A Clinical Study of Arfolitixorin in Patients With mCRC

This is a Phase 1b/2 study to determine the safety and preliminary efficacy of arfolitixorin (replacing LV) as part of eligible 5-FU based backbone treatment regimens in patients with mCRC eligible for first-line therapy. The study will include a Phase 1b dose-finding part followed by a randomized Phase 2 dose optimization part including an SoC arm. Eligible patients will undergo baseline assessments (within 28 days prior to treatment initiation) and repeat imaging using computed tomography (CT) or magnetic resonance imaging (MRI) after 6 and 12 weeks, and every 12 weeks thereafter as long as on study treatment. In Phase1b, patients will receive treatment with ARFOX + bevacizumab. In Phase 2, patients will receive treatment with arfolitixorin (replacing LV) as part of eligible 5-FU based backbone treatment (i.e., ARFOX + bevacizumab/cetuximab/panitumumab or ARFIRI + bevacizumab/cetuximab/panitumumab) or SoC (including LV) as part of eligible 5-FU based backbone treatment (i.e., FOLFOX + bevacizumab/cetuximab/panitumumab or FOLFIRI + bevacizumab/cetuximab/panitumumab). All patients will receive treatment every 14 days (+7 days) until progressive disease (PD), or clear clinical deterioration according to the Investigator's judgment, and as long as the patient is tolerating the treatment and agrees to continue. After completion of study treatment, patients will complete an EOT visit within 30 days of discontinuation, and all patients should be followed in line with the site's SoC scheme. Subsequent study follow-up contacts/visits will be performed every 90 days (±15 days) after the EOT visit treatment, until 60% of the OS events have been collected or 24 months after last patient in (LPI), whichever comes first. The follow-up contacts may be conducted via telephone, via clinic visits, via local practitioner, via review of medical records or other means found suitable. At the follow-up visits, information on any subsequent cancer treatments will be collected, recording and assessment of serious adverse events (SAEs) considered to be related to the study treatment will be performed, and survival status will be noted. All AEs collected during the reporting period still ongoing at the EOT visit will be followed until resolution or stabilization, or until deemed not necessary by the Investigator. All SAEs collected during the reporting period still ongoing at the EOT visit will be followed up until the patient has recovered, stabilized, or recovered with sequelae. During the Phase 1b part of the study, a dose escalation design will be utilized to identify the MTD and the duration of administration of arfolitixorin to be used in combination with 5-FU, oxaliplatin and bevacizumab. A Safety Review Committee (SRC) will review AEs, SAEs, dose-limiting toxicities (DLTs) as defined in the Clinical Study Protocol, and PK data and make recommendations regarding which dose level and cohort size to be tested for the next cohort, as well as the MTD. The SRC may also make recommendations of the duration of the infusion if there are safety findings that potentially correlate to a non-acceptable maximum plasma (peak) drug concentration (Cmax). The dose escalation schema will be based on a Bayesian optimal interval (BOIN) design where the decision of dose escalation or de-escalation involves a simple comparison of the observed DLT rate at the current dose with the prespecified dose escalation and de-escalation boundaries. The Phase 2 part of the study will be a randomized study where patients will be allocated to 1 of 2 dose levels of arfolitixorin, or to treatment with SoC. The higher dose level of arfolitixorin will be the MTD as determined in Phase 1b, and the lower dose will be a dose level below the MTD in Phase 1b, as determined by the SRC. The SRC will also review safety and efficacy data on a regular basis during Phase 2.