A Clinical Study of Arfolitixorin in Patients With mCRC
ConditionMetastatic Colorectal Cancer (mCRC)
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorIsofol Medical AB
About this trial
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 90 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/irinotecan and bevacizumab/cetuximab/panitumumab.
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/irinotecan and bevacizumab/cetuximab/panitumumab 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 maximum tolerated dose and 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/irinotecan and bevacizumab/cetuximab/panitumumab. The proposed study design is believed to address all the main previous findings with the purpose to increase the efficacy while maintaining an acceptable 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 maximum tolerated dose 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 or a control group (receiving the Standard of Care) 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 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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Signed ICF and ability to comply with protocol requirements.
Phase 1b: Histologically confirmed RAS mutant, MSS/pMMR, colorectal adenocarcinoma with metastatic disease, eligible for first-line therapy with 5-FU, oxaliplatin, and bevacizumab regimen.
Patients with mutated RAS who are candidates for therapy with FOLFOX or FOLFIRI plus bevacizumab.
Patients with WT RAS or WT BRAF and left-sided tumors who are candidates for therapy with FOLFOX or FOLFIRI plus cetuximab or panitumumab.
Disqualifiers
Indication for any mCRC surgery or anti-cancer treatment other than study treatment, including but not limited to resection as confirmed by a MTB.
Concomitant malignancies or previous malignancies with less than a 2-year disease free interval at the time of signing consent. Patients with adequately treated basal or squamous cell carcinoma of the skin, or adequately treated carcinoma in situ (e.g., cervix) may enroll irrespective of the time of diagnosis. Patients with controlled, advanced prostate cancer are permitted. Ongoing adjuvant antihormonal therapy after breast or prostate cancer is permitted.
Prior 5-FU, oxaliplatin, irinotecan, bevacizumab, cetuximab, or panitumumab administration for mCRC.
More than 6 cycles (3 months) of oxaliplatin exposure during adjuvant treatment.
Trial design
Design model
Parallel
Treatments tested in this trial
Arfolitixorin
DrugEvery 14 days during treatment phase, antibody treatment (bevacizumab 5 mg/kg or cetuximab 500 mg/m² or panitumumab 6 mg/kg) will be administered as an i.v. infusion, followed by oxaliplatin 85 mg/m² or irinotecan 180 mg/m² administered as an i.v. infusion, and arfolitixorin administred as an i.v. infusion, followed by 5-FU administered as a 400 mg/m² i.v. bolus + a 2400 mg/m² i.v. infusion.
Leucovorin
Other interventionPatients in the SoC group will receive treatment with leucovorin as part of eligible 5-FU based backbone treatment. Every 14 days during treatment phase, antibody treatment (bevacizumab 5 mg/kg or cetuximab 500 mg/m² or panitumumab 6 mg/kg) will be administered as an i.v. infusion, followed by oxaliplatin 85 mg/m² or irinotecan 180 mg/m² administered as an i.v. infusion, and leucovorin 400 mg/m2 administered as an i.v. infusion, followed by 5-FU administered as a 400 mg/m² i.v. bolus + a 2400 mg/m² i.v. infusion.
Treatment groups
90 Participants
are divided into 3 treatment groupsGroup A: High dose levelExperimental treatment 1 intervention
Group B: Low dose levelExperimental treatment 1 intervention
Group C: Standard of Care (leucovorin/levoleucovorin)Active comparator 1 intervention
Trial outcomes
Primary outcomes
1
Phase 1b: Number and severity of AEs and clinically significant abnormal laboratory findings
Number and severity of AEs and clinically significant abnormal laboratory findings, regardless of causal relationship to ARFOX + bevacizumab will be measured to evaluate the safety and tolerability of ARFOX + bevacizumab in patients with mCRC. The outcome of Phase 1b is to determine the MTD of arfolitixorin (ARFOX + bevacizumab).
Time frame
From enrollment until end of study, i.e. until death, an average of 24 months.2
Phase 2: Number and severity of AEs, including clinically significant abnormal laboratory findings, after 2 pre-defined dose levels of arfolitixorin
Number and severity of AEs and clinically significant abnormal laboratory findings, regardless of causal relationship to any given treatment will be measured to evaluate the safety and tolerability of two pre-defined doses of arfolitixorin, in patients with mCRC, with SoC used as an internal control. The dose levels of arfolitixorin will be MTD and a dose level below MTD.
Time frame
From enrollment until end of study, i.e. until death, an average of 24 months.3
Phase 2: Early signals of the anti-tumor activity of two pre-defined dose levels of arfolitixorin with SoC used as an internal control, in terms of ORR.
ORR will be determined by assessing early signals of the anti-tumor activity of two pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD). ORR is defined as the proportion of patients who have best overall response (BOR) of complete response (CR), or partial response (PR), measured from the start of the study treatment until the end of treatment (EOT) by the Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1).
Time frame
From enrollment until end of treatment, i.e. until progressive disease, or clear clinical deterioration according to the Investigator's judgment, and as long as the patient is tolerating the treatment and agrees to continue, an average of 11 months.4
Phase 2: Early signals of the anti-tumor activity of two pre-defined dose levels of arfolitixorin with SoC used as an internal control, in terms of duration of response (DOR).
Duration of response (DOR) will be determined by assessing early signals of the anti-tumor activity of two pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD). DOR is defined as the duration of CR or PR.
Time frame
From enrollment until end of treatment, i.e. until progressive disease, or clear clinical deterioration according to the Investigator's judgment, and as long as the patient is tolerating the treatment and agrees to continue, an average of 11 months.Secondary outcomes
1
Phase 1b: Anti-tumor activity of ARFOX + bevacizumab in terms of ORR
Anti-tumor activity of ARFOX + bevacizumab will be assessed in patients with mCRC in terms of ORR, defined as the proportion of patients who have BOR of CR, or PR, measured by RECIST (version 1.1).
Time frame
From enrollment until end of treatment, i.e. until progressive disease, or clear clinical deterioration according to the Investigator's judgment, and as long as the patient is tolerating the treatment and agrees to continue, an average of 11 months.2
Phase 1b: Anti-tumor activity of ARFOX + bevacizumab in terms of PFS.
Anti-tumor activity of ARFOX + bevacizumab will be assessed in patients with mCRC in terms of PFS, defined as the time from the first study dose date to the date of first documentation of disease progression or death (whichever occurs first).
Time frame
From the first study dose date to the date of first documentation of disease progression or death (whichever occurs first), an average 11 months.3
Phase 1b: Anti-tumor activity of ARFOX + bevacizumab in terms of OS.
Anti-tumor activity of ARFOX + bevacizumab will be assessed in patients with mCRC in terms of OS, measured from the date of study treatment initiation to the date of death.
Time frame
From enrollment until end of study, i.e. until death, an average of 24 months.4
Phase 1b: Plasma concentration of arfolitixorin
Plasma concentration of arfolitixorin will be measured to determine the PK profile of arfolitixorin, administered in combination with bevacizumab, oxaliplatin and 5-FU.
Time frame
Assessed just before the end of the infusion of arfolitixorin, and at 5, 10, 20, and 60 minutes after finished infusion of arfolitixorin, on day 1 and day 15.Sponsors and contacts
Click on the lead sponsor to view all of their trials.
Isofol Medical AB
Lead sponsor
Charite University, Berlin, Germany
Collaborator
Source ClinicalTrials.gov