The MetroHealth System

Conditions

• Acral Lentiginous Melanoma
• Clinical Stage III Cutaneous Melanoma AJCC v8
• Clinical Stage IV Cutaneous Melanoma AJCC v8
• Mucosal Melanoma

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must have clinically detectable stage
III (clinically detectable N1b, N1c, N2b, N2c, N3b and N3c) or stage IV resectable
melanoma. Patients with melanoma of mucosal or acral origin are eligible. Patients
with melanoma of uveal origin are not eligible. Patients with a history of brain
metastases are not eligible. Clinically detectable is defined as disease that is
apparent and measurable via physical examination or radiographic imaging.

- STEP 1 REGISTRATION (RANDOMIZATION): 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 (H) & eosin (E) stained slides.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients with multiple regional nodal basin
involvement are eligible. Gross or microscopic extracapsular nodal extension is
permitted.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must have histologically proven stage
IIIB or higher. This would entail pathologic confirmation beyond the primary or
initial diagnosis of melanoma involving fine needle aspiration cytology or biopsy
confirmation of any N-category or M-category resectable site.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have received previous
neoadjuvant treatment for their melanoma. Patients may have received prior
non-immunotherapy adjuvant therapy. Patients must not have had prior immunotherapy
including, but not limited to ipilimumab, interferon alfa-2b, high dose interleukin
(IL)-2, pegylated-interferon (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 treatment phases on the study.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must not be planning to receive
concomitant other biologic therapy, hormonal therapy, other chemotherapy, surgery,
while on protocol therapy.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients may have received prior radiation
therapy, including after prior surgical resection. All adverse events associated
with prior surgery and radiation therapy must have resolved to =< grade 1 prior to
randomization.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must be >= 18 years of age

- STEP 1 REGISTRATION (RANDOMIZATION): All patients must have disease status
documented by a complete physical examination and imaging studies within 42 days
prior to randomization. Imaging studies must include a CT of the chest, abdomen and
pelvis with intravenous contrast (unless contraindicated). For patients with
melanoma arising from the head and neck, dedicated neck imaging (CT with intravenous
contrast is required. If the patient has unknown primary with disease in the axilla,
neck imaging is required CT imaging must be done with intravenous contrast if there
are no contraindications for it. Extremity melanomas must be imaged using CT with
intravenous contrast or MRI with and without gadolinium

- Note: PET-CT scans are NOT acceptable to establish eligibility. Non-iodinated
CT scans that are part of common PET-CT imaging protocols do not provide
contrast for difficult to ascertain areas such as the neck and liver, and do
not provide enough CT detail to perform appropriate RECIST 1.1 measurements. As
such, a PET-CT with non-contrast CT or non-diagnostic quality CT images is
considered insufficient for the detection of melanoma.

- STEP 1 REGISTRATION (RANDOMIZATION): All patients must have a CT or magnetic
resonance imaging (MRI) of the brain within 42 days prior to randomization. The
brain CT or MRI should be performed with intravenous contrast (unless
contraindicated).

- STEP 1 REGISTRATION (RANDOMIZATION): Absolute neutrophil count (ANC) >=
1,500/microliter (mcL) (within 42 days prior to randomization).

- STEP 1 REGISTRATION (RANDOMIZATION): Platelets >= 100,000/mcL (within 42 days prior
to randomization).

- STEP 1 REGISTRATION (RANDOMIZATION): Hemoglobin >= 10 g/dL (within 42 days prior to
randomization).

- STEP 1 REGISTRATION (RANDOMIZATION): Total bilirubin =< 1.5 x institutional upper
limit of normal (IULN) (except patients with Gilbert's syndrome, who must have a
total bilirubin < 3.0 mg/dL) (within 42 days prior to randomization).

- STEP 1 REGISTRATION (RANDOMIZATION): 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
randomization).

- STEP 1 REGISTRATION (RANDOMIZATION): Alkaline phosphatase =< 2 x IULN (within 42
days prior to randomization).

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must have lactate dehydrogenase (LDH)
performed within 42 days prior to randomization.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must have adequate renal function as
evidenced by calculated creatinine clearance > 30 mL/min. The creatinine level
(mg/dL) used in the calculation must be obtained within 42 days prior to
randomization.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must have Zubrod performance status =<
2.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have a history of
(non-infectious) pneumonitis that required steroids or current pneumonitis.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have an active infection
requiring systemic therapy.

- STEP 1 REGISTRATION (RANDOMIZATION): 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.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have received live vaccines
within 42 days prior to randomization. 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.

- NOTE: The COVID-19 vaccines (currently available and those in the pipeline for
FDA emergency use authorization or FDA approval) do not contain live virus, and
therefore, COVID-19 vaccination does not affect or preclude eligibility for the
S1801 trial. For patients who have undergone lymphadenectomy, vaccines should
be delivered to a limb with an intact lymph node basin (Sentinel lymph node
biopsy in a limb is acceptable). The vaccine should not be administered in a
limb that has undergone lymphadenectomy.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients known to be human immunodeficiency
virus (HIV) positive are eligible if they meet the following criteria within 30 days
prior to randomization: stable and adequate 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.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must not have known active hepatitis B
virus (HBV) or hepatitis C virus (HCV) infection prior to randomization. Note: No
testing for hepatitis B and hepatitis C is required unless mandated by local health
authority.

- STEP 1 REGISTRATION (RANDOMIZATION): Prior malignancy is allowed providing it does
not require concurrent therapy.

- STEP 1 REGISTRATION (RANDOMIZATION): Women of childbearing potential must have a
negative urine or serum pregnancy test within 28 days prior to randomization.
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 side effects.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must be deemed medically fit to
undergo surgery by the treating medical/surgical team.

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must be willing to submit the
following surgical specimens: either all tissue blocks from the surgical specimen or
two slides per block ([1] hematoxylin and eosin [H&E] slide and [1] unstained slide
OR [2] unstained slides if H&E stained slides cannot be provided).

- STEP 1 REGISTRATION (RANDOMIZATION): Patients must be offered the opportunity to
participate in specimen banking.

- STEP 1 REGISTRATION (RANDOMIZATION): 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 1 REGISTRATION (RANDOMIZATION): As a part of the Oncology Patient Enrollment
Network (OPEN) randomization 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 (SURGERY): Patients randomized to arm 2 (neoadjuvant arm) must
be willing to submit tissue to determine pathologic response regardless of number of
pre-operative doses of pembrolizumab (MK-3475) received. Determination of pathologic
response cannot be done on less than the full surgical specimen.

- STEP 2 REGISTRATION (SURGERY): Patients must have disease assessments by CT
chest/abdomen/pelvis with IV contrast, and neck CT with IV contrast if primary head
and neck melanoma, performed within 42 days (and no more than 49 days) before the
planned date of surgery. MRI combined with non-contrast CT is an acceptable
alternative for patients with CT contrast allergy, but imaging must encompass total
body.

- STEP 2 REGISTRATION (SURGERY): Patients must register to step 2 within 17 days prior
to planned date of surgery.

- STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients must have undergone surgery prior
to Step 3 registration. The Step 2 surgery must have completely resected their
melanoma.

- Patients with gross positive residual disease following surgery do not qualify
as having disease-free status, and, therefore, such patients are not eligible
to register for adjuvant therapy.

- Patients with microscopic residual disease (i.e., positive margins) can be
treated with re-excision or radiation, per site discretion, to render the
patient disease-free prior to registration of adjuvant therapy.

- Disease-free status must be documented by a complete physical examination and
radiographic imaging studies within 42 days prior to Step 3 registration.
Imaging studies must include a CT of the chest, abdomen, and pelvis (unless
contraindicated). Extremity melanomas must be imaged using CT with intravenous
contrast or MRI with and without gadolinium. CT imaging must be done with
intravenous contrast if there are no contraindications for it.

- For patients with melanoma arising from the head and neck, dedicated neck
imaging (CT with IV contrast, unless contraindicated) is required.

- If the patient has had unknown primary with disease in the axilla, neck imaging
is required to assure the region is clear of cancer.

- Any other clinically indicated imaging studies if performed (e.g., bone scan)
must show no evidence of disease.

- STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients must be registered to step 3 no
more than 84 days after date of surgery.

- STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients with R0 or R1 resections must have
disease-free status documented by a complete physical examination and imaging
studies within 42 days prior to step 3 registration. These patients must have
disease assessments by CT chest/abdomen/pelvis with IV contrast, and neck CT with IV
contrast if primary head and neck melanoma. MRI combined with non-contrast CT is an
acceptable alternative for patients with CT contrast allergy, but imaging must
encompass total body.

- STEP 3 REGISTRATION (ADJUVANT THERAPY): Patients with R2 resections are not eligible
for step 3 and must be removed from study treatment

Study Contact

Detailed Description

PRIMARY OBJECTIVE: I. To compare event-free survival (EFS) in participants with high-risk resectable melanoma randomized to neoadjuvant pembrolizumab (MK-3475) with participants randomized to adjuvant pembrolizumab (MK-3475). SECONDARY OBJECTIVES: I. To assess the frequency and severity of toxicities on each of the arms. II. To compare between arms overall survival (OS), disease control at 24 weeks, locoregional control in the surgical site(s), and total number of pembrolizumab (MK-3475) doses received. III. On the neoadjuvant arm, to estimate the pathologic response rate, the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate (confirmed and unconfirmed complete response [CR] and partial response [PR]), and the immune-related (i)RECIST response rate (confirmed and unconfirmed CR and PR), before surgical resection; to compare definitions of pathologic partial response; and to evaluate the association between pathologic response and EFS and OS. IV. To describe the proportion of participants on each arm who received the surgery planned at randomization. ADDITIONAL OBJECTIVE: I. To bank tumor tissue and whole blood in anticipation of future correlative studies in this participant population. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Within 17 days (preferably within 14 days) days after surgical resection, patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 3 weeks for 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study, and magnetic resonance imaging (MRI) or computers tomography (CT) on study. ARM II: Patients receive pembrolizumab IV over 30 minutes on day 1 every 3 weeks for 3 cycles, then undergo surgical resection within 3 weeks. Within 84 days, patients receive pembrolizumab IV over 30 minutes every 3 weeks for 15 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood throughout the study and MRI or CT on study. After completion of study treatment, patients are followed up at 3 and 12 weeks, then every 3 months for 2 years, every 6 months for 3 years, then every 12 months for up to 10 years.