Advance pretreated melanoma MedDRA version: 21.1 Level: PT Classification code 10025671 Term: Malignant melanoma stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10025670 Term: Malignant melanoma stage III System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Stivarga
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Regorafenib
CAS Number: 755037-03-7
Current Sponsor code: EMEA/H/C/002573
Other descriptive name: Stivarga
Concentrati
Sponsors
Universitair Ziekenhuis Brussel
Eligibility
Sex/Gender
All
Inclusion criteria
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. Are the trial subjects under 18? no Numbe
Exclusion criteria
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 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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;Secondary Objective: - 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;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]);Timepoint(s) of evaluation of this end point: End of the study, until 3 years after last dose given to patient. | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 ;Timepoint(s) of evaluation of this end point: End of the study, until 3 years after last dose given to patient | — |
Countries
Belgium
Contacts
Public ContactProf. Bart Neyns
Universitair Ziekenhuis Brussel
Outcome results
None listed