Combining Regorafenib with Metronomic Chemotherapy for Advanced Colorectal Cancer

Impact of Regorafenib in Combination With Multimodal Metronomic Chemotherapy on Progression-free Survival Compared With Standard Regorafenib for the Treatment of Chemo-resistant Metastatic Colorectal Cancers

This study is testing if combining Regorafenib with a special type of chemotherapy and low-dose aspirin can help people with advanced colorectal cancer that hasn't improved with standard treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 174 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Centre Hospitalier Universitaire de Besancon (Academic / other)
• Drugs / interventions: bevacizumab, immunotherapy, chemotherapy, cyclophosphamide
• Locations: 10 sites (Auxerre and 9 other locations)
• Trial ID: NCT06425133 on ClinicalTrials.gov

What this trial studies

This study evaluates the effectiveness of Regorafenib in combination with metronomic chemotherapy, specifically capecitabine and cyclophosphamide, along with low-dose aspirin, in patients with metastatic colorectal cancer that has not responded to standard treatments. The primary goal is to assess progression-free survival compared to standard Regorafenib treatment alone. Participants will undergo various assessments, including blood samples, biopsies, and quality of life questionnaires, to monitor their response to the treatment.

Who should consider this trial

Good fit: Ideal candidates are adults over 18 with histologically confirmed metastatic colorectal cancer that has progressed after standard therapies.

Not a fit: Patients who have not been previously treated for metastatic colorectal cancer or those with a life expectancy of less than three months may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could provide a new treatment option for patients with chemo-resistant metastatic colorectal cancer.

How similar studies have performed: While there have been studies exploring Regorafenib and chemotherapy combinations, this specific approach is novel and has not been extensively tested.

Eligibility criteria

Inclusion Criteria:

1. Patients with histologically proven metastatic colorectal cancer in progression after previous standard treatments (5FU, CPT11 (Irinotecan), oxaliplatin, anti-VEGF (vascular endothelial growth factor), trifluridine/tipiracil, anti-EGFR (epidermal growth factor receptor) therapy if KRAS (Kirsten rat sarcoma) and NRAS WT (wild type), anti-BRAF therapy if BRAF V600E mutated, and anti-PD1 (Programmed Death-1) if MSI-H (microsatellite instability) /dMMR (deficient MisMatch Repair) tumor, or not considered as candidate for these treatments.
2. Life expectancy of at least 3 months
3. Female or male with age \>18 years old
4. Performance status = 0 or 1 (Annex 1)
5. Measurable disease defined according to RECIST v1.1 guidelines (scanner or MRI)
6. Adequate bone marrow, liver and renal functions.

   1. Haemoglobin ≥ 9 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L
   2. Total 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
   3. Cockcroft glomerular filtration rate \> 50 ml/min
   4. Proteinuria \<2+ (dipstick urinalysis) or ≤1g/24hour
7. No contraindication to Iodine contrast media injection during CT
8. For female patients of childbearing potential, negative pregnancy test within 14 days before starting the study drug. Men and women are required to use adequate birth control during the study (when applicable),
9. Signed and dated informed consent,
10. Ability to comply with the study protocol, in the Investigator's judgment.
11. Registration in a national health care system (CMU included).

Exclusion Criteria:

1. 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),
2. Current participation in a study of an investigational agent or in the period of exclusion
3. 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 ;
4. Patient under judicial protection (curators, autorship) and/or deprived of freedom,
5. Previous exposition to regorafenib or anti-angiogenic treatment other than bevacizumab and aflibercept
6. Treatment with any other investigational medicinal product within 28 days prior to study entry, EXCEPT for ASPIRIN,
7. Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks,
8. Chronic treatment with drug potentially interacting with regorafenib i.e. CYP3A4, CYP2C9 or UGT1A9 (UDP-glucuronosyltransferase 1-9) inductor/inhibitor; Epileptic disorder requiring medication; Recent or concomitant treatment with brivudine,
9. Complete deficit in dihydropyrimidine dehydrogenase (DPD),
10. Known hypersensitivity to any of the study drugs, study drug classes or excipient in the formulation:

    * History of severe and unexpected reactions to fluoropyrimidine therapy,
    * History of asthma induced by the administration of salicylates or substances with a similar action, notably non-steroidal anti-inflammatory medicines,
    * Mastocytosis, for whom the use of acetylsalicylic acid can cause severe hypersensitivity reactions,
11. Unresolved toxicity higher than CTCAE (v5) Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neuropathy ≤ Grade 2,
12. Subject unable to swallow oral medications or any malabsorption condition,
13. Inadequate organ functions:

    * known cardiac failure of unstable coronaropathy, respiratory failure, or uncontrolled infection or another life-risk condition
    * Congestive Heart Failure ≥ New York Heart Association (NYHA) class 2,
    * Myocardial infarction less than 6 months before start of study drug, unstable angina (anginal symptoms at rest), new-onset angina (begun within the last 3 months), Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted),
    * Uncontrolled hypertension (defined by systolic blood pressure ≥ 150 mmHg and/or diastolic pressure ≥ 100 mmHg despite optimal medical management), or history of hypertensive crisis, or hypertensive encephalopathy
    * Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2 dyspnea),
    * Interstitial lung disease with ongoing signs or symptoms,
    * Ongoing infection \>grade 2 CTCAE V5,
    * Dehydration CTCAE v5 grade ≥1,
    * Urinary tract obstruction
14. Constitutional or acquired hemorrhagic disease:

    * Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication,
    * History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to inclusion,
    * Serious, Non-healing wound, active peptic ulcer or untreated bone fracture,
    * Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication,
15. 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,
16. Known History of human immunodeficiency virus (HIV) infection; Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy,
17. Receipt of yellow fever vaccine within 28 days prior to study,
18. History of organ allograft,
19. Pregnant or breast-feeding subjects

Where this trial is running

Auxerre and 9 other locations

• CHU d'Auxerre — Auxerre, France (Recruiting)
• Centre Hospitalier Universitaire de Besançon — Besançon, France (Recruiting)
• CH de Colmar — Colmar, France (Recruiting)
• Centre Georges-François Leclerc (CGFL) — Dijon, France (Recruiting)
• Hôpital Robert Schuman — Metz, France (Recruiting)
• Hôpital Nord Franche-Comté — Montbéliard, France (Recruiting)
• CHU de Montpellier — Montpellier, France (Recruiting)
• CHU de Reims - Hôpital Robert Debré — Reims, France (Recruiting)
• Clinique Privée de Strasbourg — Strasbourg, France (Not_yet_recruiting)
• Icans — Strasbourg, France (Recruiting)

Study contacts

• Study coordinator: Angélique VIENOT, Dr

Conditions Metastatic Colorectal Cancer; Regorafenib; metronomic chemotherapy; colon cancer