Inclusion Criteria:
1. ≥ 18 years of age.
2. Signed written informed consent.
3. Histologically confirmed advanced melanoma that is either stage III (unresectable) or
stage IV (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 PD-1 blocking immune checkpoint inhibitors
(pembrolizumab, nivolumab or other experimental anti-PD-1 antibodies). Progression of
disease per RECIST, version 1.1 (Eisenhauer et al. Eur J Cancer 2009) or per immune
related response criteria (Wolchok et al, Clin Cancer Res 2009) must have been
documented during this prior treatment. 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.
5. The presence of at least one measurable lesion per RECIST, version 1.1 (Eisenhauer et
al. Eur J Cancer 2009)
6. Interval between the date of the last administration of prior therapy for melanoma and
the date of recruitment:
1. ≥ 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;
2. ≥ 4 weeks following the date of the last administration of chemotherapy (≥ 6
weeks in case of a nitrosurea or mitomycin C containing regimen);
3. Cohort-C: ≥ 12 weeks following the date of the last administration of
BRAF-/MEK-inhibitors.
7. 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.
8. The patient must 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.
9. Women of childbearing potential must have a negative serum pregnancy test within 14
days prior to recruitment and agree to use effective contraception throughout the
treatment period, and for 16 weeks after the last dose of study treatment.
10. 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.
11. An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Oken et
al, Am J Clin Oncol 1982).
12. Adequate baseline organ function as defined in Table 1.
13. Negative proteinuria on dipstick or 24 hours proteinuria <1000mg.
14. Cohort-B and -C: the melanoma must carry a documented BRAFV600 mutation.
15. 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.
16. Cohort-C: patients should be off BRAF-/MEK-inhibitors for at least 12 weeks before
initiation of the study treatment.
Exclusion Criteria:
Subjects with uveal melanoma. 15. Subjects with clinically active brain metastases
(lesions should be stable and have been definitely treated with stereotactic radiation
therapy, surgery or gamma knife therapy with no evidence of disease progression prior
to enrollment).
16. Any contra-indication for evaluation by whole body 18F-FDG-PET/CT or MRI of the
brain.
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 definitively
treated at least 3 years ago) or subjects with a history of completely resected
non-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.
20. 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.
21. 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.
22. Ongoing infection CTCAE v5.0 Grade > 2 requiring systemic therapy. 23. No enzyme
inducing anticonvulsants for ≥ 4 weeks prior to recruitment 24. A history or evidence
of cardiovascular risk including any of the following:
1. Current LVEF < LLN. 2. A QT interval corrected for heart rate using the Bazett's formula (QTcB) ≥ 480
msec;
3. A history or evidence of current clinically significant uncontrolled arrhythmias.
Exception: subjects with atrial fibrillation controlled for > 30 days prior to
recruitment are eligible.
4. A history (within 6 months prior to recruitment) of acute coronary syndromes
(including myocardial infarction or unstable angina), or coronary angioplasty;
5. History of deep venous or arterial thrombosis, or CVA the last 6 months. 6. A history or evidence of current ≥ Class II congestive heart failure as defined
by the New York Heart Association (NYHA) guidelines;
7. 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;
8. Patients with intra-cardiac defibrillators or permanent pacemakers;
9. 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).
25. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to the study treatments, their excipients, and/or dimethyl
sulfoxide (DMSO).
26. Female patients who are nursing. Prior/Concomitant therapy 27. Prior
treatment with regorafenib. 28. Cohort-B: 28.1. Patients treated with
vemurafenib/cobimetinib 28.2. Patients who are unable to initiate regorafenib
within 4 weeks after interruption BRAF-
/MEK-inhibitor therapy 29. Cohort-C: 29.1. Patients who have not interrupted
BRAF-/MEK-inhibitor therapy for at least 12 weeks prior to initiation of study
treatment. 30. Patients who received prior radiotherapy within 2 weeks of start
of study treatment or have had a history of radiation pneumonitis. Participants
must have recovered from all radiation-related toxicities. A 1-week washout is
permitted for palliative radiation (duration of ≤2 weeks of radiotherapy) 31.
Patients who have received a live vaccine or live attenuated replication
competent 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. liver
transplant) or candidates for any type of transplantation. 34. Patients on
concomitant use of CYP3A4 inducers, strong CYP3A4 inhibitors and strong UGT1A9
inhibitors (e.g. mefenamic acid, diflunisal, and niflumic acid) within 2 weeks
prior to start of study treatment. Prior/Concurrent Clinical Study Experience 35.
Previous administration of an investigational drug within 28 days, or 5
half-lives (minimum 14 days) before the start of study treatment, whichever is
shorter) or concomitant participation in another clinical study with
investigational medicinal product(s). Other Exclusions 36. History or current
evidence of any condition, therapy, or laboratory abnormality that might confound
the results of the trial, interfere with the patient's participation for the full
duration of the trial, or is not in the best interest of the patient to
participate, in the opinion of the treating investigator. 37. 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. 38. Known psychiatric or substance abuse disorders that would
interfere with cooperation with the requirements of the trial. 39. Current use of
any prohibited medication. 40. Any contra-indication for evaluation by whole body
18F-FDG-PET/CT and/or MRI of the brain
