Study to Determine Efficacy and Safety of CC-486 With Nab-Paclitaxel Versus Nab-Paclitaxel in Patients With Chemotherapy naïve Metastatic Melanoma

A Randomized, Open Label, Multi-center Phase 2 Study of Nab-Paclitaxel Versus Epigenetic Modifying Therapy of CC-4386 With Nab-Paclitaxel in Subjects With Chemotherapy naïve Metastatic Melanoma

A phase 2, open-label randomized, multicenter trial to compare CC-486 in combination with Abraxane administered weekly with respect to overall survival, objective tumor response rate and Progression-Free Survival (PFS) in participants diagnosed with metastatic malignant melanoma.

The study will consist of the following phases:

• Screening (Baseline) Assessments: Performed within 21 days of randomization.
• Randomization: Subjects will be randomized within 21 days of starting their Baseline assessments.
• Treatment: Therapy may continue in the absence of clinically significant disease progression and unacceptable toxicity.
• Response Assessments: Subjects will be evaluated by investigators for CR, PR, stable or progressive disease every 6 weeks from the start of treatment until progressive disease is documented.

Responders and subjects with stable disease (SD) should continue on study unless they develop unacceptable toxicity, they start a new anticancer therapy, withdrawal of consent, physician decision or death.

• End of Study (EOS)/Treatment Evaluation: At the time subjects are removed from study, laboratory and clinical evaluations will be performed.

• Follow-up for Disease Progression:

  - Subjects who stop treatment prior to developing disease progression should be followed without further treatment until progressive disease is documented or until the treating physician feels additional treatment is required.

• Follow-up for Survival:

  • Post study, subject survival status will be monitored on a monthly basis for 6 months from discontinuation from the study and every 3 months thereafter, until death or study termination in all subjects.

Inclusion Criteria:

• 1. Histologically or cytologically confirmed cutaneous BRAF wild-type malignant melanoma with evidence of metastasis (Stage IV).

  2. No prior cytotoxic chemotherapy for metastatic malignant melanoma is permitted. No prior adjuvant cytotoxic chemotherapy is permitted.

  • Up to one prior regimen with the following classes of agents is permitted:

    o Targeted biologic agents (e.g. interleukin 2 [IL-2], granulocyte macrophage colony stimulating factor [GM-CSF], other cytokines or unarmed monoclonal antibodies)

    o Targeted small molecule inhibitors (e.g., kinase inhibitors, heat shock protein [HSP] inhibitors, etc.).

    • Immune checkpoint inhibitors (e.g. anti-CTLA4, anti-PD1, anti-PD-L1).
    • Prior adjuvant therapy with interferon and/or vaccines is permitted.

  • Prior treatments should be completed 4 weeks prior to enrollment in the study (ie, randomization).

    3. Male or non-pregnant and non-lactating female, and ≥ 18 years of age at the time of signing the informed consent document.

  • If heterosexually active, the subject must agree to use medical doctor-approved contraception throughout the study, and for 6 months after last dose of study drug.

    4. History of malignancy in the last 5 years; subjects with prior history of in situ cancer or basal or squamous cell skin cancer are eligible.

  • Subjects with other malignancies are eligible if they were cured by surgery (with or without radiotherapy) and have been continuously disease-free for at least 5 years.

    5. Radiographically-documented measurable disease (defined by the presence of at least one radiographically documented measurable lesion including measurable cutaneous metastasis).

    6. Adequate haemtological and biochemical parameters:

  • ANC ≥ 1.5 x 109 cells/L.

  • Platelets ≥ 100 x 109 cells/L.

  • Hgb ≥ 9 g/dL.

  • AST (SGOT) or ALT (SGPT) ≥ 2.5x upper limit of normal range (ULN);

    o ≤ 5.0 x ULN if hepatic metastases present.

  • Total bilirubin ≤ ULN. Creatinine ≤ 1.5 mg/dL. 8. ECOG performance status 0 to 1.

Exclusion Criteria:

• 1. History of or current evidence of symptomatic brain metastases (brain Computed Tomography (CT)/Magnetic Resonance Imaging (MRI) is needed to exclude brain metastasis), including leptomeningeal involvement.

  2. Subject has pre-existing peripheral neuropathy of National Cancer Institute NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Scale of Grade ≥ 2.

  3. Prior radiation to a target lesion is permitted only if there has been clear progression of the lesion since radiation was completed.