Evaluation of Regorafenib Combined with Metronomic Chemotherapy and Low-Dose Aspirin Versus Regorafenib Alone in Chemo-Resistant Metastatic Colorectal Cancer
- Trial ID
- 2023-509761-21-00
- Protocol
- 2023/805
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the impact of **Regorafenib** combined with metronomic chemotherapy (capecitabine and cyclophosphamide) and low-dose aspirin on progression-free survival in patients with metastatic colorectal cancer, compared to standard Regorafenib treatment. This is clinically relevant as it aims to improve treatment outcomes in a population with limited therapeutic options due to chemo-resistance.
Secondary objectives include:
- Evaluating patients' health-related quality of life (QoL) in the two treatment arms.
- Assessing the toxicities associated with the study treatments.
- Determining the overall survival rates in the two arms.
- Assessing the disease control rate in the two arms.
- Evaluating the objective response rate in the two arms.
- Correlating CHUN morphologic criteria with RECIST v1.1 response.
- Evaluating the cost-effectiveness of adding metronomic chemotherapy and low-dose aspirin to Regorafenib.
Participants
The clinical trial involves participants diagnosed with **metastatic colorectal cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population. Participants must have adequate bone marrow, liver, and renal functions, and a life expectancy of at least three months. The selection criteria ensure that participants have measurable disease as defined by RECIST v1.1 guidelines. The sponsor has not provided the total number of participants involved in the trial. Lifestyle considerations such as diet and physical activity are not specified in the available data. The trial population was selected based on their progression after previous standard treatments and their ability to comply with the study protocol, as judged by the investigator.
Plans and Procedures
The clinical trial is designed to evaluate the impact of **regorafenib** in combination with multimodal metronomic chemotherapy, including **capecitabine**, **cyclophosphamide**, and low-dose **aspirin**, on progression-free survival in patients with chemo-resistant metastatic colorectal cancer. This study is a randomized, double-blind, controlled trial, with an estimated duration extending until August 2027. Participants will be randomly assigned to receive either the combination therapy or standard regorafenib treatment. The trial will assess primary and secondary endpoints, including progression-free survival, overall survival, and health-related quality of life.
The sequence of study visits begins with an inclusion (screening) visit, where eligibility criteria are confirmed, including histologically proven metastatic colorectal cancer and adequate organ function. Following randomization, participants will undergo regular follow-up visits to monitor treatment response and adverse events. These visits will include assessments such as imaging studies according to RECIST v1.1 guidelines, laboratory tests, and completion of quality of life questionnaires. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.
Participant involvement is expected to last up to 36 months, depending on the treatment arm and individual response. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, withdrawal of consent, or investigator's decision based on the participant's best interest. The trial aims to provide comprehensive data on the efficacy and safety of the combination therapy compared to standard treatment, contributing valuable insights into the management of metastatic colorectal cancer.
Treatment
The clinical trial involves the administration of **Stivarga** (regorafenib) 40 mg film-coated tablets, which are taken orally. The maximum daily dose is 160 mg, with a total maximum dose of 172,800 mg over a treatment period of up to 36 weeks. Regorafenib is a chemically synthesized active substance, and the tablets are manufactured by Bayer AG. The administration schedule is designed to ensure optimal therapeutic outcomes while monitoring participant compliance through regular assessments.
**Xeloda** (capecitabine) is utilized in two formulations: 500 mg and 150 mg film-coated tablets, both administered orally. The maximum daily dose for capecitabine is 1250 mg/m², with a total maximum dose of 225,000 mg/m² over a treatment period of up to 6 weeks. Capecitabine is a chemical compound produced by Cheplapharm Arzneimittel GmbH. The dosing schedule is structured to maintain consistent plasma levels, and participant adherence is monitored through pill counts and patient diaries.
**KARDEGIC** 75 mg, containing **D,L-lysine acetylsalicylate**, is provided as a powder for oral solution in sachet-dose form. The maximum daily dose is 75 mg, with a total maximum dose of 81,000 mg over a treatment period of up to 36 weeks. This chemical substance is manufactured by Sanofi Winthrop Industrie and serves as an anti-platelet agent in the trial. The administration is oral, and compliance is tracked through regular follow-ups and patient self-reports.
**ENDOXAN** (anhydrous cyclophosphamide) 50 mg coated tablets are administered orally, with a maximum daily dose of 50 mg and a total maximum dose of 9,000 mg over a treatment period of up to 6 weeks. This chemical compound is produced by Baxter SAS. The dosing regimen is carefully monitored to ensure patient safety and efficacy, with compliance checks conducted through patient logs and clinical visits.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **Progression-Free Survival (PFS)**. PFS is defined as the time from the randomization date to disease progression, as per RECIST v1.1 criteria, or death from any cause, whichever occurs first. Patients who are alive without progression will be censored at the last radiological evaluation available in the study arms treatment setting showing no progression.
Secondary endpoints for efficacy evaluation include several parameters: Health-related Quality of Life, assessed using the EORTC QLC30 + CR29 and EQ-5D-5L questionnaires, focusing on five targeted dimensions of interest such as Global Health, Pain, Physical Functioning, Fatigue, and Emotional Functioning. Additionally, the number of days of hospitalization will be recorded. Toxicities will be graded according to NCI-CTCAE criteria version. Overall Survival (OS) will be measured from the randomization date to death from any cause, with alive patients censored at the last date known to be alive. Disease Control Rate (DCR) will be calculated as the proportion of participants with a best overall response of confirmed Complete Response (CR), Partial Response (PR), or stable disease (SD). Duration of Objective Response (DOR) will be defined for responders only, from the first documented objective response to disease progression or death. The evaluation will also include CHUN morphological criteria and an economic evaluation through the incremental cost-utility ratio using the EuroQol-5D-5L (EQ-5D-5L) questionnaire and VAS, with repeated measures at baseline, week 8, months 4, 6, 8, 10, 12, and end of study at month 18.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients with histologically proven metastatic colorectal cancer in progression after previous standard treatments (5FU, CPT11, oxaliplatin, anti-VEGF, trifluridine/tipiracil, and anti-EGFR therapy if KRAS and NRAS WT, anti-BRAF therapy if BRAF V600E mutated, and anti-PD1 if MSI-H/dMMR tumor), or not considered as candidate for these treatments.
- 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).
- 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) (Annex 2)
- 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),
Exclusion Criteria
- 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),
- Current participation in a study of an investigational agent or in the period of exclusion
- 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 ;
- Patient under judicial protection (curatorship, tutorship) 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 inductor/inhibitor; Epilectic disorder requiring medication; Recent or concomitant treatment with brivudine,
- Complete deficit in dihydropyrimidine deshydrogenase (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, - Myocardal 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
- 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,
- 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,
- Known History of human immunodeficiency virus (HIV) infection; Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy,
- Receipt of yellow fever vaccine within 28 days prior to study,
- History of organ allograft,
- Pregnant or breast-feeding subjects
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 15 Feb 2024 | 174 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Xeloda 500 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 1250 | 6 | PRD9863934 |
Stivarga 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 160 | 36 | PRD1713388 |
KARDEGIC 75 mg, poudre pour solution buvable en sachet-dose | Test | POUDRE POUR SOLUTION BUVABLE EN SACHET-DOSE | ORAL | 75 | 36 | PRD432444 |
ENDOXAN 50 mg, comprimé enrobé | Test | COMPRIMÉ ENROBÉ | ORAL | 50 | 6 | PRD350176 |
Xeloda 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 1250 | 6 | PRD9863933 |