APX005M, Nivolumab, and Cabiralizumab in Treating Patients with Advanced Melanoma, Non-small Cell Lung Cancer or Renal Cell Cancer Who Have Progressed on Anti-PD1/PDL-1 Therapy

Inclusion Criteria

• Biopsy proven metastatic melanoma, NSCLC or RCC whose disease has progressed on anti-PD(L)-1 therapy without any intervening therapy. Progression will be determined by the investigator based on clinical and/or radiographic features. Additional requirements as below: * Melanoma: ** Unresectable stage III or stage IV melanoma, irrespective of BRAF status, with histologic or cytologic confirmation. * RCC: ** Histologic or cytologically documented, locally advanced unresectable or metastatic RCC irrespective of histologic subtype. * NSCLC: ** Histologic or cytologically documented, locally advanced or metastatic (i.e. Stage IIIB not eligible for definitive chemoradiotherapy, stage IV, or recurrent) NSCLC. ** Patients known to harbor an ALK rearrangement or EGFR mutation known to be sensitive to Food and Drug Administration (FDA)-approved tyrosine kinase inhibitors (TKI), are only eligible after experiencing disease progression (during or after treatment) or intolerance to an FDA approved ALK TKI or EGFR TKI, respectively. ** Patients with TKI-treated EGFR mutant NSLC harboring the secondary EGFR T790M tumor must have received prior osimertinib. ** Patients with crizotinib-treated ALK rearranged NSCLC must have received a next generation ALK inhibitor.
• 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. Subjects may forgo the pretreatment biopsy if 1) an entire archival formalin-fixed paraffin-embedded (FFPE) tumor block is available that was taken after the last systemic therapy was administered or 2) if the Investigator deems that the subject does not have tumor in a site that is amenable to biopsy.
• Able to understand and sign the informed consent form.
• Eastern Cooperative Oncology Group (ECOG) performance status < 2.
• Any number of previous treatments. Other prior systemic therapies must have been administered at least 4 weeks before administration of the study drugs; the exception to this is molecular targeted therapies which must have been administered at least 2 weeks prior to the start of the study drugs or after 5 half-lives have occurred, whichever is shorter.
• 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 mandatory tumor biopsy prior to initiation of therapy and before the fifth cycle.
• 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 >= 50 mL/min for subject with creatinine levels > 1.5 x institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]). * 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 RECIST v1.1 criteria. * 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. 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 4 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 immune therapy or chemotherapy within 4 weeks prior to study day 1, or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent will be excluded. Patients who have had prior molecular targeted therapy using small molecule inhibitors must have received their last dose no less than 2 weeks prior to or no less than five half-lives from study day 1. * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. * Note: Toxicity that has not recovered to =< grade 1 is allowed if it meets the inclusion requirements for laboratory parameters.
• Has had prior treatment with any other CSF1R inhibitor or CD40 agonist.
• 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 adverse events due to prior treatments with the exception of alopecia, clinically insignificant laboratory abnormalities, clinically insignificant rash and grade 2 neuropathy.
• 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 (e.g., 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, cabiralizumab 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.
• Current or history of clinically significant muscle disorders (e.g., myositis), recent unresolved muscle injury, or any condition known to elevate serum creatinine kinase (CK) levels.
• History of anti-drug antibodies, severe allergic, anaphylactic, or other infusion-related reaction to a previous biologic agent.
• Concomitant use of statins on study. However, a patient using statins for over 3 months prior to study drug administration and in stable status without CK rise may be permitted to enroll.
• Open wounds and active skin infections.
• Uveal melanoma in the phase Ib dose expansion trial