A Clinical Trial of Regorafenib in Patients With Pretreated Advanced Melanoma

Inclusion Criteria:

1. ≥ 18 years of age.
2. Signed written informed consent.
3. Histologically confirmed advanced melanoma that is either stage III (unresectable) orstage IV (metastatic, unresectable)
4. Subjects must have failed prior systemic treatment with immune checkpoint inhibitors,including CTLA-4 blocking immune checkpoint inhibitors (ipilimumab or otherexperimental anti-CTLA-4 antibodies), and PD-1 blocking immune checkpoint inhibitors (pembrolizumab, nivolumab or other experimental anti-PD-1 antibodies). Progression ofdisease per RECIST, version 1.1 (Eisenhauer et al. Eur J Cancer 2009) or per immunerelated response criteria (Wolchok et al, Clin Cancer Res 2009) must have beendocumented during this prior treatment. Patients with BRAFV600mutant melanoma musthave failed treatment with a BRAF-(+/-MEK) inhibitor. Patients who are not able toundergo such treatment will be considered eligible if all other eligibility criteriaare fulfilled.
5. The presence of at least one measurable lesion per RECIST, version 1.1 (Eisenhauer etal. Eur J Cancer 2009)
6. Interval between the date of the last administration of prior therapy for melanoma andthe date of recruitment:
7. ≥ 12 weeks following the date of the first administration and ≥ 3 weeks followingthe date of the last administration of an anti-CTLA-4-, PD-1- or PD-L1 blockingimmune checkpoint inhibitor;
8. ≥ 4 weeks following the date of the last administration of chemotherapy (≥ 6weeks in case of a nitrosurea or mitomycin C containing regimen);
9. Cohort-C: ≥ 12 weeks following the date of the last administration ofBRAF-/MEK-inhibitors.
10. All prior anti-cancer treatment-related toxicities (except alopecia and laboratoryvalues as listed on Table 1) and non-medical treatments (e.g. surgery and radiationtherapy) must be ≤ Grade 1 severity according to the Common Terminology Criteria forAdverse Events version 5 (CTCAE version 5.0; National Cancer Institute (NCI) 2017) atthe time of enrollment.
11. The patient must be able to swallow and retain oral medication and must not have anyclinically significant gastrointestinal abnormalities that may alter absorption suchas malabsorption syndrome or major resection of the stomach or bowels.
12. Women of childbearing potential must have a negative serum pregnancy test within 14days prior to recruitment and agree to use effective contraception throughout thetreatment period, and for 16 weeks after the last dose of study treatment.
13. Men with a female partner of childbearing potential must have either had a priorvasectomy or agree to use effective contraception from 14 days prior to administrationof the first dose of study treatment, throughout the treatment period, and for 16weeks after the last dose of study treatment.
14. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Oken etal, Am J Clin Oncol 1982).
15. Adequate baseline organ function as defined in Table 1.
16. Negative proteinuria on dipstick or 24 hours proteinuria <1000mg.
17. Cohort-B and -C: the melanoma must carry a documented BRAFV600 mutation.
18. Cohort-B: patients should be on treatment with BRAF-/MEK-inhibitors or haveinterrupted for less than 4 weeks before initiation of the study treatment.
19. Cohort-C: patients should be off BRAF-/MEK-inhibitors for at least 12 weeks beforeinitiation of the study treatment.

Exclusion Criteria:

• 14. Subjects with uveal melanoma. 15. Subjects with clinically active brain metastases (lesions should be stable and have been definitely treated with stereotactic radiationtherapy, surgery or gamma knife therapy with no evidence of disease progression priorto enrollment).

16. Any contra-indication for evaluation by whole body 18F-FDG-PET/CT or MRI of thebrain.
17. History of another malignancy. Exception: subjects who have been disease-free for 3 years, (i.e. subjects with second malignancies that are indolent or definitivelytreated at least 3 years ago) or subjects with a history of completely resectednon-melanoma skin cancer.
18. Current use of any prohibited medication. 19. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to recruitment.
19. Any serious or unstable pre-existing medical conditions (aside from malignancyexceptions specified above), psychiatric disorders, or other conditions that couldinterfere with the subject's safety, obtaining informed consent, or compliance withstudy procedures.
20. Known Human Immunodeficiency Virus (HIV), hepatitis B virus (HBV), or hepatitis Cvirus (HCV) infection. Exception: subjects with laboratory evidence of cleared HBV andHCV infection will be permitted.
21. Ongoing infection CTCAE v5.0 Grade > 2 requiring systemic therapy. 23. No enzymeinducing anticonvulsants for ≥ 4 weeks prior to recruitment 24. A history or evidenceof cardiovascular risk including any of the following:
22. Current LVEF < LLN
23. A QT interval corrected for heart rate using the Bazett's formula (QTcB) ≥ 480msec;
24. A history or evidence of current clinically significant uncontrolled arrhythmias.Exception: subjects with atrial fibrillation controlled for > 30 days prior torecruitment are eligible.
25. A history (within 6 months prior to recruitment) of acute coronary syndromes (including myocardial infarction or unstable angina), or coronary angioplasty;
26. History of deep venous or arterial thrombosis, or CVA the last 6 months
27. A history or evidence of current ≥ Class II congestive heart failure as definedby the New York Heart Association (NYHA) guidelines;
28. Treatment refractory hypertension defined as a blood pressure of systolic >140mmHg and/or diastolic > 90 mm Hg which cannot be controlled by antihypertensivetherapy;
29. Patients with intra-cardiac defibrillators or permanent pacemakers;
30. Abnormal cardiac valve morphology (≥ grade 2; moderate valvular thickening)documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mildregurgitation/stenosis] can be entered on study).
31. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugschemically related to the study treatments, their excipients, and/or dimethylsulfoxide (DMSO).
32. Female patients who are nursing. Prior/Concomitant therapy 27. Priortreatment with regorafenib. 28. Cohort-B: 28.1. Patients treated withvemurafenib/cobimetinib 28.2. Patients who are unable to initiate regorafenibwithin 4 weeks after interruption BRAF- /MEK-inhibitor therapy 29. Cohort-C: 29.1. Patients who have not interruptedBRAF-/MEK-inhibitor therapy for at least 12 weeks prior to initiation of studytreatment. 30. Patients who received prior radiotherapy within 2 weeks of startof study treatment or have had a history of radiation pneumonitis. Participantsmust have recovered from all radiation-related toxicities. A 1-week washout ispermitted for palliative radiation (duration of ≤2 weeks of radiotherapy) 31.Patients who have received a live vaccine or live attenuated replicationcompetent vaccine within 32 days prior to the first dose of study treatment.Administration of non-live vaccines are allowed.
33. Prior transplantation of human cells, tissues and organs (e.g. livertransplant) or candidates for any type of transplantation. 34. Patients onconcomitant use of CYP3A4 inducers, strong CYP3A4 inhibitors and strong UGT1A9inhibitors (e.g. mefenamic acid, diflunisal, and niflumic acid) within 2 weeksprior to start of study treatment. Prior/Concurrent Clinical Study Experience 35.Previous administration of an investigational drug within 28 days, or 5half-lives (minimum 14 days) before the start of study treatment, whichever isshorter) or concomitant participation in another clinical study withinvestigational medicinal product(s). Other Exclusions 36. History or currentevidence of any condition, therapy, or laboratory abnormality that might confoundthe results of the trial, interfere with the patient's participation for the fullduration of the trial, or is not in the best interest of the patient toparticipate, in the opinion of the treating investigator. 37. Any serious orunstable pre-existing medical conditions (aside from malignancy exceptionsspecified above), psychiatric disorders, or other conditions that could interferewith the subject's safety, obtaining informed consent, or compliance with studyprocedures. 38. Known psychiatric or substance abuse disorders that wouldinterfere with cooperation with the requirements of the trial. 39. Current use ofany prohibited medication. 40. Any contra-indication for evaluation by whole body 18F-FDG-PET/CT and/or MRI of the brain