| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advance pretreated melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with advance melanoma that have failed prior systemic treatment with immune checkpoint inhibitors. |
|
| 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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025671 |
| E.1.2 | Term | Malignant melanoma stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025670 |
| E.1.2 | Term | Malignant melanoma stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Cohort A: To estimate the anti-tumor activity of regorafenib treatment in patients with advanced pretreated melanoma.
Cohort B: To estimate the anti-tumor activity of regorafenib treatment when added to a BRAF-/MEK-inhibitor combination in
patients with advanced pretreated BRAF V600-mutant melanoma at the time of progression on a BRAF-/MEKinhibitor therapy
Cohort C: To estimate the anti-tumor activity of regorafenib treatment when combined with encorafenib/binimetinib in
patients with advanced pretreated BRAF V600-mutant melanoma who previously progressed on a BRAF-/MEK-inhibitor therapy and have
interrupted this therapy for at least 12 weeks |
|
| E.2.2 | Secondary objectives of the trial |
- To estimate the progression-free survival (PFS) and overall survival (OS) of study patients treated with regorafenib.
- To document the incidence and severity of adverse events (AE) in study patients.
- Health-Related Quality of Life (HRQOL)
- To determine the disease control rate (DCR) of regorafenib when added on to a BRAF-/MEK-inhibitor combination
(cohort-B) or of regorafenib treatment when combined with encorafenib/binimetinib (cohort-C) in patients with advanced pretreated
BRAF V600-mutant melanoma.
- Cohort B and C: To determine the intracranial and extracranial response rate separately in patients with melanoma brain metastases
- To estimate the duration of response of study patients |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥ 18 years of age.
2. Signed written informed consent.
3. Histologically confirmed advanced melanoma that is either stage III (locoregionally metastatic, unresectable) or stage IV (distant metastatic,
unresectable)
4. Subjects must have failed prior systemic treatment with immune checkpoint inhibitors, including: CTLA-4 blocking immune checkpoint inhibitors (ipilimumab or other experimental anti-CTLA-4 antibodies), and a PD-1 blocking immune checkpoint inhibitors (pembrolizumab, nivolumab or other experimental anti-PD-1 antibodies). Patients with BRAFV600mutant melanoma must have failed treatment with a BRAF-(+/- MEK) inhibitor. Patients who are not able to undergo such treatment will be considered eligible if all other eligibility criteria are fulfilled.
Progression of disease per RECIST, version 1.1 [4] or per immune related response criteria [6] must have been documented during this prior treatment.
5. Cohort-B: patients should be on treatment with BRAF-/MEK-inhibitors or have interrupted for less than 4 weeks before initiation of the study treatment.
6. Cohort-C: patients should be off BRAF-/MEK-inhibitors for at least 12 weeks before initiation of the study treatment.
7. The presence of at least one measurable lesion per RECIST, version 1.1 [4].
8. Interval between the date of the last administration of prior therapy for melanoma and the date of initiation of study treatment:
a. ≥ 12 weeks following the date of the first administration and ≥ 3 weeks following the date of the last administration of an anti-CTLA-4-, PD-1- or PD-L1 blocking immune checkpoint inhibitor;
b. ≥ 4 weeks following the date of the last administration of chemotherapy (≥ 6 weeks in case of a nitrosurea or mitomycin C containing regimen);
c. Cohort-C: ≥ 12 weeks following the date of the last administration of BRAF-/MEK-inhibitors
9. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed on Table 1) and non-medical treatments (e.g. surgery and radiation therapy) must be ≤ Grade 1 severity according to the Common Terminology
Criteria for Adverse Events version 5 (CTCAE version 5.0; National Cancer Institute (NCI) 2017) at the time of enrollment.
10. Patients should be able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
11. Women of childbearing potential must have a negative serum pregnancy test during screening and within 72 hours prior to first administration of study drug and agree to use effective contraception throughout the treatment period, and for 16 weeks after the last dose of study treatment.
12. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception from 14 days prior to administration of the first dose of study treatment, throughout the treatment
period, and for 16 weeks after the last dose of study treatment.
13. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
(Oken et al, Am J Clin Oncol 1982).
14. Adequate baseline organ function
15. Persistent proteinuria of CTCAE v5.0 Grade 3. Urine dipstick result of 3+ or abnormal, based on type of urine test strip used, is allowed if protein excretion (estimated by urine protein/creatinine ratio on a random urine sample) is <3.5 g / 24 hours. |
|
| E.4 | Principal exclusion criteria |
16. Patients with uveal melanoma.
17. Cohort-B: patients treated with vemurafenib/cobimetinib.
18. Patients who are unable to initiate regorafenib within 4 weeks after interrupting BRAF-/MEK-inhibitor therapy (cohort B) or have not interrupted such therapy for at least 12 weeks (cohort C).Patients with active brain metastases who experience ongoing progressive neurological deterioration or requiring increasing doses of steroids for at least 14 days prior to first dose of study treatment.
19. Patients who experienced or are experiencing grade > 3 treatment related adverse events related to BRAF-/MEK-inhibitor therapy.
20. Intolerance or drug allergies to tafinlar, mekinist, encorafenib, or binimetinib.
21. Any contra-indication for evaluation by whole body 18F-FDG-PET/CT and MRI of the brain.
22. History of another malignancy. Exception: subjects who have been disease-free for 3 years, (i.e., subjects with second malignancies that are indolent or definitively treated at least 3 years ago) or subjects with a history of completely resected nonmelanoma skin cancer.
23. Current use of any prohibited medication.
24. Administration of an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to recruitment.
25. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures.
26. Known Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection. Exception: subjects with laboratory evidence of cleared HBV and HCV infection will be permitted.
27. Ongoing infection CTCAE v5.0 Grade > 2 requiring systemic therapy.
28. No enzyme inducing anticonvulsants for ≥ 4 weeks prior to recruitment
29. A history or evidence of cardiovascular risk including any of the following:
a. Current LVEF < LLN
b. QT interval corrected for heart rate using the Bazett’s formula (QTcB) ≥ 480 msec;
c. History or evidence of current clinically significant uncontrolled arrhythmias; exception: subjects with atrial fibrillation controlled for > 30
days prior to recruitment are eligible.
d. History (within 6 months prior to recruitment) of acute coronary syndromes (including myocardial infarction or unstable angina), or
coronary angioplasty;
e. History of deep venous or arterial thrombosis, or CVA the last 6 months
f. History or evidence of current ≥ Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines;
g. Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by antihypertensive therapy;
h. Patients with intra-cardiac defibrillators or permanent pacemakers;
i. Abnormal cardiac valve morphology (≥ grade 2; moderate valvular thickening) documented by echocardiogram (subjects with grade 1
abnormalities [i.e., mild regurgitation/stenosis] can be entered on study).
30. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients
31. Female patients who are nursing. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate (ORR; defined as the percentage of subjects with a confirmed complete response [CR] or partial response [PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, [Eisenhauer et al. Eur J Cancer 2009]) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of the study, until 3 years after last dose given to patient. |
|
| E.5.2 | Secondary end point(s) |
- Progression-free survival (PFS; defined as the time from the date of the first dose administration of regorafenib until the earliest date of documented disease progression [per RECIST v1.1] or death due to any cause) and overall survival (OS; defined as the time from the date of the first dose administration of regorafenib until the date of death due to any cause)
- Safety as assessed by anamnesis, clinical examination, analysis of blood and urine, electrocardiograms, cardiac echocardiography, and any additional medical examination that is indicated. AE will be graded by the Common Terminology Criteria of Adverse events (CTCAE), version 5.0 (National Institutes of Health, National Cancer Institute).
• The generic health status of the patients will be assessed by means of the EuroQOL-5D-3L (EQ-5D-3L).
• Health-related quality of life (HRQoL) will be assessed with the European Organization for Research and Treatment of Cancer quality of life questionnaire-C30 (EORTC-QLQ-C30).
• Melanoma specific health-related quality of life will be evaluated with the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M)
- Disease control rate (DCR; defined as the percentage of subjects with a confirmed stable disease (SD), partial response (PR) or complete response (CR) at any time per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1
- Duration of response (DOR; defined as the time from the date of first documented response (SD, PR or CR) until the earliest
date of documented disease progression.
- Objective response rate (ORR; defined as the percentage of subjects with a confirmed complete response [CR] or partial response
[PR] at any time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, and RANO-BM criteria) determined separately for extra- and intracranial metastases, respectively
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of the study, until 3 years after last dose given to patient. |
|
| 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) | 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 | 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) | 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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