PRIMARY OBJECTIVE:
I. To evaluate the rate of pathologic complete response (pCR) rate in patients in each arm of
the trial.
SECONDARY OBJECTIVES:
I. To evaluate the rate of pathologic near-complete/major response (pMR) of the neoadjuvant
therapy in each arm.
II. To evaluate the pathologic response rate of un-injected lesions on the combination arm.
III. To evaluate relapse-free survival (RFS) in each arm. IV. To evaluate overall survival
(OS) in each arm. V. To evaluate the preoperative radiographic response rate in each arm. VI.
To evaluate safety and toxicity of neoadjuvant therapy in each arm.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A:
NEOADJUVANT PHASE: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day
1. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression
or unacceptable toxicity.
SURGERY: Patients undergo surgery 1-2 weeks after completion of neoadjuvant phase.
ADJUVANT PHASE: After recovery from surgery, patients receive pembrolizumab IV over 30
minutes on day 1 of every other cycle. Treatment repeats every 21 days for up to 16 cycles in
the absence of disease progression or unacceptable toxicity.
ARM B:
NEOADJUVANT PHASE: Patients receive VLP-encapsulated TLR9 agonist CMP-001 (CMP-001)
subcutaneously (SC) on day 1 of cycle 1 and then intratumorally on days 8 and 15 of cycle 1,
days 1, 8, and 15 of cycle 2, and day 1 of cycle 3. Patients also receive pembrolizumab IV
over 30 minutes on day 8 of each cycle. Treatment repeats every 21 days for up to 3 cycles in
the absence of disease progression or unacceptable toxicity.
SURGERY: Patients undergo surgery 1-2 weeks after completion of neoadjuvant phase.
ADJUVANT PHASE: After recovery from surgery, patients receive pembrolizumab IV over 30
minutes on day 1 of every other cycle. Treatment repeats every 21 days for up to 16 cycles in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 3
months if < 2 years from study entry, every 6 months if 2-5 years from study entry, and every
12 months if > 5 years from study entry for up to 10 years (15 years total follow up).
Inclusion Criteria:
- Patient must be >= 18 years of age
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1
- Patient must have a histologic diagnosis of melanoma belonging to the following
American Joint Committee on Cancer (AJCC) 8th edition TNM stages:
- T0, Tx or T1-4; and
- N2b, N2c, N3b or N3c
- Patients may have a presentation with primary melanoma with concurrent regional nodal
and/or in-transit metastasis; or patients may have a history of primary melanoma or
unknown primary melanoma presenting with clinically detected regional nodal and/or
in-transit recurrence; and may belong to any of the following groups:
- Primary cutaneous melanoma with clinically apparent regional lymph node
metastases and/or in-transit metastases
- Clinically detected recurrent melanoma at the proximal regional lymph node(s)
basin
- Primary cutaneous melanoma with concurrent nodal disease involving a single
regional nodal group
- Clinically detected nodal melanoma (if single site) arising from an unknown
primary
- In-transit cutaneous metastases with or without regional lymph node involvement
permitted if considered potentially surgically resectable at baseline
- NOTE: Patients with mucosal and/or uveal melanoma are not eligible for the
study
- Patient must be a candidate for definitive surgery and have met with the treating
surgical oncologist prior to randomization
- Patient must have the presence of injectable and measurable disease based on Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1, documented by scans obtained within
4 weeks prior to randomization
- NOTE: Injectable disease is defined as an accessible lesion in the skin,
subcutaneous tissue or lymph nodes (LN) close to the skin and palpable by
physical examination or approachable with ultrasound guidance
- Absolute neutrophil count (ANC) >= 1,500 /mcL (obtained within 4 weeks prior to
randomization)
- Hemoglobin (Hgb) >= 9 g/dL or >= 5.6 mmol/L (obtained within 4 weeks prior to
randomization)
- Platelets >= 100,000 / mcL (obtained within 4 weeks prior to randomization)
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or measured or calculated
creatinine clearance > 60 mL/min (glomerular filtration rate [GFR] can also be used in
place of creatinine or creatinine clearance [CrCl] for patients with creatinine levels
> 1.5 x institutional ULN) (obtained within 4 weeks prior to randomization)
- Serum total bilirubin =< 1.5 x ULN; for total bilirubin levels > 1.5 x ULN, but =< 3 x
ULN, the direct bilirubin must be =< the ULN (obtained within 4 weeks prior to
randomization)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
ULN (obtained within 4 weeks prior to randomization)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
patient is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants (obtained
within 4 weeks prior to randomization)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless patient is receiving
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
of anticoagulants (obtained within 4 weeks prior to randomization)
- Patient must have the ability to understand and the willingness to sign a written
informed consent document. Patients with impaired decision-making capacity (IDMC) who
have a legally authorized representative (LAR) or caregiver and/or family member
available will also be considered eligible
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better
Exclusion Criteria:
- Patient must not have received any live vaccine within 30 days prior to randomization
and while participating in the study. Live vaccines include, but are not limited to,
the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus
Calmette-Guerin (BCG), and typhoid (oral) vaccine. Patients are permitted to receive
inactivated vaccines and any non-live vaccines including those for the seasonal
influenza and COVID-19 (Note: intranasal influenza vaccines, such as Flu-Mist are live
attenuated vaccines and are not allowed). If possible, it is recommended to separate
study drug administration from vaccine administration by about a week (primarily, in
order to minimize an overlap of adverse events)
- Patients must not be pregnant or breast-feeding due to the potential harm to an unborn
fetus and possible risk for adverse events in nursing infants with the treatment
regimens being used. All patients of childbearing potential must have a blood test or
urine study within 14 days prior to randomization to rule out pregnancy. A urine or
serum pregnancy test must be repeated within 72 hours prior to receiving the first
dose of pembrolizumab if the test done for eligibility/randomization is done outside
of this 72 hour window. If the urine test is positive or cannot be confirmed as
negative, a serum pregnancy test will be required. A patient of childbearing potential
is defined as anyone, regardless of sexual orientation or whether they have undergone
tubal ligation, who meets the following criteria: 1) has achieved menarche at some
point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not
been naturally postmenopausal (amenorrhea following cancer therapy does not rule out
childbearing potential) for at least 24 consecutive months (i.e., has had menses at
any time in the preceding 24 consecutive months)
- Patients must not expect to conceive or father children by using accepted and
effective method(s) of contraception or abstaining from sexual intercourse from time
of randomization, while on study treatment, and continue for 26 weeks after the last
dose of protocol treatment
- Patient must not have received prior systemic therapy for melanoma including systemic
therapy with an anti-PD-1, anti-PD-L1, anti-CTLA-4, BRAF/MEK inhibitor combination
and/or TLR-9 agonist
- Patient must not have a diagnosis of immunodeficiency or be receiving systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to
randomization, except as noted here
- Patients who are currently receiving steroids at a dose of prednisone =< 5 mg
daily (or equivalent) are permitted to enroll
- Patients who require topical, ophthalmologic and inhalational steroids are
permitted to enroll
- Patients with hypothyroidism who are stable on hormone replacement are permitted
to enroll
- Patients who require active immunosuppression with corticosteroids at a dose of
prednisone > 5 mg daily (or equivalent) for any reason are ineligible
- Patients with adrenal insufficiency are ineligible
- Patients who have developed autoimmune disorders of grade 4 while on prior
immunotherapy are not permitted to enroll on this study. Patients who developed
autoimmune disorders of grade =< 3 may enroll if the disorder has resolved to
grade =< 1 and the patient has been off systemic corticosteroids at doses > 5 mg
for at least 2 weeks prior to randomization
- Patients with a history of brain metastases are not eligible for this study as they do
not meet the eligibility staging criteria
- Patient must not have had an allogeneic tissue/solid organ transplant
- Patient must not have a history of (non-infectious) pneumonitis that required steroids
or current pneumonitis
- Patient must not have severe hypersensitivity (>= grade 3) to pembrolizumab and/or any
of its excipients
- Patient must not have an active infection requiring systemic therapy
- Patient must not have a known psychiatric or substance abuse disorder that would
interfere with the patient's ability to cooperate with the requirements of the study
