| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| cancer colorectal métastatique |
| cancer colorectal métastatique |
|
| E.1.1.1 | Medical condition in easily understood language |
| cancer colorectal métastatique |
| cancer colorectal métastatique |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this clinical trial is to assess the interest of regorafenib in combination of metronomic chemotherapies and low-dose aspirin as a 2 months induction therapy before chemotherapy initiation in the second-line metastatic colorectal carcinoma in term of:
- best objective response during treatment period (phase II)
- and overall survival (OS) (phase III) |
|
| E.2.2 | Secondary objectives of the trial |
1. For phase II: To assess the overall survival (OS)
For phase III: To assess the best response
2. To assess the Progression Free Survival (PFS)
3. To assess the Disease Control Rate (DCR)
4. To assess the duration of objective Response (DOR)
5. To assess the patient’s health related quality of life (QoL)
6. To evaluate the safety
7. To evaluate the correlation between different tumoral assessment methods (RECIST,
CHUN) and biomarkers criteria (serum stromal biomarkers)
8. To assess the impact of the experimental treatment on efficacy on regorafenib when
prescribed in subsequent line of therapy
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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
- FOLFOX + anti-VEGFA (bevacizumab only)
- FOLFOX + anti-EGFR
- FOLFIRI
- FOLFIRI + anti-VEGFA (bevacizumab only)
- FOLFIRI + anti-EGFR
- FOLFIRINOX or FOLFOXIRI
- FOLFIRINOX or FOLFOXIRI + anti-VEGFA (bevacizumab only)
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 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.
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,
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 mutation and a known RAS status.
9. 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
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). |
|
| E.4 | Principal exclusion criteria |
Non-eligible to a clinical trial:
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 cancer, bladder in situ),
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 (curatorship, tutorship) and/or deprived of freedom,
Cancer-specific or treatment-specific exclusion criteria:
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 deshydrogenase (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,
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 inducers/inhibitors.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase II:
The primary outcome will be the best response rate evaluated with RECIST v1.1 criteria per an independent radiologist committee during the treatment period defined as the number of patients with CR or PR as best response divided by the total numer of patients evaluable. Patients for whom best overall tumor response is not CR or PR will be considered non-responders.
Phase III:
Overall survival (OS): defined as the time from the randomization to death from any cause.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Overall survival (OS): defined as the time from the randomization to death from any cause (phase II). Alive patient will be censored at last date known to be alive.
2. Best response rate: defined as the number of patients with CR or PR as best response divided by the total number of evaluable patients (phase III)
3. Progression-free survival (PFS): defined as the time from the randomization to disease progression or death from any cause. Alive patient without progression will be censored at last radiological evaluation available showing no progression.
4. Disease control rate (DCR): DCR is defined as the proportion of participants with best overall response of confirmed CR or PR or stable disease (SD).
5. Duration of objective response (DOR) defined as the time from the first documented objective response of PR or CR, whichever is noted earlier, to disease progression or death (if death occurs before progression is documented). DOR will be defined for responders only, i.e. patients with a CR or PR. The actual dates the tumor scans were performed will be used for this calculation. DOR for patients who have not progressed or died at the time of analysis will be censored at the date of their last tumor evaluation.
6. Health related Quality of life (HRQoL):
a. EORTC QLC30, CR29 and EQ-5D questionnaires
b. TUDD (Time Until Definitive Deterioration) of 5 targeted dimensions: Global health/ Pain/ Physical Functioning/ Fatigue / Emotional Functioning
c. Number and volumes of paracentesis and drainages (ascites or pleural effusion)
d. Number of days of hospitalization
e. Number of days taking level 3 analgesics (the number of days with opioid treatments)
7. Toxicities: Adverse events (AEs), drug related AEs, drug related AE leading to dose reduction or discontinuation during treatment, SAE and SUSAR, according to NCI-CTCAE V5.0.
8. Evaluation of CHUN morphological criteria and correlation with response according to RECIST v1.1 and serum stromal biomarkers.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| le dernier suivi du dernier patient inclus |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
Print
