| Eligibility |
Inclusion Criteria:
- Patients must have signed and dated an Institutional Review Board (IRB)/Independent
Ethics Committee (IEC)-approved written ICF in accordance with regulatory and
institutional guidelines. This must be obtained before the performance of any
protocol-related procedures that are not part of normal patient care.
- Patients must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests, tumor biopsies, and other requirements of the study.
- All patients must be either Stage IIIb/c/d or Stage IV melanoma according to the
American Joint Committee on Cancer (AJCC) (8th edition) and have
histologically-confirmed melanoma that is felt to be surgically unresectable in order
to be eligible. Please refer to the AJCC 8th edition Cancer Staging Manual for a
description of tumor, lymph node, metastasis, and staging.
- All melanomas, except ocular/uveal melanoma, regardless of primary site of disease
will be allowed; mucosal melanomas are eligible.
- Patients must not have received prior anticancer treatment for metastatic disease (for
example, but not limited to, systemic, local, radiation, radiopharmaceutical).
- Exceptions: Surgery for melanoma and/or post-resection brain radiotherapy (RT) if CNS
metastases and adjuvant RT for locoregional disease after resection and/or prior
treatment with adjuvant IFN-alpha, ipilimumab or nivolumab (as described in Exclusion
Criterion 2).
- All patients must have their disease status documented by a complete physical
examination and imaging studies within 4 weeks prior to the first dose of study drug.
Imaging studies must include computerized tomography (CT) scan of chest, abdomen,
pelvis, and all known sites of resected disease in the setting of Stage IIIb/c/d or
Stage IV disease, and brain magnetic resonance imaging ([MRI]; brain CT is allowable
if MRI is contraindicated).
- The complete set of baseline radiographic images must be available before treatment
initiation.
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
- Tumor tissue from the resected site of disease must be provided for biomarker analyses
- Prior treated CNS metastases must be without MRI evidence of recurrence for at least 4
weeks after treatment. Patients must be off immunosuppressive doses of systemic
steroids (10 mg/day prednisone or equivalent) for at least 14 days prior to study drug
administration, and must have returned to neurologic baseline status postoperatively.
- The 4-week period of stability is measured after the completion of the neurologic
interventions (i.e., surgery and/or radiation).
- In addition to neurosurgery to treat CNS metastases, adjuvant radiation after the
resection of CNS metastasis is allowed. Immunosuppressive doses of systemic steroids
(doses > 10 mg/day prednisone or equivalent) must be discontinued at least 14 days
before study drug administration.
- Prior surgery that required general anesthesia must be completed at least 4 weeks
before study drug administration. Surgery requiring local/epidural anesthesia must be
completed at least 72 hours before study drug administration.
- Normal labs
- Patient Re-enrollment: This study permits the re-enrollment of a patient that has
discontinued the study as a screen failure (i.e., patient has not been dosed/has not
been treated). If re-enrolled, the patient must be re-consented and satisfy all
eligibility criteria.
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[hCG] hormone) within 24 hours prior to the start of study drug.
- Women of childbearing potential must agree to follow instructions for method(s) of
contraception for the duration of treatment with study drug(s) plus 5 half-lives of
study drug plus 30 days (duration of ovulatory cycle). The half-life of nivolumab and
ipilimumab is up to 25 days and 18 days, respectively. WOCBP should therefore use an
adequate method to avoid pregnancy for a total of 23 weeks post treatment completion
(Section 4.5).
- Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of treatment with study drug(s) plus 5
half lives of the study drug (s) plus 90 days (duration of sperm turnover). The half
lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. Men
should therefore use an adequate method of contraception for a total of 31 weeks post
treatment completion (Section 4.5).
- Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
from contraceptive requirements. However, they must still undergo pregnancy testing as
described in this section.
Exclusion Criteria:
- Patients with carcinomatosis meningitis or a history of current ocular/uveal melanoma
are excluded.
- Patients with previous nonmelanoma malignancies are excluded unless a complete
resection or remission was achieved at least 2 years prior to study entry and no
additional therapy is required or anticipated to be required during the study period
(exceptions include, but are not limited to, nonmelanoma skin cancers, in situ bladder
cancer, in situ gastric cancer or gastrointestinal stromal tumor, in situ colon
cancers, in situ cervical cancers/dysplasia, or breast carcinoma in situ).
- Patients with active, known, or suspected autoimmune disease. Patients with type I
diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only
requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or
alopecia) not requiring systemic treatment are permitted to enroll. For any cases of
uncertainty, it is recommended that the Principal Investigator be consulted prior to
signing informed consent.
- Patients with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids are permitted in the
absence of active autoimmune disease.
- Prior therapy for melanoma with the following exceptions which are allowed: 1) surgery
for the melanoma lesion(s), 2) adjuvant RT after neurosurgical resection for CNS
lesions or for resected locoregional disease, and 3) prior adjuvant IFN-alpha,
ipilimumab and nivolumab (see qualifier below).
- Prior treatment with adjuvant IFN-alpha, adjuvant ipilimumab and/or nivolumab are
allowed if completed 6 months prior to treatment.
- Treatment directed against the melanoma (eg, chemotherapy, targeted agents,
biotherapy, limb perfusion) that is administered after a prior complete resection
other than adjuvant radiation after neurosurgical resection or resection of
locoregional disease and IFN-alpha, ipilimumab and nivolumab for resected melanoma.
- abnormalities labs
- Corrected QT interval using Fridericia's formula value > 480 msec at screening; family
or personal history of long QTc syndrome or ventricular arrhythmias including
ventricular bigeminy at screening; previous history of drug induced QTc prolongation
or the need for treatment with medications known or suspected of producing prolonged
QTc intervals on electrocardiogram (ECG).
- Congestive heart failure (New York Heart Association Class III or IV), myocardial
infarction
- Any serious or uncontrolled medical disorder or active infection
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