UAMS - Translational Research Institute

Conditions

• Clinical Stage III Cutaneous Melanoma AJCC v8
• Clinical Stage IV Cutaneous Melanoma AJCC v8
• Metastatic Cutaneous Melanoma
• Metastatic Mucosal Melanoma
• Metastatic Non-Cutaneous Melanoma
• Non-Cutaneous Melanoma
• Recurrent Cutaneous Melanoma
• Recurrent Mucosal Melanoma
• Recurrent Non-Cutaneous Melanoma

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- STEP 1 REGISTRATION:

- Patients must have completely resected melanoma of cutaneous origin or of unknown
primary in order to be eligible for this study; patients must be classified as stage
IIIA (N2a), IIIB, IIIC, or stage IV melanoma; patients with non-ulcerated T1b N1a
disease are not eligible; patients with melanoma of mucosal or other non-cutaneous
origin are eligible; patients with melanoma of ocular origin are not eligible;
patients with a history of brain metastases are ineligible

- Patients are eligible for this trial either at initial presentation of their
melanoma or at the time of the first detected nodal, satellite/in-transit, distant
metastases, or recurrent disease in prior lymphadenectomy basin or distant site;
nodal, satellite/in-transit metastasis, distant metastases or disease in a prior
complete lymphadenectomy basin must have been confirmed histologically by
hematoxylin and eosin (H & E) stained slides

- Patients with multiple regional nodal basin involvement are eligible; gross or
microscopic extracapsular nodal extension is permitted

- Patients at initial presentation of melanoma must undergo an adequate wide excision
of the primary lesion, if present; patients with previously diagnosed melanoma must
have had all current disease resected with pathologically negative margins and must
have no evidence of disease at the primary site or must undergo re-resection of the
primary site; a full lymphadenectomy meeting the criteria outlined is required for
all node-positive patients including those with positive sentinel nodes; patients
with recurrent disease who have had a prior complete lymphadenectomy fulfill this
requirement as long as all recurrent disease has been resected; for all patients,
all disease must have been resected with negative pathological margins and no
clinical, radiologic, or pathological evidence of any incompletely resected
melanoma; patients must be registered within 98 days of the last surgery performed
to render the patient free of disease

- Patients must have available and be willing to submit a minimum of five unstained
slides from primary, lymph node, or metastatic site to determine PD-L1 expression;
the tumor tissue must be adequate for PD-L1 testing (defined as >= 100 tumor cells
as confirmed by the treating institution's local pathologist); this must be
documented by having a pathologist sign the S1404 Local Pathology Review form prior
to step 1 registration; the specimens may come from an archived block but must be
submitted within 20 days from cutting the slides

- Patients must be offered the opportunity to participate in specimen banking as
outlined

- Patients must be willing to have blood draws for PK/ADA analysis as outlined, should
the patient be randomized to the MK-3475 arm

- Patients may have received prior radiation therapy, including after the surgical
resection; all adverse events associated with prior surgery and radiation therapy
must have resolved to =< grade 1 prior to registration

- Patients must not have received neoadjuvant treatment for their melanoma; patients
must not have had prior immunotherapy including, but not limited to ipilimumab,
interferon alfa-2b, high dose IL-2, pegylated (PEG)-IFN, anti-PD-1, anti-PD-L1
intra-tumoral, or vaccine therapies; patients must not be planning to receive any of
the prohibited therapies during the screening or treatment phases of the study

- Patients must not be planning to receive concomitant other biologic therapy,
radiation therapy, hormonal therapy, other chemotherapy, surgery or other therapy
after step 2 registration

- All patients must have disease-free status documented by a complete physical
examination and imaging studies within 42 days prior to registration; imaging
studies must include a total body positron emission tomography (PET)-computed
tomography (CT) scan that is of diagnostic quality (with or without brain) or a CT
of the chest, abdomen and pelvis; for patients with melanoma arising from the head
and neck, dedicated neck imaging (CT with IV contrast or PET-CT through the region)
is required; if the patient has had unknown primary with disease in the axilla, neck
imaging is required to assure region is clear of cancer; CT imaging should be done
with intravenous contrast if there are no contraindications for it; any other
clinically-indicated imaging studies if performed (e.g. bone scan) must show no
evidence of disease

- All patients must have a CT or magnetic resonance imaging (MRI) of the brain within
90 days prior to registration; the brain CT or MRI should be performed with
intravenous contrast (unless contraindicated)

- Absolute neutrophil count (ANC) >= 1,500 microliter (mcL) (within 42 days prior to
registration)

- Platelets >= 100,000 mcL (within 42 days prior to registration)

- Hemoglobin >= 10 g/dL (within 42 days prior to registration)

- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (except
Gilbert's syndrome, who must have a total bilirubin < 3.0 mg/dL) (within 42 days
prior to registration)

- Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST])
and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =<
2 x IULN (within 42 days prior to registration)

- Alkaline phosphatase =< 2 x IULN (within 42 days prior to registration)

- Serum creatinine =< IULN OR measured or calculated creatinine clearance >= 60 mL/min
(within 42 days prior to registration)

- Patients must have lactate dehydrogenase (LDH) performed within 42 days prior to
registration

- Patients must have Zubrod performance status =< 1

- Patients must have a baseline electrocardiogram (ECG) performed within 42 days of
registration that is normal or considered not clinically significant by the site
investigator

- Patients must not have a history of (non-infectious) pneumonitis that required
steroids or current pneumonitis

- Patients must not have an active infection requiring systemic therapy

- Patients must not have active autoimmune disease that has required systemic
treatment in past 2 years (i.e., with use of disease modifying agents,
corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine,
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment

- Patients must not have received live vaccines within 42 days prior to registration;
examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, chicken pox, shingles, yellow fever, rabies, bacillus
Calmette-Guerin (BCG), and typhoid (oral) vaccine; seasonal influenza vaccines for
injection are generally killed virus vaccines and are allowed; however, intranasal
influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not
allowed

- Patients known to be human immunodeficiency virus (HIV) positive are eligible if
they meet the following criteria within 30 days prior to registration: stable and
adequate cluster of differentiation 4 (CD4) counts (>= 350 mm^3), and serum HIV
viral load of < 25,000 IU/ml; patients may be on or off anti-viral therapy so long
as they meet the CD4 count criteria

- Patients must not have known active hepatitis B virus (HBV) or hepatitis C virus
(HCV) infection prior to registration

- Patients must not have a history or current evidence of any condition, therapy or
laboratory abnormality that might confound the trial results, interfere with the
patient's participation for the full duration of the trial, or indicate that
participation in the trial is not in the patient's best interests, in the opinion of
the treating investigator

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, lobular carcinoma
of the breast in situ, atypical melanocytic hyperplasia or melanoma in situ,
adequately treated stage I or II cancer (including multiple primary melanomas) from
which the patient is currently in complete remission, or any other cancer from which
the patient has been disease free for three years

- Women of childbearing potential must have a negative urine or serum pregnancy test
within 28 days prior to registration; women/men of reproductive potential must have
agreed to use an effective contraceptive method for the course of the study through
120 days after the last dose of study medication; should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy, or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures, he/she is responsible for beginning
contraceptive measures; patients must not be pregnant or nursing due to unknown
teratogenic side effects

- Patients who are able to complete questionnaires in English, Spanish or French must
participate in the quality of life assessments; (those patients who cannot complete
the quality of life questionnaires in English, Spanish or French can be registered
to S1404 without contributing to the quality of life studies)

- Patients must be informed of the investigational nature of this study and must sign
and give written informed consent for this protocol in accordance with institutional
and federal guidelines

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has
been entered in the system

- STEP 2 REGISTRATION (RANDOMIZATION CRITERIA):

- Patients must not be registered until receiving confirmation from the Southwest
Oncology Group (SWOG) Statistical Center that the patient's tissue specimen was
adequate for PD-L1 testing; patients must be registered within 7 working days of
receiving the e-mail notification

- Women of childbearing potential must plan to have a urine or serum pregnancy test
within 72 hours prior to receiving the first dose of study medication; if the urine
test is positive or cannot be confirmed as negative, a negative serum pregnancy test
will be required

- No tests or exams are required to be repeated for step 2 registration
(randomization); however, patients who are known to have a change in eligibility
status after step 1 registration are not eligible for step 2 registration; for
example, ANC is not required to be repeated between step 1 and step 2 registration,
but the most recent ANC performed before step 2 registration is required to be >=
1,500 mcL

Detailed Description

PRIMARY OBJECTIVES: I. To compare overall survival (OS) of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon recombinant interferon alfa-2b (alfa-2b) or ipilimumab versus MK-3475 (pembrolizumab). II. Among patients who are PD-L1 positive, to compare OS of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab versus MK-3475 (pembrolizumab). III. To compare relapse-free survival (RFS) of patients with resected stage III and IV melanoma treated with physician/patient choice of either high dose interferon alfa-2b or ipilimumab to MK-3475 (pembrolizumab). SECONDARY OBJECTIVES: I. To estimate OS and RFS for patients who are PD-L1 negative or PD-L1 indeterminate in this population. II. To compare OS and RFS of patients between the two arms within PD-L1 positive and negative subgroups and to look at the interaction between PD-L1 (positive versus negative) and treatment arm. III. To assess the safety and tolerability of the regimens. ADDITIONAL OBJECTIVES: I. To bank tissue and whole blood in anticipation of future correlative studies in this patient population. II. To evaluate PD-L1 expression through immunohistochemistry assay. III. To evaluate the effect of treatment-related side effects that may have an impact on the health-related domains of quality of life (QOL) using the Functional Assessment of Cancer Therapy (FACT)-Biological Response Modifiers (BRM), European Quality of Life Five Dimension Three Level Scale (EQ-5D-3L), and Functional Assessment of Chronic Illness Therapy Diarrhea (FACIT-D) between patients treated with physician/patient choice of either high-dose interferon alfa-2b or ipilimumab and MK-3475 (pembrolizumab). IV. Pharmacokinetic (PK) and anti-drug antibody (ADA) testing will be performed on all patients receiving MK-3475 (pembrolizumab). TRANSLATIONAL OBJECTIVES RELATED TO T-CELL RECEPTOR BETA CHAIN SEQUENCING: I. To evaluate the association between TCR beta variable gene (TRBV) haplotype and grade 3-4 immune-related adverse events (irAEs) among stage III melanoma patients treated with adjuvant ipilimumab or pembrolizumab. II. To describe the TRBV haplotype distribution among this cohort of patients studied. TRANSLATIONAL MEDICINAL OBJECTIVE RELATED TO ASSOCIATION OF CIRCULATING TUMOR DNA (ctDNA) WITH RELAPSE-FREE SURVIVAL IN HIGH-RISK, RESECTED MELANOMA PATIENTS. I. To evaluate associations between pretreatment ctDNA (present versus absent) and relapse within 2 years of randomization in a case-control analysis across treatment arms. II. To evaluate associations between pretreatment ctDNA (present versus absent) and relapse within 2 years of randomization in a case-control analysis across treatment arms. III. To evaluate associations between pretreatment ctDNA and relapse within 2 years of randomization in a case-control analysis within each treatment arm (after treatment arm data are unblinded to investigators). IV. To evaluate associations between "early-on treatment" ctDNA levels and relapse within 2 years of randomization. V. To describe ctDNA levels at end of therapy and time of relapse. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: INDUCTION THERAPY: Patients receive high-dose recombinant interferon alfa-2B intravenously (IV) over 20 minutes on days 1-5. Treatment repeats weekly for 4 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 3 weeks for a total of 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive high-dose recombinant interferon alfa-2B subcutaneously (SC) on days 1, 3, and 5. Treatment repeats every 6 weeks for up to 48 weeks in the absence of disease progression or unacceptable toxicity. Or patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 12 weeks for 3 years in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 3 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, positron emission tomography (PET) scan, magnetic resonance imaging (MRI) and blood sample collection throughout the study. After completion of study treatment, patients are followed up at 30 days, 6 and 12 weeks, every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.