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
