A multicenter, open-label, phase 2 study of intratumoral CMP-001 in combination with intravenous nivolumab in subjects with refractory unresectable or metastatic melanoma

Inclusion Criteria:

Subjects enrolled in the study must meet all of the following inclusion criteria to be eligible.

1. Histopathologically-confirmed diagnosis of malignant melanoma that is metastatic or unresectable at Screening.
2. Known BRAF mutation status; if BRAF V600 mutation positive, must have had prior treatment with a local Health Authority approved BRAF inhibitor, with or without mitogen-activated protein kinase inhibitor. Patients with BRAF V600 mutations who refuse a BRAF inhibitor will not be eligible.

3. Refractory to PD-1 blockade either as monotherapy or in combination with other therapies, as defined by the following criteria:

   1. Received treatment with a Food and Drug Administration approved PD-1 blocking antibody for 12 weeks or longer.
   2. Have PD (according to RECIST v1.1) within 12 weeks of the last dose of a PD-1 blocking antibody, either as monotherapy or in combination with other agents.

   Evidence of confirmed PD must be established by investigator assessment at least 4 weeks after the initial date of PD. The second assessment may serve as the Baseline for this study if completed within 30 days before to the start of study treatment. NOTE: in subjects with histologically confirmed recurrence on or after adjuvant PD-1 blocking antibody, confirmatory imaging is not required.

4. Measurable disease, as defined by RECIST v1.1 and all of the following:

   1. At least 1 accessible lesion amenable to repeated IT injection.
   2. One or more measurable lesions at least 1 cm in diameter that are not intended for CMP 001 injection and can be followed as target lesions per RECIST v1.1.
   3. Documented disease progression in any lesion that was previously radiated in order to serve as a target lesion.
5. Able to provide tissue from a core or excisional biopsy (fine needle aspirate is not sufficient). A fresh tissue biopsy (within 90 days before the start of study treatment) is preferred but an archival sample is acceptable if no intervening therapy was received. Note: For tissue sampling details, please refer to the laboratory manual.

6. Adequate organ function based on most recent laboratory values within 3 weeks before first dose of study treatment on Week 1 Day 1 (W1D1):

   1. Bone marrow function:

      • neutrophil count ≥ 1500/mm3
      • platelet count ≥ 100,000/mm3
      • hemoglobin concentration ≥ 9 g/dL
      • white blood cells ≥ 2000/mm3

   2. Liver function:

      • total bilirubin ≤ 1.5 times the upper limit of normal (ULN) with the following exception: patients with Gilbert Disease total serum bilirubin ≤ 3 times ULN
      • aspartate aminotransferase and alanine aminotransferase ≤ 3 times the ULN
   3. Lactate dehydrogenase ≤ 2 times the ULN
   4. Renal function: estimated (Cockcroft-Gault) or measured creatinine clearance ≥ 30 mL/min.

   5. Coagulation:

      • International normalized ratio or prothrombin time (PT) ≤ 1.5 times ULN, unless subject is receiving anticoagulant therapy, as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
      • Activated partial thromboplastin time or PTT ≤ 1.5 times ULN, unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants
7. Age ≥ 18 years at time of consent.
8. Eastern Cooperative Oncology Group Performance Status of 0 to 1 at Screening.
9. Capable of understanding and complying with protocol requirements.
10. Women of childbearing potential must have negative serum pregnancy test before dosing at W1D1 and be willing to use an adequate method of contraception from the time of consent until at least 150 days after last dose of study treatment.
11. Able and willing to provide written informed consent and to follow study instructions. Subjects unable to provide written informed consent on their own behalf will not be eligible for the study.

Exclusion Criteria:

Subjects presenting with any of the following will not qualify for entry into the study:

1. Uveal, acral, or mucosal melanoma.
2. Received radiation therapy (or other nonsystemic therapy) within 2 weeks before first dose of study treatment on W1D1. Patients should have recovered (ie, Grade ≤1 or at baseline) from radiation-related toxicities.
3. Treatment with complementary medications (eg, herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before start of study treatment. Refer to Section 4.4. for prohibited therapies.

4. Received systemic pharmacologic doses of corticosteroids ≥10 mg/day prednisone within 30 days before first dose of study treatment on W1D1.

   1. Subjects who are currently receiving steroids at a prednisone-equivalent dose of ≤ 10 mg/day do not need to discontinue steroids before enrollment.
   2. Replacement doses, topical, ophthalmologic, and inhalational steroids are permitted.
   3. Stress-dose corticosteroids will be required in subjects with adrenal insufficiency
5. History of immune-related AE that required permanent discontinuation of PD-1 blocking antibody.

6. Not fully recovered from AEs (to Grade 1 or less [per CTCAE v5.0], with the exception of persistent adverse events or sequelae, eg, vitiligo, alopecia, hypothyroidism, diabetes mellitus, and adrenal and/or pituitary insufficiency) due to prior treatment.

   NOTE: Subjects previously treated with a CTLA-4-blocking antibody, subjects receiving corticosteroids with daily doses > 5 mg and ≤ 10 mg of prednisone equivalent for 2 weeks, and subjects with clinical symptoms and/or laboratory findings suggesting risk for adrenal insufficiency should undergo diagnostic tests for adrenal insufficiency via local laboratory.

7. Active pneumonitis or history of noninfectious pneumonitis that required steroids.
8. Severe uncontrolled cardiac disease within 6 months of Screening, including but not limited to poorly controlled hypertension, unstable angina, myocardial infarction, congestive heart failure (New York Heart Association Class II or greater), pericarditis within the previous 6 months, cerebrovascular accident, or implanted or continuous use of a pacemaker or defibrillator.
9. Known history of immunodeficiency.
10. Known additional malignancy that is progressing or required active treatment within the past 3 years. Exceptions include cancers that have undergone potentially curative therapy, eg, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, localized prostate cancer with prostate-specific antigen level below 4.0 ng/mL, in situ cervical cancer on biopsy or a squamous intraepithelial lesion on Papanicolaou smear, and thyroid cancer (except anaplastic), in situ breast cancer, and adjuvant hormonal therapy for breast cancer > 3 years from curative-intent surgical resection.
11. Active autoimmune disease that has required systemic treatment in past 2 years; replacement therapy is not considered a form of systemic treatment.
12. Untreated, symptomatic, or enlarging central nervous system metastases or carcinomatous meningitis (including leptomeningeal metastases from solid tumors).
13. Prior allogenic tissue/solid organ transplant.
14. Active infection requiring systemic therapy.
15. Known or suspected active infection with severe acute respiratory syndrome coronavirus 2 virus.
16. Known or suspected active infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus (testing is not required unless suspected).
17. Received a live virus/attenuated vaccination within 30 days before first dose of study treatment on W1D1.
18. Received blood products (including platelets or red blood cells) or colony stimulating factors (including granulocyte colony stimulating factor, granulocyte/macrophage colony stimulating factor, or recombinant erythropoietin) within 30 days before the start of Screening.
19. History of allergy or hypersensitivity to nivolumab and/or any of its excipients.
20. Any concurrent uncontrolled illness, including mental illness or substance abuse, which in the opinion of the Investigator would make the subject unable to cooperate or participate in the study.
21. Participation in another clinical study of an investigational anticancer therapy or device within 30 days before first dose of study treatment on W1D1. Participation in the follow-up phase (receiving no study treatment) of a prior study is allowed.
22. Requires prohibited treatment (ie, non-protocol specified anticancer pharmacotherapy, surgery, or radiotherapy) for treatment of malignant tumor.
23. Has a life expectancy of less than 3 months and/or has rapidly progressing disease (eg, tumor bleeding, uncontrolled tumor pain) in the opinion of the treating Investigator.
24. Received previous CMP-001 treatment.
25. Pregnant or breastfeeding or expecting to conceive or donate eggs within the projected duration of the study, from the time of consent until at least 150 days after last dose of study treatment for women.