This is a phase II pilot study comparing MPR rate between two neoadjuvant. This study is
designed to evaluate a neoadjuvant regimen [nivolumab in combination with Toll-like receptor
9 (TLR9) agonist CMP-001] of 20 patients as compared against nivolumab monotherapy. This
study includes an integrated [18F]F-AraG imaging biomarker that aims assess the imaging
biomarker in patients receiving either neoadjuvant CMP-001/nivolumab or neoadjuvant
nivolumab.
Patients with stage IIIB-IIID cutaneous (or unknown primary) melanoma with palpable nodal
disease and/or in-transit disease who have yet to undergo definitive surgery are eligible to
enroll. Patients with nodal and/or in-transit relapse including those who have received prior
adjuvant IFN and/or ipilimumab are eligible to enroll.
Suitable patients will be identified pre-operatively. Patients will undergo a 28 day
screening evaluation including surgical assessment, clinical assessment, systemic/CNS staging
scans, and laboratory studies to confirm suitability. Biopsies will occur pre-treatment, W4-5
and the injected lesion(s) will be resected at the time of surgery.
Eligible patients will be randomized 1:1 to receive Arm A (neoadjuvant Nivolumab/CMP) vs. Arm
B (neoadjuvant Nivolumab) during the (Prime Phase) pre-operatively for 6-7 weeks. Patients
randomized to Arm A will receive: Nivolumab 240mg IV q2 x3 and CMP-001 5mg SC 1st dose then
10mg IT 2nd-7th doses (7 weeks). Patients randomized to Arm B will receive: Nivolumab 240mg
IV q2 x3 (6 weeks). In the Prime Phase, CMP-001 will be administered weekly via sub-cutaneous
injection (5mg SC; week 1) then intra-tumorally (10mg IT; weeks 2-7).
[18F]F-AraG PET-CT scan (18-F PET) is an integrated biomarker and will be performed at 2
imaging time-points: pre-treatment (pre-W1) and on-treatment (W4). At each imaging timepoint,
[18F]F-AraG will be administered by a licensed nuclear medicine technologist under the
supervision of a nuclear medicine physician on an outpatient basis. Each patient will receive
a single bolus injection of 5 mCi [18F]F-AraG IV into a hand or arm vein. At pre-W1/W4
imaging timepoints, following [18F]F-AraG injection, a 30-min static PET-CT scan will be
performed covering the brain to the upper legs.
Following the Prime Phase and restaging systemic scans, patients will undergo surgical
resection.
Post-operatively, patients will continue to receive maintenance therapy (Boost Phase) per
randomization. In the Boost Phase, patients randomized to Arm A (neoadjuvant Nivolumab/CMP)
will receive Nivolumab and CMP (480mg IV q4 x12; CMP-001 5mg SC q4 x12; 48 weeks); while
patients randomized to Arm B (neoadjuvant Nivolumab) will receive Nivolumab (480mg IV q4 x12;
48 weeks). In the post-operative period, CMP-001 will be administered subcutaneously.
Inclusion Criteria:
1. Be willing and able to provide written informed consent for the study.
2. Be ≥ 18 years of age on day of signing informed consent.
3. Willingness to undergo [18F]F-AraG PET imaging at pre- and week 5 timepoints.
4. Diagnosis of histologically or cytologically confirmed diagnosis of cutaneous melanoma
belonging to one of the following AJCC TNM stages:
1. Tx or T1-4 and
2. N1b, or N1c, or N2b, or N2c, or N3b, or N3c and
3. M0
Patients are eligible for this trial either at presentation for primary melanoma with
concurrent regional nodal and/or in-transit metastasis; or at the time of clinical
detected 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.
- Clinically detected recurrent melanoma at the proximal regional lymph node(s)
basin.
- Clinically detected primary cutaneous melanoma involving multiple regional nodal
groups.
- Clinical detected nodal melanoma (if single site) arising from an unknown
primary.
- In-transit and/or satellite metastases with or without regional lymph node
involved permitted if considered potentially surgically resectable at baseline.
- NOTE: Determination of potential resectability must be made at baseline to be
eligible for this neoadjuvant study.
- NOTE: Patients with mucosal and/or uveal melanoma are not permitted to enroll.
Patients with melanomas of unknown primary may be enrolled at the discretion of
the treating investigator in discussion with Principal Investigator.
5. Presence of injectable and measurable disease based on RECIST 1.1.
6. Willing to undergo tumor biopsy (core, punch, incisional or excisional). Patients must
undergo biopsy (core, punch) or open biopsy (incisional, excisional) within 4 weeks of
registration on the study and at W4-5.
7. Performance status of 0 or 1 on the ECOG Performance Scale.
8. Demonstrate adequate organ function as defined below performed on screening labs
obtained within 4 weeks of registration.
- Absolute neutrophil count (ANC) ≥1,500 /mcL
- Hemoglobin ≥9 g/dL or ≥5.6 mmol/L
- Platelets ≥100,000 / mcL
- Serum creatinine or Measured or calculated creatinine clearance (GFR can also be
used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60
mL/min for subject with creatinine levels > 1.5 X institutional ULN.
- Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with
total bilirubin levels > 1.5 ULN.
- AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN.
- International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants.
- Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
of intended use of anticoagulants.
9. Female subject of childbearing potential should have a negative urine or serum
pregnancy 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 serum pregnancy test
will be required.
10. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 26 weeks after the last dose of study medication (Section 5.7.2).
Subjects of childbearing potential are those who have not been surgically sterilized
or have not been free from menses for > 1 year.
11. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 26 weeks after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.
Exclusion Criteria:
1. History of uveal or mucosal melanoma.
2. Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 4 weeks of the first dose of
treatment.
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to a previously administered agent.
- Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
may qualify for the study.
- Note: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
therapy.
- Note: Subjects with autoimmune disorders of Grade 4 while on prior immunotherapy
will be excluded. Subjects who developed autoimmune disorders of Grade ≤ 3 may
enroll if the disorder has resolved to Grade ≤1 and the subject has been off
systemic steroids at doses >10 mg/d for at least 2 weeks.
5. Active (i.e., symptomatic or growing) central nervous system (CNS) metastases.
6. Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy.
7. Has a systemic disease that requires systemic pharmacologic doses of corticosteroids
greater than 10mg daily prednisone (or equivalent). Subjects who are currently
receiving steroids at a dose of ≤10mg daily do not need to discontinue steroids prior
to enrollment Subjects that require topical, ophthalmologic and inhalational steroids
would not be excluded from the study. Subjects with hypothyroidism stable on hormone
replacement or Sjogren's syndrome will not be excluded from the study. Subjects who
require active immunosuppression (greater than steroid dose discussed above) for any
reason are excluded.
8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
9. Has an active infection requiring systemic therapy.
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
11. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 26 weeks after the last dose of trial treatment.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or
BRAF/MEK inhibitor. Prior treatment with ipilimumab or interferon alfa is allowed.
Patients with history of allergic or hypersensitivity reaction to interferon alfa or
ipilimumab are also excluded.
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected. Patients with treated Hepatitis B/C with no evidence of
active infection may be enrolled.
