Colo-rectal Cancer
Conditions
Brief summary
This is a multicenter, randomized, parallel-group, Phase III study in at least 440 patients with advanced colorectal cancer to compare the efficacy of treatment with arfolitixorin versus Leucovorin in combination with 5-fluorouracil, oxaliplatin, and bevacizumab according to modified FOLFOX-6 until PD according to RECIST 1.1 criteria.
Interventions
DRUGArfolitixorin
Bevacizumab 5 mg/kg intravenous infusion; Oxaliplatin 85 mg/m2 intravenous infusion; 5-FU 400 mg/m2 intravenous bolus; Arfolitixorin 60 mg/m2 intravenous bolus; 5-FU 2400 mg/m2 intravenous infusion; Arfolitixorin 60 mg/m2 intravenous bolus
DRUGLeucovorin
Bevacizumab 5 mg/kg intravenous infusion; Oxaliplatin 85 mg/m2 intravenous infusion; Leucovorin 400 mg/m2 intravenous infusion; 5-FU 400 mg/m2 intravenous infusion; 5-FU 2400 mg/m2 intravenous infusion
Sponsors
Isofol Medical AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Colorectal adenocarcinoma verified by biopsy. 2. Availability of biopsy material, from the primary tumor or metastasis, allowing for analysis of tumor gene expression. 3. Non-resectable metastatic CRC planned for first line therapy with 5-FU, Leucovorin, oxaliplatin, and bevacizumab. 4. Evaluable disease with at least one measurable lesion of metastatic disease (≥10 mm in longest diameter on axial image on CT-scan or alternatively MRI with \<5 mm reconstruction interval) or lymph node (≥ 15 mm in shortest axis when assessed by CT) obtained within 28 days of randomization. 5. Life expectancy of more than 4 months. 6. ECOG performance status 0 or 1. 7. Hemoglobin (Hb) \> 80 g/L, Absolute neutrophil count (ANC) \> 1.5x10E9/L. Thrombocytes \> 100x10E9/L. 8. Creatinine clearance \> 50 mL/min, Total bilirubin \< 1.5 x ULN, AST and ALT \< 3 x ULN (and \< 5 x ULN in case of liver metastases). 9. Male or female ≥18 years of age. 10. Female patients of childbearing potential must have a negative urine pregnancy test and use adequate contraceptive measures . Male patients must use adequate contraceptive measures . 11. Voluntarily signed informed consent before performance of any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
Exclusion criteria
1. Malignant tumors other than colorectal adenocarcinomas (current or within the previous five years), with the exception for curatively treated non-melanoma skin cancer or in situ carcinoma of the cervix. 2. Less than 6 months between randomization and completion of the last anti-cancer treatment (chemotherapy/radiotherapy/immunotherapy, etc.). (NB: Rectal cancer treatment shorter than 8 weeks of chemo/radiation therapy is allowed.) 3. Confirmation of progressive disease within 6 months after completion of prior adjuvant anti-cancer treatment. 4. Indication for any metastatic Colo-rectal Cancer (mCRC) surgery or anti-cancer treatment other than study treatment. 5. Prior treatment with arfolitixorin. 6. Indication for treatment with a 5-FU analogue, or 5-FU for a condition other than mCRC. 7. Known Dihydropyrimidine Dehydrogenase Deficiency (DPD) deficiency. 8. Known or suspected central nervous system (CNS) metastases. 9. Unresolved bowel obstruction, uncontrolled Crohn's disease, or ulcerative colitis. 10. History of cardiac disease with a New York Heart Association Class II or greater, congestive heart failure, myocardial infarction, or unstable angina at any time during the 6 months prior to randomization, or serious arrhythmias requiring medication for treatment. 11. Current CTCAE ≥ grade 3 diarrhea. 12. Current chronic infection or uncontrolled serious illness causing immunodeficiency. 13. Known or suspected hypersensitivity or intolerance to arfolitixorin, LV, 5-FU, oxaliplatin, or bevacizumab. 14. Breastfeeding patients. 15. Patient who received investigational drugs in other clinical trials within 28 days, or 5 half-lives of the investigational drug, prior to randomization. 16. Patient with serious medical or psychiatric illness likely to interfere with participation in this clinical study. 17. Ongoing drug or alcohol abuse, as deemed by the Investigator. 18. Any condition that, in the opinion of the Investigator, could compromise the patient's safety or adherence to the study protocol. 19. Involvement, or related to people involved in the planning or conduct of the study (applies to both Isofol Medical AB (publ) staff and staff at the study site) 20. Surgery (excluding previous diagnostic biopsy) in the 28-day period before randomization
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Until disease progression, an average of ten months | Best ORR, defined as the best response recorded from the start of the study treatment until the end of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Until disease progression, an average of ten months | PFS, defined as the time from randomization to first occurrence of tumor progression based on CT-scans/MRIs. |
| Duration of Response | Until disease progression, an average of ten months | The duration of response is measured from the time measurement criteria are first met for CR/PR until the first date that recurrent or progressive disease is objectively documented. |
Countries
Australia, Austria, Canada, France, Germany, Greece, Japan, Spain, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group A ARFOX (Arfolitixorin and 5-FU and Oxaliplatin) and Bevacizumab
Arfolitixorin: Arfolitixorin and 5-FU and Oxaliplatin and Bevacizumab | 245 |
| Group B mFOLFOX-6 (Leucovorin and 5-FU and Oxaliplatin) and Bevacizumab
Leucovorin: Leucovorin and 5-FU and Oxaliplatin and Bevacizumab | 245 |
| Total | 490 |
Baseline characteristics
| Characteristic | Group A | Total | Group B |
|---|---|---|---|
| Age, Continuous | 62.4 years STANDARD_DEVIATION 10.5 | 62.5 years STANDARD_DEVIATION 10.6 | 62.6 years STANDARD_DEVIATION 10.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 204 Participants | 418 Participants | 214 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 41 Participants | 72 Participants | 31 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 36 Participants | 71 Participants | 35 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 30 Participants | 48 Participants | 18 Participants |
| Race (NIH/OMB) White | 179 Participants | 371 Participants | 192 Participants |
| Sex: Female, Male Female | 83 Participants | 177 Participants | 94 Participants |
| Sex: Female, Male Male | 162 Participants | 313 Participants | 151 Participants |
| Time since initial diagnosis, months | 9.7 months STANDARD_DEVIATION 20.9 | 8.7 months STANDARD_DEVIATION 18.1 | 7.7 months STANDARD_DEVIATION 15.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 118 / 243 | 100 / 238 |
| other Total, other adverse events | 239 / 243 | 231 / 238 |
| serious Total, serious adverse events | 81 / 243 | 86 / 238 |
Outcome results
Primary
Overall Response Rate
Best ORR, defined as the best response recorded from the start of the study treatment until the end of treatment.
Time frame: Until disease progression, an average of ten months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A | Overall Response Rate | Stable Disease | 106 Participants |
| Group A | Overall Response Rate | Non-CR/Non-PD | 6 Participants |
| Group A | Overall Response Rate | Partial Response | 116 Participants |
| Group A | Overall Response Rate | No BOR Available | 6 Participants |
| Group A | Overall Response Rate | Progressive Disease | 7 Participants |
| Group A | Overall Response Rate | Not Evaluable | 2 Participants |
| Group A | Overall Response Rate | Complete Response | 2 Participants |
| Group B | Overall Response Rate | Not Evaluable | 6 Participants |
| Group B | Overall Response Rate | Complete Response | 5 Participants |
| Group B | Overall Response Rate | Partial Response | 116 Participants |
| Group B | Overall Response Rate | Stable Disease | 86 Participants |
| Group B | Overall Response Rate | Progressive Disease | 11 Participants |
| Group B | Overall Response Rate | Non-CR/Non-PD | 3 Participants |
| Group B | Overall Response Rate | No BOR Available | 18 Participants |
Secondary
Duration of Response
The duration of response is measured from the time measurement criteria are first met for CR/PR until the first date that recurrent or progressive disease is objectively documented.
Time frame: Until disease progression, an average of ten months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A | Duration of Response | 12.2 months |
| Group B | Duration of Response | 12.9 months |
Secondary
Progression Free Survival
PFS, defined as the time from randomization to first occurrence of tumor progression based on CT-scans/MRIs.
Time frame: Until disease progression, an average of ten months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A | Progression Free Survival | 12.8 months |
| Group B | Progression Free Survival | 11.6 months |