A Phase III Randomized Trial Comparing Physician/Patient Choice of Either High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in Patients with High Risk Resected Melanoma
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 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 H & E stained
- 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 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
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.
- Patients must be willing to have blood draws for PK/ADA analysis, 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, PEG-IFN, anti-PD-1, anti-PD-L1
intra-tumoral or vaccine therapies.
- 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.
- Patients must be ≥ 18 years of age.
- 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 PET-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 MRI of the brain within 90 days prior to
registration. The brain CT or MRI should be performed with intravenous contrast
- Patients must have adequate bone marrow function as evidenced by all of the
following: ANC ≥ 1,500 microliter (mcL); platelets ≥ 100,000/mcL; Hemoglobin ≥
10 g/dL. These results must be obtained within 42 days prior to registration.
- Patients must have adequate hepatic function as evidenced by the following: 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), and SGOT (AST) and
SGPT (ALT) and alkaline phosphatase ≤ 2 x IULN. These results must be obtained
within 42 days prior to registration.
- Patients must have adequate renal function as evidenced by ONE of the following:
serum creatinine ≤ IULN OR measured or calculated creatinine clearance ≥ 60
mL/min. This result must have been obtained within 42 days prior to registration.
- Patients must have LDH performed within 42 days prior to registration.
- Patients must have Zubrod Performance Status ≤ 1.
- Patients must have a baseline 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, 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 HIV positive are eligible if they meet the following criteria
within 30 days prior to registration: stable and adequate CD4 counts (≥ 350 mm3),
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
- 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
outlined in the protocol, he/she is responsible for beginning contraceptive
measures. Patients must not be pregnant or nursing due to unknown teratogenic
- 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.
Step 2 Registration
- Patients must not be registered until receiving confirmation from the 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
- 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.
- Physician/patient choice of either High-dose Interferon: IV for 5 days out of 7 days every week for 4 week then subcutaneous every other day 3 times each week for 48 weeks or
- Ipilimumab: IV every 3 weeks for 4 doses then IV every 12 weeks for a total of 3 years
- MK-3475 (Pembrolizumab) IV every 3 weeks for 18 doses
** MK-3475 (Pembrolizumab) will be provided free of charge for this study.