Tocilizumab, Ipilimumab, and Nivolumab for the Treatment of Advanced Melanoma, Non-Small Cell Lung Cancer, or Urothelial Carcinoma

Exclusion Criteria

• •Cohort 2:
• •Urothelial Carcinoma (n=10 patients) 1. Histologically or cytologically documented locally advanced or transitional cell carcinoma of the urothelium including renal pelvis, ureters, urinary bladder, or urethra. Patients with mixed histologies are required to have a dominant transitional cell pattern.
• •2\. Enrollment of urothelial carcinoma 1st line patients who are cisplatin-ineligible and who, after consultation with the investigator, choose to forego front-line chemotherapy or immunotherapy.
• •3\. Treatment naïve, cisplatin-eligible patients who refuse chemotherapy standard of care or treatment naive, cisplatin-ineligible patients who meet at least one of the following criteria:
• •\- Common Terminology Criteria for Adverse Events (CTCAE) v5 Grade ≥ 2 audiometric hearing loss. CTCAE v5 Grade ≥ 2 peripheral neuropathy.
• •* Cisplatin ineligibility defined as: GFR less than 60 and ≥ 15 mL/min or; CHF NYHA class III or higher or; peripheral neuropathy grade 2 or higher or ECOG PS 2 or higher or; impaired hearing grade 2 or higher.
• •* GFR is either measured using a 24 hour urine, calculated using Cockroft-Gault, or estimated using the MDRD method from the National Kidney Disease Education Program (NKDEP) (the method reported by MDACC laboratories).
• •a. Cockroft-Gault formula: CLcr = \[(140-age) • wt(kg)\]/\[72 •Creat (mg/dL)\] (Multiply by 0.85 for females).
• •4\. No prior chemotherapy for inoperable locally advanced or metastatic urothelial carcinoma.
• •5\. Prior local intravesical chemotherapy is allowed if completed at least 4 weeks prior to the initiation of study treatment.
• •6\. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval of more than 12 months between the last treatment administration and the date of recurrence is required to be considered treatment naive in the metastatic setting. Patients must not have received neoadjuvant or adjuvant therapy with any immuno-oncology regimens. Please note that this small population of patients will be excluded.
• •Cohort 3: (n=10 patients)
• •1. Subjects diagnosed with histologically or cytologically confirmed locally advanced/metastatic NSCLC with EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
• •2. Subjects must have received one prior line of therapy with an EGFR TKI in the locally advanced/metastatic setting.
• •3. Subjects need to meet either A or B. A) Must have received and progressed on an approved first or second generation EGFR TKI (eg, erlotinib or gefitinib \[first generation\] or afatinib \[second generation\]) and must be T790M negative by an approved testing assay on tumor biopsy at the time of progression. B) Patient must have received third generation TKI Osimertinib and progressed on this therapy for study entry. C) TKI needs to be the last therapy. D) Prior chemotherapy received in the neoadjuvant or adjuvant settings will not be considered a line of therapy.
• •1\) Medical Conditions
• •a) Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.
• •b) Uveal melanoma is excluded. c) Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the patient from adhering to the protocol or would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results (eg, a condition associated with diarrhea or acute diverticulitis).
• •d) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
• •e) Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• •f) Participants with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of week 0 day 1. Inhaled or topical steroids, and adrenal replacement steroid doses \> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Please see Section 4.3for permitted therapies.
• •g) History of organ transplant or tissue that requires systemic use of immune suppressive agents h) Active infection requiring systemic therapy within 14 days prior to week 0 day 1.
• •i) Known cardiac history including: i) History of unstable or deteriorating cardiac disease within the previous 12 months prior to screening including but not limited to the following:
• •(1) Unstable angina or myocardial infarction (2) Transient ischemic attack (TIA)/Cerebrovascular accident (CVA) (3) Congestive heart failure (New York Heart Association \[NYHA\] Class III or IV) (4) Uncontrolled clinically significant arrhythmias j) Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally.
• •2\) Prior/Concomitant Therapy
• •a) Use of an investigational agent or an investigational device within 28 days before administration of first dose of study drug b) Participants who have received a live / attenuated vaccine within 30 days before first treatment c) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways with the exception of treatment with adjuvant intent as described in inclusion 2a.
• •d) Participants with history of life-threatening toxicity related to prior immune therapy (e.g. anti- CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T- cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g. Hormone replacement after adrenal crisis) e) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to study treatment initiation.
• •3\) Physical and Laboratory Test Findings
• •1. WBC \< 2000/μL
• •2. Neutrophils \< 1500/μL
• •3. Platelets \< 100,000/μL
• •4. Hemoglobin \< 9.0 g/dL NOTE: May not transfuse within 14 days of study treatment initiation to meet eligibility criteria 3a through 3d.
• •5. Serum creatinine \> 1.5 x ULN, unless creatinine clearance ≥ 40 mL/min (measured or calculated using the Cockroft-Gault formula) Female CLcr = (140- age in years) x weight in kg x 0.85 72 x serum creatinine in mg/ dL Male CLcr = (140- age in years) x weight in kg x 1.00 72 x serum creatinine in mg/ dL
• •6. AST/ALT: \> 3.0 x ULN
• •7. Total bilirubin \> 1.5 x ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of \< 3.0x ULN)
• •8. Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative).
• •4\) Allergies and Adverse Drug Reaction
• •a) History of allergy or hypersensitivity to study drug components b) History of severe hypersensitivity reaction to any monoclonal antibody c) Known hypersensitivity to Tocilizumab, Ipilimumab, or Nivolumab.
• •1. Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific circumstances a person who has been imprisoned may be included or permitted to continue as a participant.
• •2. Participants who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
• •Eligibility criteria for this study have been carefully considered to ensure the safety of the study participants and that the results of the study can be used. It is imperative that participants fully meet all eligibility criteria.