PRIMARY OBJECTIVE:
I. To compare event-free survival (EFS) in participant with high-risk resectable melanoma
randomized to neoadjuvant MK-3475 (pembrolizumab) with participants randomized to adjuvant
MK-3475 (pembrolizumab).
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 MK-3475 (pembrolizumab) 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.
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.
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 a total of 10
years.
Inclusion Criteria:
- STEP 1 REGISTRATION (RANDOMIZATION)
- Patients must have resectable melanoma in order to be eligible for this study.
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.
- 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.
- Patients with multiple regional nodal basin involvement are eligible. Gross or
microscopic extracapsular nodal extension is permitted.
- 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.
- 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.
- 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.
- 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).
- Absolute neutrophil count (ANC) >= 1,500/microliter (mcL) (within 42 days prior to
randomization).
- Platelets >= 100,000/mcL (within 42 days prior to randomization).
- Hemoglobin >= 10 g/dL (within 42 days prior to 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).
- 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).
- Alkaline phosphatase =< 2 x IULN (within 42 days prior to randomization).
- Patients must have lactate dehydrogenase (LDH) performed within 42 days prior to
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.
- Patients must have Zubrod performance status =< 2.
- 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.
- Prior malignancy is allowed providing it does not require concurrent therapy.
- 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.
- Patients must be deemed medically fit to undergo surgery by the treating
medical/surgical team.
- 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).
- Patients must be offered the opportunity to participate in specimen banking.
- 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) 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 MK-3475
(pembrolizumab) received. Determination of pathologic response cannot be done on less
than the full surgical specimen.
- Patients must have disease assessments by PET-CT with iodinated CT contrast (i.e.
diagnostic quality CT) or 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.
- 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 at the time of 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 total body PET-CT that is of diagnostic quality (i.e.,
iodinated contrast), 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 with 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 the 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.
- Patients must be registered to step 3 no more than 84 days after date of surgery.
- 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.
- Patients with R2 resections are not eligible for step 3 and must be removed from study
treatment
Exclusion Criteria:
- 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.
- Patients must not be planning to receive concomitant other biologic therapy, hormonal
therapy, other chemotherapy, surgery, while on protocol therapy.
- 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 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.
- 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.
