Combining regorafenib with low-dose chemotherapy and aspirin for metastatic colorectal cancer

Induction Regorafenib in Combination With Metronomic Cyclophosphamide, Capecitabine, and Low-dose Aspirin Followed by Chemotherapy in Second Line Metastatic Colorectal Cancer Carcinoma An Open-label Randomized Phase II-III Study

This study is testing if combining regorafenib with low-dose chemotherapy and aspirin can help people with metastatic colorectal cancer feel better before starting standard treatment.

Quick facts

• Phase: Phase2; Phase3
• Study type: Interventional
• Enrollment: 446 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Centre Hospitalier Universitaire de Besancon (Academic / other)
• Drugs / interventions: bevacizumab, chemotherapy, immunotherapy
• Locations: 16 sites (Besançon and 15 other locations)
• Trial ID: NCT05462613 on ClinicalTrials.gov

What this trial studies

This study evaluates the effectiveness of regorafenib in combination with metronomic chemotherapies and low-dose aspirin as an induction therapy for patients with metastatic colorectal cancer. The approach involves a two-month treatment period before initiating standard chemotherapy in patients who have progressed after first-line treatment. The study aims to assess the potential benefits of this combination therapy on patient outcomes and quality of life. Participants will undergo quality of life assessments and provide blood samples throughout the study.

Who should consider this trial

Good fit: Ideal candidates are patients with histologically confirmed metastatic colorectal cancer who have progressed after first-line chemotherapy.

Not a fit: Patients who have not received first-line chemotherapy or those with non-metastatic colorectal cancer may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could improve outcomes and quality of life for patients with metastatic colorectal cancer.

How similar studies have performed: Other studies have explored similar combination therapies, showing promising results, but this specific approach is relatively novel.

Eligibility criteria

Inclusion Criteria:

1. Patients with histologically proven metastatic colorectal cancer in progression after a first line of chemotherapy +/- targeted therapy
2. Patients must have been treated for their metastatic disease with one of the following regimens as first-line therapy:

   * FOLFOX (Oxaliplatine, 5-Fluoro-uracil)
   * FOLFIRI (Irinotecan, 5-Fluoro-uracil)
   * FOLFIRINOX (Irinotecan, oxaplipatin, 5-Fluoro-uracil) or FOLFOXIRI (irinotecan, oxaliplatin, 5-Fluoro-uracil)
   * FOLFOX and anti-VEGFA (bevacizumab only)
   * FOLFIRI and anti-VEGFA (bevacizumab only)
   * FOLFIRINOX or FOLFOXIRI and anti-VEGFA (bevacizumab only)
   * FOLFOX and anti-EGFR (Epiderman Growth Factor Recepto)
   * FOLFIRI and anti-EGFR
   * FOLFIRINOX 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.
3. 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 5-Fluoro-uracil-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.
4. Life expectancy of at least 3 months
5. Female or male with age ≥18 years old
6. Performance status Eastern Cooperative Oncology Group World Health Organization (ECOG-WHO) ≤1 (Appendix 1),
7. Measurable disease defined according to RECIST v1.1 (scanner or MRI)
8. Molecular status: patients eligible should have microsatellite-stable (MSS) status, absence of BRAF V600E (B(Raf gene, val600-to-glu) mutation and a known RAS (Retrovirus Associated Sequences) status.
9. Adequate bone marrow, liver and renal functions.

   * Haemoglobin ≥ 9 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L
   * 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
   * Cockcroft glomerular filtration rate \> 50 ml/min
   * Proteinuria \<2+ (dipstick urinalysis) or ≤1g/24hour
10. No contraindication to Iodine contrast media injection during CT
11. 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),
12. Signed and dated informed consent,
13. Ability to comply with the study protocol, in the Investigator's judgment.
14. 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. Patients might be included at least 21 days following the last investigational agent administration.
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. 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,
6. Previous exposure to regorafenib,
7. Previous exposure to other anti-angiogenic treatment than bevacizumab,
8. Complete deficit in dihydropyrimidine dehydrogenase (DPD),
9. Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication,
10. Pregnant or breast-feeding subjects,
11. Congestive Heart Failure ≥ New York Heart Association (NYHA) class 2, unstable angina (anginal symptomatology at rest),
12. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months),
13. Myocardial infarction less than 6 months before start of study drug,
14. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted),
15. 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
16. Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2 dyspnea),
17. Ongoing infection \>grade 2 CTCAE V5 (Appendix 6 ),
18. Known History of human immunodeficiency virus (HIV) infection,
19. Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy,
20. Subjects with seizure disorder requiring medication,
21. History of organ allograft,
22. Subjects with evidence or history of any bleeding diathesis, irrespective of severity,
23. Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication,
24. Serious, Non-healing wound, active ulcer or untreated bone fracture,
25. History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to inclusion,
26. Dehydration CTCAE v4 grade ≥1,
27. Known hypersensitivity to any of the study drugs, study drug classes or excipient in the formulation,
28. Interstitial lung disease with ongoing signs or symptoms,
29. Persistent proteinuria of CTCAE Grade 3 (\>3.5 g/24 hours),
30. Subject unable to swallow oral medications,
31. 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,
32. Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks,
33. Treatment with any other investigational medicinal product within 28 days prior to study entry, EXCEPT for ASPIRIN,
34. Co-administration of drugs potentially interacting with regorafenib i.e. CYP3A4 or UGT1A9 (UDP-glucuronosyltransferase 1-9) inducers/inhibitors.

Where this trial is running

Besançon and 15 other locations

• CHU de Besançon — Besançon, France (Recruiting)
• CHU Estain — Clermont-Ferrand, France (Not_yet_recruiting)
• Hôpital Henri Mondor — Créteil, France (Recruiting)
• Centre Georges François Leclerc — Dijon, France (Recruiting)
• Centre Léon Bérard — Lyon, France (Not_yet_recruiting)
• Hôpital Privé Jean Mermoz — Lyon, France (Recruiting)
• Hôpital Nord Franche Comté — Montbéliard, France (Recruiting)
• CHU Montpellier — Montpellier, France (Recruiting)
• Groupe hospitalier de la région de Mulhouse et Sud Alsace — Mulhouse, France (Recruiting)
• Centre Antoine Lacassagne — Nice, France (Not_yet_recruiting)
• Hôpital Européen Georges Pompidou — Paris, France (Recruiting)
• Hôpital la Pitié-Salpétrière — Paris, France (Recruiting)
• Hôpital Saint antoine — Paris, France (Recruiting)
• Institut Mutualiste Montsouris — Paris, France (Recruiting)
• CHU de Reims - Hôpital Robert Debré — Reims, France (Recruiting)
• Hôpital FOCH — Suresnes, France (Not_yet_recruiting)

Study contacts

• Study coordinator: Angélique VIENOT, MD, PhD

Conditions Metastatic Colorectal Cancer