| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RAS-mutated metastatic colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| RAS-mutated metastatic colorectal cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Phase I: To determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D), based on the Dose Limiting Toxicities (DLT) of the combination evaluated during the three first cycles following initiation of therapy (observational period),
To evaluate the safety profile of the combination
Phase II : To evaluate the efficacy (48-week disease-control rate) of the study combination
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| E.2.2 | Secondary objectives of the trial |
- Safety of combination (NCI-CTC v5, neurotoxicity being also evaluated with the Levi’s scale),
- Overall response rate and disease control rate according to RECIST 1.1,
- Duration of response in patients who were not operated on for their metastases,
- 8-weeks response rate according to RECIST 1.1,
- Deepness of response,
- Resectability (R0-R1) and unresectability rates (including R2) among patients with liver-only metastases,
- Progression-free survival,
- Progression-free survival since maintenance therapy onset with regorafenib,
- Overall survival
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent for full study.
2. Measurable disease, defined as at least one unidimensional measurable lesion on a CT scan, according to RECIST version 1.1.
3. ECOG performance status ≤1.
4. Life expectancy of at least 3 months.
5. Adequate bone marrow, renal and liver functions as evidenced by the following laboratory requirements within 7 days prior to study treatment initiation
6. Lipase ≤ 1.5 x ULN.
7. Adequate coagulation, as assessed by the following laboratory test results
8. For women of reproductive potential, negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test obtained within 7 days before the start of study treatment. Women not of reproductive potential are female patients who are postmenopausal or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy).
9. For women of childbearing potential and men, agreement to use an adequate contraception for the duration of study participation and up to 4 months following completion of therapy for women and 6 months for male patients. Females of childbearing potential who are sexually active with a non-sterilized male partner must use 2 methods of effective contraception. The investigator or a designated associate is requested to advise the patient on how to achieve an adequate birth control.
Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care.
10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
11. Affiliation to the Social Security System
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|
| E.4 | Principal exclusion criteria |
1. Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to study inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non invasive tumor), Tis (carcinoma in situ) and T1 (lamina propria invasion)].
2. Discovery of metastases within 6 months after the termination of adjuvant chemotherapy.
3. Previous treatment for metastatic disease.
4. Radiotherapy within 28 days prior to first dose of
treatment.
5. Active cardiac disease including any of the following:
a. Congestive heart failure New York Heart
Association (NYHA) class 2,
b. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months),
c. Myocardial infarction less than 6 months before first
dose of treatment,
d. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
6. ECG with a QT/QTc interval higher than 450 ms for men and higher than 470 ms for women Uncontrolled hypertension.
7. Uncontrolled hypertension. (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management).
8. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before start of treatment.
9. Persistent proteinuria of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V5) grade 3 (i.e. urinary protein ≥ 3.5 g/24 hrs)
10. Peripheral neuropathy > grade1 (NCI-CTCAE v5).
11. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to first dose of
Treatment.
12. Ongoing infection >grade 2 (NCI-CTCAE v5).
13. Known history of human immunodeficiency virus (HIV) infection.
14. Chronic hepatitis B or C infection (if hepatitis status cannot be obtained from medical records, re-testing is required).
15. Seizure disorder requiring medication.
16. Symptomatic metastatic brain or meningeal tumors.
17. Evidence or history of any bleeding diathesis, irrespective of severity. Any hemorrhage or bleeding event grade 3 (NCI-CTCAE v5) within 4 weeks prior to the start of study medication.
18. History of organ allograft.
19. Non-healing wound, ulcer, or bone fracture.
20. Dehydration Grade > 1 NCI-CTCAE v5).
21. Substance abuse, medical, psychological, or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
22. Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products.
23. Interstitial lung disease with ongoing signs and symptoms.
24. Concomitant intake of St. John's wort.
25. Live attenuated vaccines are prohibited 10 days before the treatment, during the treatment and 3 months after the termination of treatment
26. History of gastrointestinal fistula or perforation
27. Inability to swallow oral medication.
28. Any malabsorption condition.
29. Pregnant or breast-feeding subjects.
30. Any condition that, in the opinion of the investigator, would interfere with the evaluation of study treatment or interpretation of patient safety or study results.
31. Participation in another clinical study with an
investigational product during the last 30 days before inclusion.
32. Patients who might be interconnected with or dependent on the sponsor site or the investigator.
33. Legal incapacity or limited legal capacity
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I: Adverse events as graded using the common toxicity criteria from the NCI-CTCAE v5 and incidence rates of DLT at each dose level during the 3 first cycles of combination therapy
Phase II: 48-week disease-control rate |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I: DLT is defined by during the three first cycles of treatment:
1. Missing >7 days daily doses of regorafenib due to drug-related toxicity (scheduled treatment pause of regorafenib will not be counted),
2. Non-Hematologic DLT
3. Hematologic DLT
Phase II: defined as the rate of non-progressing patients after central review, at 48-week post-initiation of therapy, to all treated patients. |
|
| E.5.2 | Secondary end point(s) |
| Phase II : Progression-free survival (PFS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Defined as the time from date of inclusion to date of first observed disease progression (investigator’s radiological or clinical assessment) or death due to any cause |
|
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| 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
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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