Takeda; Advisory / Consultancy: Servier. H.J. Lenz: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Boehringer Ingelheim. H.P. Nygren: Shareholder / Stockholder / Stock options: Oncopeptides; Research grant / Funding (institution), Licensing / Royalties: Respos Pharma. C. Papadimitriou: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Genesis; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck.