APX005M, Nivolumab and Ipilimumab for the Treatment of Stage III or IV Melanoma or Locally Advanced Unresectable or Metastatic Renal Cell Cancer

Inclusion Criteria

• Biopsy proven unresectable melanoma or RCC who have not received prior therapy with PD-1/PD-L1 or CTLA4 inhibitors. Prior adjuvant immune therapy is allowed provided that at least 6 months have lapsed from the last dose. Additional requirements are as below: * Melanoma: ** Unresectable stage III or stage IV melanoma, irrespective of BRAF status, with histologic or cytologic confirmation. Uveal melanoma is excluded. * RCC: ** Histologic or cytologically documented, locally advanced unresectable or metastatic clear cell RCC. Non-clear cell RCC irrespective of histologic subtypes are excluded.
• At least 1 site of disease must be accessible to provide repeat biopsies for tumor tissue. This site may be a target lesion as long as it will not be made unmeasurable by the biopsy procedure. Patients who do not have tumors accessible for biopsy may be considered upon discussion with the study principal investigators (PIs)
• Age >= 18, able to understand and sign the informed consent form
• Eastern Cooperative Oncology Group (ECOG) performance status < 2
• No prior systemic therapy for advanced (unresectable) disease. Adjuvant therapy is allowed provided that at least 6 months have lapsed from the last dose of an immune checkpoint inhibitor. Prior small molecule inhibitors must be discontinued within 2 weeks after starting study. Previous targeted therapy is permitted
• Life expectancy of at least 6 months
• A history of previously treated brain metastases is allowed, provided that they are stable for at least 4 weeks
• Willingness to undergo tumor biopsy (if amenable) prior to initiation of therapy, at day 8 (+/-2 days) following cycle 2 and at the time of tumor progression
• Willingness to provide an archival specimen block, if available, for research
• Absolute neutrophil count (ANC) >= 1,500 /mcL
• Platelets >= 100,000 / mcL
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCL]) >= 50 mL/min for subject with creatinine levels > 1.5 X institutional ULN * Creatinine clearance should be calculated per institutional standard
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN
• Albumin > 2.5 mg/dL
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X 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 (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 24 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 a highly effective contraception (hormonal or intrauterine device [IUD]) or be surgically sterile, or abstain from heterosexual activity for a period of at least 5 months after the last dose of study drug. Subjects 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 at least 7 months after the last dose of study drug
• Patients must have at least one measurable lesion at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Tumor sites situated in a previously irradiated area, or in an area subjected to other loco-reginal therapy, are not considered measurable unless there has been demonstrated progression in the lesion
• Prior focal radiotherapy must be completed before first dose of study drug administration, although palliative radiation may be allowed on treatment (see permitted concomitant therapies below). Radiation to pulmonary or intestinal sites must be completed at least 4 weeks prior to study day 1. There is no time restriction prior to study day 1 for patients who have received radiation to bone, soft tissue sites or other sites. No radiopharmaceuticals (strontium, samarium) within 8 weeks before first dose of study drug administration
• Major surgery must be completed at least 2 weeks before first dose of study drug administration. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before first dose of study drug administration and patients should have recovered. Surgical wounds must be healed

Exclusion Criteria

• Untreated brain metastases
• A patient who has had prior treatment with immune checkpoint therapy for advanced disease. Prior immune checkpoint inhibitors as adjuvant therapy is allowed provided over 6 months have lapsed from the last dose. Prior targeted therapy is allowed within 2 weeks of study enrollment
• Use of corticosteroids to control immune related adverse events at enrollment will not be allowed, and patients who previously required corticosteroids for symptom control must be off steroids for at least 2 weeks. Low-dose steroid use (=< 10 mg of prednisone or equivalent) as corticosteroid replacement therapy for primary or secondary adrenal insufficiency is allowed
• Has not recovered (i.e., =< grade 1 or at baseline) from immune related (ir)AEs due to previous therapies with exceptions such as alopecia
• History of grade 3-4 neurologic or cardiac toxicity or life-threatening liver toxicity poorly responsive to steroids with prior anti-PD-1/anti-PDL1 monotherapy
• Presence of leptomeningeal disease
• Has active autoimmune disease unrelated to immune checkpoint inhibitors that has required systemic treatment in the past year (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Pregnancy or breast feeding. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab, ipilimumab or APX005M, breastfeeding must be discontinued if the mother is enrolled on this trial
• Patients may not be receiving any other investigational agents and may not have participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment
• Patients with either a concurrent medical condition (including medical illness, such as active infection requiring treatment with intravenous antibiotics or the presence of laboratory abnormalities) or history of a prior condition that places the patient at unacceptable risk if he/she were treated with the study drug or a medical condition that confounds the ability to interpret data from the study
• Concurrent, active malignancies in addition to those being studied (other than cutaneous squamous cell carcinoma or basal cell carcinoma)
• Active (non-infectious) pneumonitis
• Has a known human immunodeficiency virus (HIV), hepatitis B (HBV), or hepatitis C (HCV) acute or chronic infection
• Has received a live vaccine within 30 days prior to the first dose of trial treatment
• History of myocardial infarction or unstable angina within 3 months prior to cycle 1, day 1
• Prisoners, or subjects who are under compulsory detention
• Open wounds and active skin infections
• Uveal melanoma
• Non-clear cell RCC histologic subtypes