Clinical trial NCT06425133: Regorafenib in Combination With Multimodal Metronomic Chemotherapy for Chemo-resistant Metastatic Colorectal Cancers
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: Regorafenib
metronomic chemotherapy
colon cancer
Lead sponsor: Centre Hospitalier Universitaire de Besancon
Sponsor class: OTHER
Collaborators: name: Groupement Interrégional de Recherche Clinique et d'Innovation
First posted: 2024-05-22
Enrollment: 174
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main objective is to evaluate the impact of a Regorafenib combined with metronomic chemotherapy (capecitabine and cyclophosphamide) and low-dose aspirin compared to standard Regorafenib treatment in patients with metastatic colorectal cancer by assessing progression-free survival.


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

Primary outcomes:
measure: To evaluate the impact of a Regorafenib combined with metronomic chemotherapy and low-dose aspirin compared to standard Regorafenib treatment by assessing progression-free survival
timeFrame: 5 months average
Secondary outcomes:
Other outcomes:
Locations:
city: Auxerre
country: France
facility: CHU d'Auxerre
city: Besançon
country: France
facility: Centre Hospitalier Universitaire de Besançon
city: Colmar
country: France
facility: CH de Colmar
city: Dijon
country: France
facility: Centre Georges-François Leclerc (CGFL)
city: Metz
country: France
facility: Hôpital Robert Schuman
city: Montbéliard
country: France
facility: Hôpital Nord Franche-Comté
city: Montpellier
country: France
facility: CHU de Montpellier
city: Reims
country: France
facility: CHU de Reims - Hôpital Robert Debré
city: Strasbourg
country: France
facility: Clinique Privée de Strasbourg
city: Strasbourg
country: France
facility: ICANS
Study officials:
References: