Study of CBL0137 in Combination With Ipilimumab and Nivolumab Therapy in Melanoma

This is an interventional treatment trial for Locally Advanced or Metastatic Melanoma Read More

Inclusion Criteria:

1. Patients must have:

   1. Pathologically proven stage III melanoma with one or more macroscopic lymph node metastases (measurable according to RECIST v. 1.1) amenable to biopsy and/or surgery OR:
   2. Patients considered to have stage III or stage IV disease amenable to serial biopsies as determined by the treating physician. Note: patients with in-transit metastasis may be eligible after surgical consultation if not surgical candidates.
   3. Patients must have disease amenable to and must be willing to undergo protocol-directed repeat biopsies and blood draws.
2. Age > 18 years
3. ECOG performance status 0 or 1

4. Patients must have normal organ and marrow function as defined below

   • Leukocytes > 3,000/mcL
   • Absolute neutrophil count > 1,500/mcL
   • Platelets > 100,000/mcL
   • Hemoglobin ≥ 9 mg/dL

   • Total bilirubin ≤ 1.52.0x ULN

     • Patients with suspected Gilbert's disease may enroll provided that historic fluctuations in total bilirubin does not exceed 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 23 times upper limit of normal
   • AST/ALT (SGOT/SGPT) < 35 times institutional normal limits
   • Creatinine ≤ 2x normal institutional limits OR
   • Creatinine clearance > 40 Ml/min/1.73 m2 for patients with creatinine levels above institutional normal
5. 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 principal investigator or a designated associate.
6. Ability to understand and willingness to sign a written informed consent and HIPAA consent document and comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.

Exclusion Criteria:

1. 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
2. Patients may not be receiving any other investigational agents
3. Patients with a known active autoimmune disease
4. History of allergic reactions attributed to compound of similar chemical or biologic composition to the agent(s) used in this study
5. Receiving or requiring the continued use of medications that are known to strongly inhibit or induce CYP3A4/5 (Appendix III). To participate in this study, such subjects should discontinue use of such agents for at least 2 weeks before cycle 1 day 1.
6. Prior treatment with CTLA-4 or PD1/PD-L1 pathway targeted systemic treatment
7. 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.
8. 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.
9. Known 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.
10. 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 ECG.

11. 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).

    a. Patients with treated hepatitis B or C, with no evidence of continued infection or requirement for antiviral medications, are permitted

12. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic corticosteroids
13. Patients with ongoing diarrhea (> 4 bowel movements/day) unresolved despite medical and best supportive care in the two weeks preceding therapy
14. Major surgery (as assessed by treating clinician) within 28 days of study registration.
15. 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.
16. Pregnant or breast feeding. Refer to section 4.4 for further detail.