A Clinical Study of Arfolitixorin in Patients With mCRC
brief summary
This is a clinical research study taking place in Germany. Patients with colorectal cancer at a stage of the disease where metastases occur may take part in the study. A maximum of 60 people will participate in the study. There is already a standard therapy for treatment of colorectal cancer. This therapy contains a combination of the medicines leucovorin, fluorouracil, oxaliplatin and bevacizumab. The sponsoring company is developing the new therapy called arfolitixorin. In this study, patients with colorectal cancer will be given arfolitixorin instead of the standard treatment leucovorin. Different patients will receive treatment with different strengths (doses) of arfolitixorin. Treatment with fluorouracil, oxaliplatin and bevacizumab will also be administrated. The researchers want to find out if arfolitixorin could have an advantage over the standard therapy with leucovorin. They also want to investigate which dose of arfolitixorin is the most optimal dose to give to other patients and also to study if arfolitixorin is safe to use. The product being tested, arfolitixorin, like leucovorin, belongs to a group of substances called folates which are naturally occurring forms of a type of B vitamin. Folates are administered in combination with one or more chemotherapeutic agents to enhance their effect on cancer cells. The main mechanism of action of arfolitixorin is the same as that of leucovorin when used together with fluorouracil. However, leucovorin must first be converted into the active form in the body, whereas arfolitixorin already is in the active form. Leucovorin does not work equally well in all patients. By bypassing the metabolic activation of arfolitixorin, it is assumed that arfolitixorin works in a larger number of patients and has a stronger and longer efficacy in cancer treatment together with fluorouracil. However, the efficacy of arfolitixorin has not yet been proven, and the substance has not been approved for the treatment of colorectal cancer. To date, arfolitixorin has been tested by around 420 volunteers and patients with colorectal cancer in different clinical studies. These studies have shown that arfolitixorin is safe and potentially can be of clinical benefit in patients with colorectal cancer when used in combination with fluorouracil, oxaliplatin and bevacizumab. In the largest clinical study completed so far, arfolitixorin was shown to be equally effective compared to standard therapy with leucovorin, but not more effective. Additional results from this study suggested that the dose of arfolitixorin given did not deliver a sufficiently high amount of active substance into the tumor. Therefore, higher doses of arfolitixorin will be tested in this study to possibly achieve a better clinical effect. Further analyses also indicated that high accuracy regarding the timing and duration of the administration of the different treatments is important to achieve better efficacy of arfolitixorin. Based on the available data, and the risk and benefit assessments performed, the Sponsor deems that it is relevant to further investigate the safety and tolerability, as well as the efficacy of arfolitixorin when given in combination with fluorouracil, oxaliplatin and bevacizumab. The proposed study design is believed to address all the main previous findings with the purpose to increase the efficacy with a remaining safety profile. The study is divided into two parts. In the first part, up to five different doses of arfolitixorin will be investigated to find the optimal dose (i.e. the highest and well tolerated) of arfolitixorin as well as the optimal duration time of administration. The second part of the study will be based on the results from the first part. Two doses of arfolitixorin will be tested for safety, tolerability and anti-tumor effect. In the second part, participants will be randomly assigned to one of two dose groups using a computer program. This so-called randomization procedure is comparable to tossing a coin. All patients that participate in the study will receive treatment with arfolitixorin (+ fluorouracil, oxaliplatin and bevacizumab) every 2 weeks. The treatment will be given as an infusion into a vein. The number of treatment administrations that will be given is not predetermined but depends on the progression of the patient's disease.The treatment will continue every 2 weeks as long as the patient benefits from the treatment. During the study period, the patient's disease and potential response to treatment, including shrinkage of the tumor and/or improvement of symptoms, will be monitored by imaging examinations, using so-called computer tomography (CT) or magnetic resonance imaging (MRI). The patient's state of health will also be monitored by physical examinations, and laboratory tests of urine and blood, as well as assessment of any side effects.
detailed description
This is a Phase 1b/2 study to determine the safety and preliminary efficacy of ARFOX + bevacizumab in patients with mCRC eligible for first-line therapy with 5-FU, oxaliplatin, and bevacizumab regimen. Prior treatment with 5-FU, oxaliplatin or bevacizumab administration for mCRC or more than 6 cycles (3 months) of oxaliplatin exposure during adjuvant treatment, is prohibited.
The study will include a Phase 1b dose-finding part followed by a randomized Phase 2 dose optimization part. Phase 1b will be conducted at 1 study site in Germany, and Phase 2 will be conducted at approximately 3 sites in Germany.
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.
All patients will receive treatment with ARFOX + bevacizumab 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 standard of care 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.
During the Phase 1b part of the study, a dose escalation design will be utilized to identify the optimal dose and 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) 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).
official title
A Phase 1b/2 Study of Arfolitixorin Combined With 5-fluorouracil, Oxaliplatin, and Bevacizumab in First-line Treatment of Metastatic Colorectal Cancer