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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
90
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 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.
Patients 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.
Charité - Universitaetsmedizin Berlin
Berlin, Germany
RECRUITINGUniversitaetsklinikum Essen AöR, Department of Medical Oncology
Essen, Germany
NOT_YET_RECRUITINGMuenchen Klinik gGmbH, Klinik für Onkologie und Hämatologie
München, Germany
NOT_YET_RECRUITINGPhase 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.
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.
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.
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.
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.
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.
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.
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.
Phase 2: Anti-tumor activity of 2 pre-defined dose levels of arfolitixorin, in terms of OS.
Anti-tumor activity of 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD) with SoC used as an internal control, in patients with mCRC will be assessed in terms of OS. OS (efficacy endpoint), measured from the date of study treatment initiation to the date of death.
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Time frame: From enrollment until end of study, i.e. until death, an average of 24 months.
Phase 2: Anti-tumor activity of 2 pre-defined dose levels of arfolitixorin, in terms of PFS.
Anti-tumor activity of 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD) with SoC used as an internal control, in patients with mCRC will be assessed in terms of PFS, defined as the time from the date of the first study dose 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.
Phase 2: Anti-tumor activity of 2 pre-defined dose levels of arfolitixorin, in terms of time to response (TTR).
Anti-tumor activity of 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD) with SoC used as an internal control, in patients with mCRC will be assessed in terms of time to response (TTR). TTR, defined as the time from the first study dose date to the date of first documentation of CR or PR measured by RECIST (version 1.1).
Time frame: Measured from the start of the study treatment until the EOT visit, an average of 11 months.
Phase 2: Anti-tumor activity of 2 pre-defined dose levels of arfolitixorin, in terms of disease control rate (DCR).
Anti-tumor activity of 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD) with SoC used as an internal control, in patients with mCRC will be assessed in terms of disease control rate (DCR). DCR, defined as the proportion of patients who have BOR of CR, PR, or SD ≥8 weeks.
Time frame: Measured from the start of the study treatment until the EOT visit, an average of 11 months.
Phase 2: Anti-tumor activity of 2 pre-defined dose levels of arfolitixorin, in terms of depth of response (DpR).
Anti-tumor activity of 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD) with SoC used as an internal control, in patients with mCRC will be assessed in terms of depth of response (DpR). DpR, defined as the maximum percentage change in tumor size compared with baseline.
Time frame: Measured from the start of the study treatment until the EOT visit, an average of 11 months.
Phase 2: OS as a safety outcome
OS will be assessed as a safety outcome for 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD) with SoC used as an internal control, in patients with mCRC.
Time frame: OS (safety [harm] endpoint), measured from the date of study treatment initiation to the date of death, 24 months.
Phase 2: Proportion of patients qualifying for curative metastasis resection after treatment with study drug
The effect of 2 pre-defined dose levels of arfolitixorin (MTD and a dose level below MTD) with SoC used as an internal control, in patients with mCRC, will be assessed by measuring the proportion of patients qualifying for curative metastasis resection.
Time frame: Measured from the start of the study treatment until the EOT visit, an average of 11 months.