CMP-001 in Combo With Nivolumab in Stage IIIB/C/D Melanoma Patients With Clinically Apparent Lymph Node Disease

Patients are being asked to take part in this clinical research study because they have stage IIIB, IIIC or IIID cutaneous (or unknown primary) melanoma with lymph node disease and have yet to undergo surgery. There are two phases, Prime Phase and a Boost Phase. If they participate they will receive nivolumab in combination with CMP-001 for a total of 7 weeks (Prime Phase) prior to surgery. Surgery will be performed approximately 2-4 weeks after completion of the Prime Phase. After recovery from surgery patients will receive additional nivolumab in combination with CMP-001 for approximately 46 additional weeks (Boost Phase).

The main goal of this research study to determine if the combination of nivolumab and CMP-001 improves the likelihood of eradicating (destroying) disease in the lymph node (pathologic response rate). Pathologic responses are associated with improved relapse-free and overall survival in melanoma.

Prior to surgery (Prime Phase) Nivolumab 240mg, will be administered as a 30-minute IV infusion on an outpatient basis. During the Prime Phase, 3 cycles of Nivolumab will be administered every 2 weeks over a 6 week period starting with cycle 2, cycle 4 and then cycle 6.

Prior to surgery (Prime Phase) CMP-001 will be given as an injection from a syringe weekly for a total of 7 weeks. The first injection (week 1), 5mg, will be applied directly into the skin and the remaining injections, 10mg will be administered, will be given intra-tumorally for weeks 2-7.

Surgery will be performed to the cancerous lymph node 2-4 weeks after the Prime Phase is completed.

After recovery from surgery (Boost Phase) Nivolumab will be administered at 240mg every 2 weeks or 480 mg every 4 weeks depending on the physician's preference. CMP-001, 5mg, will be administered by injections intra-tumorally every 4 weeks for up to 54 weeks.

Patients will be followed to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. This will be done every 3 months.

• CMP-001 (Drug): A molecule comprised of a 30 nucleotide strand, flanked by 10 guanines on either end. The nucleotide strand is surrounded by a Qβ viral-like protein. The intended mechanism of action of CMP-001 in oncology is the activation of TLR9 in pDC within the tumor or the tumor-draining lymph nodes (tumor-associated pDC).
• Nivolumab (Biological): A fully human Ig G4 antibody that blocks PD-1. Nivolumab was initially approved by the FDA for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Nivolumab has also been FDA approved to treat patients with advanced (metastatic) squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy, as well as advanced renal cell carcinoma.

Primary outcomes

• Major Pathologic Response Rate (MPR) [Every 6 weeks from start of study treatment, up to 52 weeks]: Distribution of pathologic response in the 30 evaluable patients. Major pathologic response was defined on surgical specimens analyzed by blinded two independent dermatopathologists using immune related pathologic response criteria (irPRC). Residual viable tumor (RVT) (wherein RVT = viable tumor area/total tumor bed area) was calculated depending on the quantity of viable malignant cells on H\&E-stained slides and confirmatory SOX-10-stained representative sections in ambiguous cases; and thresholds defined as follows: complete response (pCR, 0% RVT), major response (pMR, 0%< RVT ≤10%), partial response (pPR, 10%< RVT ≤50%), and pNR (RVT >50%).

Secondary outcomes

• Radiographic Response Rate [Up to 31 months]: Number of patients with Complete response \[CR\], partial response \[PR\], or stable disease \[SD\], per RECIST v1.1 criteria. Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10mm short axis);PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters; SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease \[PD\], taking as reference the smallest sum diameters while on study. PD: ≥20% (relative) increase in sum of diameters of target lesions referencing smallest sum on study (includes baseline sum if is smallest on study) and, the sum must also demonstrate an absolute increase of at least 5 mm; appearance of one or more new lesions.
• Relapse-Free Survival (RFS) [Up to 31 months]: Length of time from the initiation of treatment that patients survive without recurrence of disease. Per RECIST v1.1, progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.
• 6-month Relapse-free Survival [Up to 6 months]: Percentage of patients who did not experience disease relapse, 6-months post start of treatment.
• 12-month Relapse-free Survival [Up to 12 months]: Percentage of patients who did not experience disease relapse, 12 months post treatment.
• 24-month Relapse-free Survival [Up to 24 months]: Percentage of patients who did not experience disease relapse, 24-months post start of treatment.
• Overall Survival (OS) [Up to 31 months]: The length of time from the start of treatment that patients remain alive.
• 6-month Overall Survival (OS) [Up to 6 months]: Percentage of patients that remain alive.
• 12-month Overall Survival (OS) [Up to 12 months]: Percentage of patients that remain alive.
• 24-month Overall Survival (OS) [Up to 24 months]: Percentage of patients that remain alive.

Other outcomes

• Expression of Inhibitory and Activating Receptors and Ligands [3 years]: Circulating and intra-tumoral immune cells, including T-cells (CD8, CD4, Tregs) and antigen-presenting cells (monocytes, macrophages, MDSCs), will be compared pre and post nivolumab and CMP-001 combination treatment.
• TCR Clonality/Diversity Analyses of Circulating and Intra-tumoral CD8+ T-cells [3 years]: TCR clonality/diversity will be compared pre and post nivolumab and CMP-001 combination treatment.
• Genetic and Transcriptomic Signatures of Response/Non-response [3 years]: Genetic and transcriptomic signatures will be compared between patients who do and do not respond to study treatment.
• Novel Tumor Imaging Characteristics in Responders and Non-responders [3 years]: Tumor imaging characteristics will be compared between patients who do and do not respond to study treatment.

Sex: All, ages: 18 Years to any

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. 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.
4. Presence of injectable and measureable disease based on RECIST 1.1.
5. 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.
6. Performance status of 0 or 1 on the ECOG Performance Scale.
7. 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.
8. Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days 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.
9. 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. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
10. 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. 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.

Participant flow

Outcome results

• Major Pathologic Response Rate (MPR) (Primary), Count of participants, Participants: Nivolumab and CMP-001 Combination 14
• Radiographic Response Rate (Secondary), Count of participants, Participants: Nivolumab and CMP-001 Combination 14
• Relapse-Free Survival (RFS) (Secondary), Median, months: Nivolumab and CMP-001 Combination NA (22.0 to NA)
• 6-month Relapse-free Survival (Secondary), Number, percentage of patients: Nivolumab and CMP-001 Combination 81 (62 to 91)
• 12-month Relapse-free Survival (Secondary), Number, percentage of patients: Nivolumab and CMP-001 Combination 74 (55 to 86)
• 24-month Relapse-free Survival (Secondary), Number, percentage of patients: Nivolumab and CMP-001 Combination 62 (41 to 77)
• Overall Survival (OS) (Secondary), Median, months: Nivolumab and CMP-001 Combination NA (NA to NA)
• 6-month Overall Survival (OS) (Secondary), Number, percentage of participants: Nivolumab and CMP-001 Combination 100 (100 to 100)
• 12-month Overall Survival (OS) (Secondary), Number, percentage of participants: Nivolumab and CMP-001 Combination 87 (69 to 95)
• 24-month Overall Survival (OS) (Secondary), Number, percentage of participants: Nivolumab and CMP-001 Combination 83 (63 to 93)
• Expression of Inhibitory and Activating Receptors and Ligands (Other pre specified)
• TCR Clonality/Diversity Analyses of Circulating and Intra-tumoral CD8+ T-cells (Other pre specified)
• Genetic and Transcriptomic Signatures of Response/Non-response (Other pre specified)
• Novel Tumor Imaging Characteristics in Responders and Non-responders (Other pre specified)

Adverse events

Time frame: Adverse Events monitored up to 31 months, All-Cause Mortality monitored up to 31 months

Serious adverse events by term

Other adverse events by term

161 more terms not shown.

• Results publication: Davar D, Morrison RM, Dzutsev AK, Karunamurthy A, Chauvin JM, Amatore F, Deutsch JS, Das Neves RX, Rodrigues RR, McCulloch JA, Wang H, Hartman DJ, Badger JH, Fernandes MR, Bai Y, Sun J, Cole AM, Aggarwal P, Fang JR, Deitrick C, Bao R, Duvvuri U, Sridharan SS, Kim SW, A Choudry H, Holtzman MP, Pingpank JF, O'Toole JP, DeBlasio R, Jin Y, Ding Q, Gao W, Groetsch C, Pagliano O, Rose A, Urban C, Singh J, Divarkar P, Mauro D, Bobilev D, Wooldridge J, Krieg AM, Fury MG, Whiteaker JR, Zhao L, Paulovich AG, Najjar YG, Luke JJ, Kirkwood JM, Taube JM, Park HJ, Trinchieri G, Zarour HM. Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial. Cancer Cell. 2024 Nov 11;42(11):1898-1918.e12. doi: 10.1016/j.ccell.2024.10.007. Epub 2024 Oct 31. PMID 39486411
• Results publication: Gorry C, McCullagh L, O'Donnell H, Barrett S, Schmitz S, Barry M, Curtin K, Beausang E, Barry R, Coyne I. Neoadjuvant treatment for stage III and IV cutaneous melanoma. Cochrane Database Syst Rev. 2023 Jan 17;1(1):CD012974. doi: 10.1002/14651858.CD012974.pub2. PMID 36648215

• Study Protocol and Statistical Analysis Plan (PDF, 2022-08-18)

• Diwakar Davar, MD, Principal investigator, University of Pittsburgh Medical Center