CBL0137 in Combination with Ipilimumab and Nivolumab for the Treatment of Stage III-IV Metastatic, Unresectable, or Recurrent Melanoma

Inclusion Criteria

• Patients must have pathologically confirmed: * Recurrent stage III melanoma with one or more macroscopic lymph node metastases (measurable according to RECIST v. 1.1) OR * Newly diagnosed unresectable stage III melanoma (measurable according to RECIST v. 1.1) OR * Patients considered to have stage IV metastatic melanoma (including oligometastatic). Disease must be measurable according to RECIST v.1.1 ** Note: patients with in-transit metastasis may be eligible if surgical consultation confirms the disease is unresectable
• Patients must have disease amenable to and must be willing to undergo protocol-directed repeat biopsies and blood draws
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 mg/dL
• Total bilirubin =< 1.5 x upper limit of normal (ULN) * Patients with suspected Gilbert’s disease may enroll provided that total bilirubin must be < 3 mg/dL * Patient with known liver metastasis may enroll provided total bilirubin has been stable over the screening period and at least 2 weeks, and not exceeding 2 times upper limit of normal
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (serum glutamic oxaloacetic transaminase [SGOT]/serum glutamic pyruvic transaminase [SGPT]) =< 3 times institutional normal limits
• Creatinine =< 2 x normal institutional limits OR creatinine clearance >= 40 Ml/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Female patients must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. Male patients must be surgically sterile or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. The decision of effective contraception will be based on the judgment of the treating physician or a designated associate
• Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document and comply with the study scheduled visits, treatment plans, laboratory tests and other procedures

Exclusion Criteria

• Patients with primary stage III disease who are candidates for resection with curative intent
• Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Prior combination CTLA-4/PD-1 therapy is not allowed. However, prior monotherapy with PD1/PD-L1 with evidence of recurrence is allowable
• Prior grade 2 or more immuno-oncology (IO) toxicity in patients with prior PD1 treatment
• Patients may not be receiving any other investigational agents
• Patients with a known active autoimmune disease
• History of allergic reactions attributed to compound of similar chemical or biologic composition to the agent(s) used in this study
• Receiving or requiring the continued use of medications that are known to strongly inhibit or induce CYP3A4/5. To participate in this study, such subjects should discontinue use of such agents for at least 2 weeks before cycle 1 day 1
• Uncontrolled intercurrent illness including, but not limited to, other ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients on any other active malignancy that is likely to interfere with the safety or efficacy assessment of the investigational regimen. Need for concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy outside of the context of this protocol with the following exceptions: Adjuvant endocrine therapy for a history of breast cancer, endocrine therapy for patients with prostate cancer, somatastatin analogue use and hormone use (not including steroid use) for nonmalignant diseases
• Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with CBL0137. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
• Has a QT interval corrected by Fridericia's formula (QTcF) prolongation to > 470 msec (female subjects) or > 450 msec (male subjects) based on a screening single 12-lead electrocardiogram (ECG)
• Active bacterial fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV), requiring treatment with IV antibiotic, IV anti-fungal, or anti-viral (testing IS required for eligibility) * Patients with treated hepatitis B or C, with no evidence of continued infection or requirement for antiviral medications, are permitted
• Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic corticosteroids
• Patients with ongoing diarrhea (> 4 bowel movements/day) unresolved despite medical and best supportive care in the two weeks preceding therapy
• Major surgery (as assessed by treating clinician) within 28 days of study registration
• Patients with clinically significant intracranial hemorrhage/hemorrhagic cardiovascular accident (CVA), or patients with gastrointestinal bleeding due to thrombocytopenia that has not resolved with medical therapy
• Pregnant or breast feeding