Evaluation of Regorafenib with Metronomic Cyclophosphamide, Capecitabine, and Low-Dose Aspirin in Second-Line Metastatic Colorectal Carcinoma
- Trial ID
- 2024-516709-22-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the efficacy of **regorafenib** in combination with metronomic chemotherapies and low-dose aspirin as a two-month induction therapy prior to chemotherapy initiation in second-line metastatic colorectal cancer. This is assessed in terms of the best objective response during the treatment period in phase II and overall survival (OS) in phase III. The clinical relevance of this objective lies in potentially improving treatment outcomes and survival rates for patients with metastatic colorectal cancer, a condition with significant morbidity and mortality.
Secondary objectives include:
- For phase II: Assessing overall survival (OS).
- For phase III: Evaluating the best response.
- Assessing progression-free survival (PFS).
- Evaluating the disease control rate (DCR).
- Assessing the duration of objective response (DOR).
- Evaluating the patient's health-related quality of life (QoL).
- Evaluating the safety of the treatment.
- Assessing the correlation between different tumoral assessment methods (RECIST, CHUN) and biomarkers criteria (serum stromal biomarkers).
- Assessing the impact of the experimental treatment on the efficacy of regorafenib when prescribed in a subsequent line of therapy.
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 life expectancy of at least three months and a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. The trial does not include a vulnerable population. Participants must have histologically confirmed metastatic colorectal cancer that has progressed following a first line of chemotherapy, with or without targeted therapy. They should have been treated with specific chemotherapy regimens such as FOLFOX, FOLFIRI, FOLFIRINOX, or FOLFOXIRI, potentially in combination with anti-VEGFA or anti-EGFR therapies. Adequate bone marrow, liver, and renal functions are necessary, and participants must have a measurable disease as defined by RECIST v1.1. The trial requires participants to have microsatellite-stable (MSS) status, absence of BRAF V600E mutation, and a known RAS status. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **regorafenib** in combination with metronomic chemotherapies and low-dose aspirin as an induction therapy before chemotherapy initiation in patients with metastatic colorectal cancer. This study is structured as an open-label, randomized, phase II-III trial. The primary objective is to assess the best objective response during the treatment period and overall survival. The trial is expected to run from September 2022 to September 2026, with participant involvement lasting up to 14 months, depending on individual response and treatment tolerance.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as histologically proven metastatic colorectal cancer, progression after first-line chemotherapy, and adequate organ function. The inclusion visit will involve baseline assessments and initiation of the study drug regimen. Follow-up visits will occur regularly to monitor treatment response, adverse events, and overall health status. The end-of-study visit will include final assessments to evaluate the primary and secondary endpoints, such as overall survival and progression-free survival.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or withdrawal of consent. The trial employs a rigorous methodology, including independent radiological assessments using RECIST v1.1 criteria to evaluate response rates. The study's design ensures that data collected will provide robust evidence on the efficacy and safety of the treatment regimen in the specified patient population.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Xeloda** is provided in two formulations: 500 mg and 150 mg film-coated tablets, both containing the active substance **capecitabine**. These tablets are administered orally with a maximum daily dose of 1250 mg/m², and the treatment period is limited to 2 months. The medication is classified under fluoropyrimidines and is produced by CHEPLAPHARM ARZNEIMITTEL GMBH.
**ENDOXAN** 50 mg, a coated tablet containing **anhydrous cyclophosphamide**, is administered orally. The maximum daily dose is 50 mg, with a total dose not exceeding 3000 mg over a 2-month period. This medication is categorized as an immunosuppressant and is manufactured by BAXTER SAS.
**OXALIPLATIN** is provided as a solution for infusion, containing the active substance **oxaliplatin**. It is administered as a concentrate for solution for infusion with a maximum daily dose of 85 mg/m² and a total dose of 2380 mg/m² over a 14-month period. This medication is used in chemotherapy regimens.
**KARDEGIC** 75 mg, a powder for oral solution in sachet-dose form, contains **D,L-lysine acetylsalicylate**. It is administered orally with a maximum daily dose of 75 mg and a total dose of 4500 mg over a 2-month period. This medication is classified as a non-steroidal anti-inflammatory drug and is produced by SANOFI WINTHROP INDUSTRIE.
**IRINOTECAN** is administered as a concentrate for solution for infusion, containing **irinotecan hydrochloride**. The maximum daily dose is 180 mg/m², with a total dose of 5040 mg/m² over a 14-month period. It is used in chemotherapy regimens.
**BEVACIZUMAB** is provided as a solution for infusion, containing the active substance **bevacizumab**. It is administered intravenously with a maximum daily dose of 5 mg/kg and a total dose of 140 mg/kg over a 14-month period. This medication is used in various therapeutic regimens.
**FLUOROURACIL** is administered as a solution for infusion, containing the active substance **fluorouracil**. It is given intravenously with a maximum daily dose of 2400 mg/m² and a total dose of 67200 mg/m² over a 14-month period. This medication is classified under antimetabolite drugs.
**BAY 73-4506**, containing **regorafenib**, is provided as a film-coated tablet. It is administered orally with a maximum daily dose of 160 mg and a total dose of 9600 mg over a 2-month period. This medication is produced by BAYER HEALTHCARE AG.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed regimens. The trial also includes non-experimental treatments such as standard-of-care therapies, which may be used as comparator treatments or placebos, depending on the study design. The administration of these medications is conducted under strict clinical supervision to ensure participant safety and data integrity.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the best objective response during the treatment period for Phase II, evaluated using RECIST v1.1 criteria by an independent radiologist committee, and overall survival (OS) for Phase III. The best response rate is defined as the number of patients achieving a complete response (CR) or partial response (PR) divided by the total number of evaluable patients. Patients whose best overall tumor response is not CR or PR will be considered non-responders.
Secondary endpoints encompass a range of measures, including overall survival (OS) from randomization to death from any cause, progression-free survival (PFS) from randomization to disease progression or death, and disease control rate (DCR), which is the proportion of participants with a confirmed CR, PR, or stable disease (SD). The duration of objective response (DOR) is calculated from the first documented objective response to disease progression or death, applicable only to responders. Health-related quality of life (HRQoL) will be evaluated using EORTC QLC30, CR29, and EQ-5D questionnaires, along with TUDD of five targeted dimensions. Additional measures include the number and volumes of paracentesis and drainages, days of hospitalization, and days taking level 3 analgesics.
Toxicities will be monitored, including adverse events (AEs), drug-related AEs, and serious adverse events (SAEs) according to NCI-CTCAE V5.0. The evaluation of CHUN morphological criteria and correlation with response according to RECIST v1.1 and serum stromal biomarkers will also be conducted. These assessments will provide a comprehensive evaluation of the efficacy of the treatment regimen in patients with metastatic colorectal cancer.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients with histologically proven metastatic colorectal cancer in progression after a first line of chemotherapy +/- targeted therapy
- Patients must have been treated for their metastatic disease with one of the following regimens as first-line therapy: o FOLFOX o FOLFIRI o FOLFIRINOX or FOLFOXIRI o FOLFOX and anti-VEGFA (bevacizumab only) o FOLFIRI and anti-VEGFA(bevacizumab only) o FOLFIRINOX or FOLFOXIRI and anti-VEGFA (bevacizumab only) o FOLFOX and anti-EGFR o FOLFIRI and anti-EGFR o 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.
- 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 5FU-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.
- Life expectancy of at least 3 months
- Female or male with age ≥18 years old
- Performance status Eastern Cooperative Oncology Group World Health Organization (ECOG-WHO) ≤1 (Appendix 2),
- Measurable disease defined according to RECIST v1.1 (scanner or MRI) (Appendix 3)
- Molecular status: patients eligible should have microsatellite-stable (MSS) status, absence of BRAF V600E mutation and a known RAS status.
- Adequate bone marrow, liver and renal functions. a. Haemoglobin ≥ 9 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L b. 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 c. Cockcroft glomerular filtration rate > 50 ml/min d. 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 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),
- 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).
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. Patients might be included at least 21 days following the last investigational agent administration.
- 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,
- 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,
- Previous exposure to regorafenib,
- Previous exposure to other anti-angiogenic treatment than bevacizumab,
- Complete deficit in dihydropyrimidine deshydrogenase (DPD),
- Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication,
- Pregnant or breast-feeding subjects,
- Congestive Heart Failure ≥ New York Heart Association (NYHA) class 2, unstable angina (anginal symptomatology at rest),
- Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months),
- Myocardial infarction less than 6 months before start of study drug,
- Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted),
- 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
- Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2 dyspnea),
- Ongoing infection >grade 2 CTCAE V5 (Appendix 4),
- Known History of human immunodeficiency virus (HIV) infection,
- Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy,
- Subjects with seizure disorder requiring medication,
- History of organ allograft,
- Subjects with evidence or history of any bleeding diathesis, irrespective of severity,
- Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication,
- Serious, Non-healing wound, active ulcer or untreated bone fracture,
- History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to inclusion,
- Dehydration CTCAE v4 grade ≥1,
- Known hypersensitivity to any of the study drugs, study drug classes or excipient in the formulation,
- Interstitial lung disease with ongoing signs or symptoms,
- Persistent proteinuria of CTCAE Grade 3 (>3.5 g/24 hours),
- Subject unable to swallow oral medications,
- 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,
- Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks,
- Treatment with any other investigational medicinal product within 28 days prior to study entry, EXCEPT for ASPIRIN,
- Co-administration of drugs potentially interacting with regorafenib i.e. CYP3A4 or UGT1A9 inducers/inhibitors,
- Active peptic ulcer,
- History of asthma induced by the administration of salicylates or substances with a similar action, notably non-steroidal anti-inflammatory medicines,
- Any constitutional or acquired hemorrhagic disease,
- Urinary tract obstruction,
- Recent or concomitant treatment with brivudine,
- Patient on platelet antiaggregants treatment
- Hypokalemia less than normal, hypomagnesemia, hypocalcemia
- QT/QTc interval longer than 450 msec for men and longer than 470 msec for women on the inclusion ECG
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 27 Sept 2022 | 94 |
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 |
|---|---|---|---|---|---|---|
BAY 73-4506 | Test | FILM-COATED TABLET | ORAL | 160 | 2 | PRD124398 |
KARDEGIC 75 mg, poudre pour solution buvable en sachet-dose | Test | POUDRE POUR SOLUTION BUVABLE EN SACHET-DOSE | ORAL | 75 | 2 | PRD432444 |
FLUOROURACIL | Other | — | INTRAVENOUS | 2400 | 14 | SUB07721MIG |
Xeloda 500 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 1250 | 2 | PRD9863934 |
Xeloda 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL | 1250 | 2 | PRD9863933 |
BEVACIZUMAB | Other | — | INTRAVENOUS | 5 | 14 | SUB16402MIG |
ENDOXAN 50 mg, comprimé enrobé | Test | COMPRIMÉ ENROBÉ | ORAL | 50 | 2 | PRD350176 |
IRINOTECAN | Other | PHF00230MIG | CONCENTRATE FOR SOLUTION FOR INFUSION | 180 | 14 | SCP139021 |
OXALIPLATIN | Other | — | CONCENTRATE FOR SOLUTION FOR INFUSION | 85 | 14 | SUB09490MIG |