REGORAFENIB for Metastatic colorectal cancer

Inclusion criteria

• {"criterion_text":"- Patients with histologically proven metastatic colorectal cancer in progression after a first line of chemotherapy +/- targeted therapy\n- No contraindication to Iodine contrast media injection during CT\n- For female patients of childbearing potential, negative pregnancy test within 14 days before starting the study drug through at 210 days after the last dose of regorafenib. Men and women are required to use adequate birth control during the study (when applicable),\n- Signed and dated informed consent,\n- Ability to comply with the study protocol, in the Investigator’s judgment.\n- Registration in a national health care system (CMU included).\n- Patients must have been treated for their metastatic disease with one of the following regimens as first-line therapy: o\tFOLFOX o\tFOLFIRI o\tFOLFIRINOX or FOLFOXIRI o\tFOLFOX and anti-VEGFA (bevacizumab only) o\tFOLFIRI and anti-VEGFA(bevacizumab only) o\tFOLFIRINOX or FOLFOXIRI and anti-VEGFA (bevacizumab only) o\tFOLFOX and anti-EGFR o\tFOLFIRI and anti-EGFR o\tFOLFIRINOX or FOLFOXIRI and anti-EGFR Of note, a chemotherapy prescribed for metastases occurring within six months after the end of an adjuvant chemotherapy are considered as a second line of therapy.\n- Patients should have a history of resistance to first line chemotherapy defined by: - Disease progression during the first line of their metastatic disease, less than 3 months after the last exposition to chemotherapy (even a chemotherapy regimen mentioned above or a 5FU-based maintenance therapy). - Disease relapse within 6 months after the end of an adjuvant FOLFOX based chemotherapy. - Disease relapse within 6 months after the surgical resection of metastases following a first line of chemotherapy.\n- Life expectancy of at least 3 months\n- Female or male with age ≥18 years old\n- Performance status Eastern Cooperative Oncology Group World Health Organization (ECOG-WHO) ≤1 (Appendix 2),\n- Measurable disease defined according to RECIST v1.1 (scanner or MRI) (Appendix 3)\n- Molecular status: patients eligible should have microsatellite-stable (MSS) status, absence of BRAF V600E mutation and a known RAS status.\n- Adequate bone marrow, liver and renal functions. a.\tHaemoglobin ≥ 9 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L b.\tTotal serum bilirubin ≤ 1.5 times upper normal value (ULN), serum alkaline phosphatase < 5 times ULN, aminotransferases (AST/ALT) ≤ 3 × ULN in absence of hepatic metastasis or ≤ 5 if presence of hepatic lesions c.\tCockcroft glomerular filtration rate > 50 ml/min d.\tProteinuria <2+ (dipstick urinalysis) or ≤1g/24hour"}

Exclusion criteria

• {"criterion_text":"- Diagnosis of additional malignancy within 2 years prior to the inclusion (exception of curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical and/or bladder cancer),\n- Pregnant or breast-feeding subjects,\n- Congestive Heart Failure ≥ New York Heart Association (NYHA) class 2, unstable angina (anginal symptomatology at rest),\n- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months),\n- Myocardial infarction less than 6 months before start of study drug,\n- Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted),\n- Uncontrolled hypertension (Systolic blood pressure >150 mmHg and/or diastolic pressure >100 mmHg despite optimal medical management), or history of hypertensive crisis, or hypertensive encephalopathy,\n- Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2 dyspnea),\n- Ongoing infection >grade 2 CTCAE V5 (Appendix 4),\n- Known History of human immunodeficiency virus (HIV) infection,\n- Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy,\n- Current participation in a study of an investigational agent. Patients might be included at least 21 days following the last investigational agent administration.\n- Subjects with seizure disorder requiring medication,\n- History of organ allograft,\n- Subjects with evidence or history of any bleeding diathesis, irrespective of severity,\n- Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication,\n- Serious, Non-healing wound, active ulcer or untreated bone fracture,\n- History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to inclusion,\n- Dehydration CTCAE v4 grade ≥1,\n- Known hypersensitivity to any of the study drugs, study drug classes or excipient in the formulation,\n- Interstitial lung disease with ongoing signs or symptoms,\n- Persistent proteinuria of CTCAE Grade 3 (>3.5 g/24 hours),\n- Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before inclusion in the trial;,\n- Subject unable to swallow oral medications,\n- Any malabsorption condition, unresolved toxicity higher than CTCAE (V4) Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neuropathy ≤ Grade 2,\n- Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks,\n- Treatment with any other investigational medicinal product within 28 days prior to study entry, EXCEPT for ASPIRIN,\n- Co-administration of drugs potentially interacting with regorafenib i.e. CYP3A4 or UGT1A9 inducers/inhibitors,\n- Active peptic ulcer,\n- History of asthma induced by the administration of salicylates or substances with a similar action, notably non-steroidal anti-inflammatory medicines,\n- Any constitutional or acquired hemorrhagic disease,\n- Urinary tract obstruction,\n- Recent or concomitant treatment with brivudine,\n- Patient under judicial protection (curatorship, tutorship) and/or deprived of freedom,\n- Patient on platelet antiaggregants treatment\n- Hypokalemia less than normal, hypomagnesemia, hypocalcemia\n- QT/QTc interval longer than 450 msec for men and longer than 470 msec for women on the inclusion ECG\n- Planned surgical procedure within the first month of treatment or any procedure that might change the timing of regorafenib administration during the first month of treatment,\n- Previous exposure to regorafenib,\n- Previous exposure to other anti-angiogenic treatment than bevacizumab,\n- Complete deficit in dihydropyrimidine deshydrogenase (DPD),\n- Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication"}

Primary endpoints

• {"endpoint_text":"- Phase II: The primary outcome will be the best response rate evaluated with RECIST v1.1 criteria per an independent radiologist committee during the treatment period defined as the number of with complete response (CR) or partial response (PR) as best response divided by the total numer of patients evaluable. Patients for whom best overall tumor response is not CR or PR will be considered non-responders. Phase III: Overall survival (OS","definition_or_measurement_approach":"Phase II: Best response rate evaluated with RECIST v1.1 criteria by an independent radiologist committee during the treatment period; defined as number of patients with complete response (CR) or partial response (PR) as best response divided by total number of evaluable patients. Phase III: Overall survival (OS) measured as time from randomization to death from any cause."}

Secondary endpoints

• {"endpoint_text":"- Overall survival (OS): defined as the time from the randomization to death from any cause (phase II). Alive patient will be censored at last date known to be alive.","definition_or_measurement_approach":"OS defined as time from randomization to death from any cause; alive patients censored at last known alive date."}
• {"endpoint_text":"- Best response rate: defined as the number of patients with CR or PR as best response divided by the total number of evaluable patients (phase III)","definition_or_measurement_approach":"Best response rate defined as number of patients with CR or PR as best overall response divided by total evaluable patients (phase III); assessed by RECIST v1.1"}
• {"endpoint_text":"- Progression-free survival (PFS): defined as the time from the randomization to disease progression or death from any cause. Alive patient without progression will be censored at last radiological evaluation available showing no progression.","definition_or_measurement_approach":"PFS defined as time from randomization to disease progression or death; alive without progression censored at last radiological evaluation showing no progression."}
• {"endpoint_text":"- Disease control rate (DCR): DCR is defined as the proportion of participants with best overall response of confirmed CR or PR or stable disease (SD).","definition_or_measurement_approach":"DCR = proportion of participants with best overall response of confirmed CR, PR, or stable disease (SD)."}
• {"endpoint_text":"- Duration of objective response (DOR) defined as the time from the first documented objective response of PR or CR, whichever is noted earlier, to disease progression or death (if death occurs before progression is documented). DOR will be defined for responders only, i.e. patients with a CR or PR. The actual dates the tumor scans were performed will be used for this calculation. DOR for patients who have not progressed or died at the time of analysis will be censored at the date of their last TE","definition_or_measurement_approach":"DOR = time from first documented objective response (PR or CR) to disease progression or death; defined for responders only; use actual tumor scan dates; censor at last tumor evaluation if not progressed or died."}
• {"endpoint_text":"- Health related Quality of life (HRQoL): a.\tEORTC QLC30, CR29 and EQ-5D questionnaires b.\tTUDD (Time Until Definitive Deterioration) of 5 targeted dimensions: Global health/ Pain/ Physical Functioning/ Fatigue / Emotional Functioning c.\tNumber and volumes of paracentesis and drainages (ascites or pleural effusion) d.\tNumber of days of hospitalization e.\tNumber of days taking level 3 analgesics (the number of days with opioid treatments)","definition_or_measurement_approach":"HRQoL assessed by EORTC QLQ-C30, CR29 and EQ-5D questionnaires; TUDD for 5 dimensions; record number/volumes of paracenteses and drainages; days hospitalized; days on level 3 analgesics (opioids)."}
• {"endpoint_text":"- Toxicities: Adverse events (AEs), drug related AEs, drug related AE leading to dose reduction or discontinuation during treatment, SAE and SUSAR, according to NCI-CTCAE V5.0.","definition_or_measurement_approach":"Safety endpoints: AEs, drug-related AEs, dose modifications/discontinuations, SAEs and SUSARs graded per NCI-CTCAE v5.0."}
• {"endpoint_text":"- Evaluation of CHUN morphological criteria and correlation with response according to RECIST v1.1 and serum stromal biomarkers.","definition_or_measurement_approach":"Assessment of CHUN morphological criteria and correlation with RECIST v1.1 response and serum stromal biomarkers."}

France

Earliest CTIS Part Ii Submission Date

03-12-2024

Latest Decision Or Authorization Date

08-10-2025

Processing Time Days

309

Number Of Sites

15

Number Of Participants

94

Primary sponsor

Full Name

Centre Hospitalier Regional Universitaire

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France