Regorafenib in Combination With Multimodal Metronomic Chemotherapy for Chemo-resistant Metastatic Colorectal Cancers

NCT06425133 | Recruiting Phase 2 DMC

• 1 other identifier: 2023/805
• Study Type: interventional
• Target: 174
• Locations: 1 country
• Sites: 10

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.

Conditions

Metastatic Colorectal Cancer

Keywords

Regorafenib; metronomic chemotherapy; colon cancer

Outcome Measures

Primary Outcomes (1)

• 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

  Progression-free survival (PFS): defined as the time from the randomization to objective disease progression as per RECIST v1.1 or death from any cause, whichever occurs first. The time of the progression or recurrence event is determined using the first date when there is documented evidence that the criteria have been met, even in situations where progression is observed after one or more missed visits, treatment discontinuation, or new anti-cancer treatment. Patients with no defined events observed during the follow up period will be censored at the date of last news

  5 months average

Study Arms (2)

Regorafenib

ACTIVE COMPARATOR

• Regorafenib will be administered 3 weeks out of 4 (1 cycle corresponding to 4 weeks) until progression or unacceptable toxicity. For the first cycle: Regorafenib will be administered according to the "REDOS" schedule week 1: 80 mg regorafenib daily week 2: 120 mg regorafenib daily week 3: 160 mg regorafenib daily week 4 : no regorafenib For the following cycles: regorafenib will be administered at 160mg in the absence of significant toxicity during cycle 1 or at a 80/120mg daily dose according to toxicity observed with the last dose used in the first cycle.

Procedure: Blood sample; Other: Quality of life questionnaires; Procedure: Biopsy; Drug: Regorafenib

Regorafenib+ metronomic chemotherapy + aspirin

EXPERIMENTAL

• Regorafenib will be administered 3 weeks out of 4 (1 cycle corresponding to 4 weeks) until progression or unacceptable toxicity. For the first cycle: Regorafenib will be administered according to the "REDOS" schedule: week 1: 80 mg daily week 2: 120 mg daily week 3: 160 mg daily week 4 : OFF. For the following cycles: regorafenib will be administered at 160mg in the absence of significant toxicity during cycle 1 or at a 80/120mg daily dose according to toxicity observed with the last dose used in the first cycle. * Metronomic chemotherapy will be administrated as following:Cyclophosphamide: 50 mg per os, daily, for 6 months,Capecitabine: 625mg/m²/orally twice daily, for 6 months. * Low-dose Aspirin: 75 mg orally, daily, until progression.

Procedure: Blood sample; Other: Quality of life questionnaires; Procedure: Biopsy; Combination Product: Regorafenib + metronomic chemotherapy

Interventions

Blood sample PROCEDURE

Blood sample for plasma collection, Blood sample for ctDNA (circulating tumoral DNA) collection

Regorafenib; Regorafenib+ metronomic chemotherapy + aspirin

Quality of life questionnaires OTHER

EORTC QLQ-C30 questionnaire (Quality of life questionnaire Cancer 30) CR29 questionnaire (Colo-rectal cancer 29) EQ-5D5L questionnaire (EuroQol-5 Dimensions, 5 levels): repeated measures at baseline, M2, M4, M6, M8, M10, M12 and during the end of treatment visit and during the follow-up

Regorafenib; Regorafenib+ metronomic chemotherapy + aspirin

Biopsy PROCEDURE

Fresh tumor biopsy at baseline and week 8

Regorafenib; Regorafenib+ metronomic chemotherapy + aspirin

Regorafenib DRUG

For the first cycle: Regorafenib will be administered according to the "REDOS" schedule: week 1: 80 mg regorafenib daily week 2: 120 mg regorafenib daily week 3: 160 mg regorafenib daily week 4 : OFF. For the following cycles: regorafenib will be administered at 160mg in the absence of significant toxicity during cycle 1 or at a 80/120mg daily dose according to toxicity observed with the last dose used in the first cycle.

Regorafenib

Regorafenib + metronomic chemotherapy COMBINATION_PRODUCT

• Regorafenib will be administered 3 weeks out of 4 (1 cycle corresponding to 4 weeks) until progression or unacceptable toxicity. For the first cycle: Regorafenib will be administered according to the "REDOS" schedule: week 1: 80 mg regorafenib daily week 2: 120 mg regorafenib daily week 3: 160 mg regorafenib daily week 4 : OFF. For the following cycles: regorafenib will be administered at 160mg in the absence of significant toxicity during cycle 1 or at a 80/120mg daily dose according to toxicity observed with the last dose used in the first cycle. * Metronomic chemotherapy will be administrated as following:Cyclophosphamide: 50 mg per os, daily, for 6 months,Capecitabine: 625mg/m²/orally twice daily, for 6 months. * Low-dose Aspirin: 75 mg orally, daily, until progression.

Regorafenib+ metronomic chemotherapy + aspirin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Life expectancy of at least 3 months
• Female or male with age \>18 years old
• Performance status = 0 or 1 (Annex 1)
• Measurable disease defined according to RECIST v1.1 guidelines (scanner or MRI)
• 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
• No contraindication to Iodine contrast media injection during CT
• 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),
• Signed and dated informed consent,
• Ability to comply with the study protocol, in the Investigator's judgment.
• Registration in a national health care system (CMU included).

You may not qualify if:

• Patient under judicial protection (curators, autorship) and/or deprived of freedom,
• Previous exposition to regorafenib or anti-angiogenic treatment other than bevacizumab and aflibercept
• Treatment with any other investigational medicinal product within 28 days prior to study entry, EXCEPT for ASPIRIN,
• Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks,
• 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,
• Complete deficit in dihydropyrimidine dehydrogenase (DPD),
• 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,
• Unresolved toxicity higher than CTCAE (v5) Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neuropathy ≤ Grade 2,
• Subject unable to swallow oral medications or any malabsorption condition,
• 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,

Sponsors & Collaborators

• Centre Hospitalier Universitaire de Besancon: lead
• Groupement Interrégional de Recherche Clinique et d'Innovation: collaborator

Study Sites (10)

CHU d'Auxerre

Auxerre, France

RECRUITING

Centre Hospitalier Universitaire de Besançon

Besançon, 25000, 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

MeSH Terms

Conditions

Colorectal Neoplasms; Colonic Neoplasms

Interventions

Blood Specimen Collection; Biopsy; regorafenib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Cytodiagnosis; Cytological Techniques; Diagnostic Techniques, Surgical

Central Study Contacts

Angélique VIENOT, Dr

CONTACT

+33 370632278; a3vienot@chu-besancon.fr

Christophe BORG, Pr

CONTACT

xtoph.borg@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 17, 2024
• First Posted: May 22, 2024
• Study Start: July 19, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2028
• Last Updated: December 24, 2024

Record last verified: 2024-11

Locations

FR (10)