Avadomide and Nivolumab in Treating Patients with Unresectable or Metastatic Melanoma

Inclusion Criteria

• Unresectable or metastatic melanoma of cutaneous, mucosal, conjunctival, or unknown origin. Uveal melanoma is not permitted. * Cohort 1: Naive to anti-PD1 therapy * Cohort 2: Progressed on previous anti-PD1 therapy. Subjects who have received anti-PD1 therapy in the adjuvant setting for previously resected melanoma are eligible for this cohort provided the disease relapse has occurred within 6 months of the last dose of anti-PD1 therapy. If this interval is equal to or greater than 6 months from the last dose of anti-PD1 therapy, they will be eligible to participate in Cohort 1. Patients with BRAF V600 mutant melanoma who have PD-1 refractory disease must have received treatment with BRAF and/or MEK inhibitors.
• Be willing and able to provide written informed consent for the trial.
• Have measurable disease based on RECIST 1.1.
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale.
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours 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.
• 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 28 days after last dose of avadomide or 5 months after the last dose of nivolumab; whichever is longer. Females of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 3 months after the last dose of avadomide or 7 months after last dose of nivolumab; whichever is longer.
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.
• Platelets >= 100,000 x 10^6/L.
• Hemoglobin (Hgb) >= 9 g/dL, without the need for transfusion.
• Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) OR measured creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN.
• Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (or =< 5 x ULN in case of liver metastases).
• Serum bilirubin =< 1.5 x ULN (or =< 3 X ULN if known Gilbert’s syndrome).

Exclusion Criteria

• Has received an investigational drug or other anti-cancer therapy within 3 weeks of the first dose of treatment or =< 5 half-lives of that agent, whichever is shorter. Any toxicity from prior therapy must have recovered to =< grade 1.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (equivalent to > 10mg/d of prednisone) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment (only exception to this is the need for steroids for central nervous system [CNS] metastases. Inhaled, intra-articular, or topical steroids are permissible.
• Has a history of hypersensitivity to nivolumab.
• Has a known additional malignancy that is progressing or requires active treatment, the lack of which would pose a risk to the health of the subject, in the opinion of the investigator.
• Has known symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable without evidence of progression by imaging for at least four weeks after definitive intervention and using no more than the equivalent of dexamethasone 2 mg/d for the management of vasogenic edema, if necessary. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy [=< 10 mg/d equivalent of prednisone] for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Had previous toxicity from anti-PD1/PD-L1 immunotherapy that led to treatment discontinuation.
• Has active pneumonitis or a history of non-infectious pneumonitis that required steroids.
• Has grade >= 2 peripheral neuropathy.
• Has clinically significant cardiac disease including any of the following: Left ventricular ejection fraction (LVEF) < 45% as determined by a by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO), complete left bundle branch or bifascicular block, congenital long QT syndrome, persistent or clinically meaningful ventricular arrhythmias, corrected QT interval by Fredericia (QTcF) > 460 msec on screening electrocardiogram (ECG), unstable angina pectoris or myocardial infarction =< 6 months prior to starting study treatment, uncontrolled hypertension (blood pressure > 140/90 mmHg on at least 2 measurements on sequential visits, despite blood pressure medication), or troponin-T/I value > ULN or brain natriuretic peptide (BNP) > 300 pg/mL.
• Has a history of persistent skin rash.
• Has an active infection requiring systemic therapy.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial, in the opinion of the investigator.
• Is pregnant or breastfeeding.
• Has a known history of human immunodeficiency virus (HIV), active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] is detected).
• Has received a live vaccine within 30 days of planned start of study therapy. * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed.