Evaluation of Treatment PERSOnalization Based on Its Therapeutic Monitoring in Patients With Metastatic Colorectal Cancer Treated With REgorafenib

• Status: Active, not recruiting
• Trial end date: 2024-01-01
• Target enrollment: 0
• Participant gender: All

Summary

Regorafenib has demonstrated a significant benefit in overall survival in metastatic colorectal cancer (mCRC) patients. However, more than 50% of patients had severe adverse events (grade 3-4), leading to temporary or definitive discontinuation of treatment.

The RePERSO study proposes to adapt the regorafenib dose regimen taking into account firstly the measurement of sum of metabolites M-2 and M-5 and secondly the occurrence of toxicity during treatment. This treatment personalization through therapeutic drug monitoring pharmacological dosing optimization strategy aims at validating the proof of concept of regorafenib therapeutic drug monitoring and at improving the benefit in OS in patients, using the previously defined Csum therapeutic range.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Rennes University Hospital

Criteria

Inclusion Criteria:

• - Signed and dated informed consent

• Male or female patients ≥ 18 years-old at time of Informed Consent Form (ICF) signature

• Patients must have a histologically proven metastatic colorectal cancer

• Patients who have previously been treated with standard therapy including a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF (bevacizumab or aflibercept) and an anti-EGFR (cetuximab or panitumumab) for patients who had a RAS wild-type tumor

• Patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer who have previously received an immunotherapy.

• Patients with a BRAF V600E mutation who have previously received treatment with a BRAF inhibitor.

• ECOG PS = 0 or 1

• Imaging target greater than one cm must be visible on CT

• Patients must have adequate bone marrow, renal, and hepatic function, as evidenced by the pre-therapeutic check-up performed within 7 days before regorafenib initiation: Normal organ functions as defined below :

1. Absolute neutrophil count ≥ 1.3 Giga/L

2. Platelets > 100 Giga/L

3. Hemoglobin ≥ 9 g/dL

4. Serum creatinine ≤ 1.5 x ULN (Upper Limit of Normal) or Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 according to the modified Diet in Renal Disease (MDRD) or CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) abbreviated formula

5. AST and ALT ≤2.5 x ULN (≤5.0 × ULN for patients with liver involvement of their cancer)

6. Total Bilirubin ≤1.5 X ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN (except for patients with Gilbert disease for whom a total serum bilirubin ≤ 3ULN is acceptable)

7. Alkaline phosphatase ≤3 x ULN (≤5 x ULN in patient with liver involvement of their cancer and/or with bone metastases). If Alkaline phosphatase > 3 ULN, hepatic isoenzymes 5-nucleotidase or GGT tests must be performed; hepatic isoenzymes 5-nucleotidase must be within the normal range and/or GGT < 1.5 x ULN

8. Lipase ≤1.5 x ULN

9. No proteinuria: Spot urine < 1+ or more protein in urine or the patient will require a repeat urine analysis. If repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion <1000 mg/24 hours

• INR/PTT ≤1.5 x ULN

• Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care

• Recovery to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) V5.0 Grade 0 or 1 level or recovery to baseline preceding the prior treatment from any previous drug/procedure related toxicity (except alopecia, anemia, and hypothyroidism)

• Women of childbearing potential and male patients must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy

• Women of childbearing potential must have a negative serum β-HCG pregnancy test within 7 days prior randomization

• Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures

• Patients affiliated to the Social Security System

Exclusion Criteria:

• - Prior treatment with regorafenib, and with any prior antiangiogenic inhibitor

• Hypersensitivity to the active substance or to any of the excipients

• Systemic anticancer therapy including cytotoxic therapy, antibodies, immunotherapy ≤3 weeks prior to start of regorafenib

• Concomitant treatment with a cytochrome P450 3A4 (CYP3A4) inducer or inhibitor or UGT1A9 inhibitor

• Patients unable to swallow oral medication

• Digestive obstruction, chronic inflammatory bowel disease or any malabsorption condition

• Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])

• Ongoing uncontrolled infection (viral, bacterial or fungal)

• Known history of human immunodeficiency virus (HIV) infection, active or chronic hepatitis B or C

• Breastfeeding

• Uncontrolled hypertension (systolic blood pressure >140 mmHg or diastolic pressure >90 mmHg despite optimal medical management)

• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication

• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)

• Myocardial infarction less than 6 months before the start of study medication

• Any hemorrhage or bleeding event ≥ Grade 3, NCI-CTCAE v 5.0 within 4 weeks prior to the start of study medication

• Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication

• Non-healing wound, ulcer or bone fracture

• Unresolved toxicity higher than Grade 1, NCI-CTCAE v 5.0, attributed to any prior therapy/procedure excluding alopecia and oxaliplatin induced neuropathy

• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

• Adults legally protected (judicial protection, guardianship or supervision), person deprived of their liberty