Phase I-II Study of Intratumoral Urelumab Combined With Nivolumab in Patients With Solid Tumors

Inclusion Criteria

• •1. Written informed consent.
• •2. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing and other requirements of the study.
• •3. Patients must present the following tumor types:
• •1. For the phase I part, patients with any tumor type are eligible.
• •2. For the phase II part, two cohorts will be established:
• •i. Cohort A will include patients presenting tumor types with known sensitivity to Programmed cell death protein 1 (PD1)/ Programmed Death-ligand 1 (PDL1) blockade (e.g: melanoma, renal cancer, lung cancer, urothelial cancer, colorectal cancer presenting microsatellite instability (MSI), …). These patients must be naïve to PD1/PDL1 blockade.
• •ii. cohort B will include patients with PD1/PDL1 sensitive tumors that have progressed following previous PD1/PDL1 blockade (e.g: melanoma, NSCLC, renal cancer, bladder cancer ...). Additional treatments may be administered between prior PD1/PDL1 blockade and inclusion in the study, but if administered immediately before, a minimum wash-out period of four weeks must be observed between both treatments.
• •4. Patients must have received standard therapy, according to investigator´s criteria, or must be ineligible for standard therapy.
• •5. Patients must present at least one tumor lesion that is amenable to perform sequential intratumoral therapy and biopsies.
• •6. Measurable disease according to RECIST criteria. The measurable lesion(s) must be different than the lesion treated with intratumoral urelumab.
• •8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• •9. Life expectancy \>12 weeks.
• •10. Adequate organ function defined by:
• •1. Bone Marrow Reserve: white blood cells (WBC): \>=2000/ mm3 absolute neutrophil count (ANC) \>=1500x 109/L; platelet count \>=100000/ mm3 100 x 109/L; hemoglobin \>=9.0 g/dL).
• •2. Hepatic: bilirubin \<1.5 times the upper limit of normality (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<3.0 x ULN (BR\< 3 x ULN for patients with Gilbert´s Syndrome).
• •3. Renal: creatinine \<1.5 x ULN or estimated creatinine clearance \> 40 ml/min, using the Cokcroft-Gault formula.
• •11. Women of childbearing potential (WOCBP, i.e: fertile, following menarche and until becoming post-menopausal unless permanently sterile) must use a highly effective method to avoid pregnancy (i.e: combined estrogen and progestogen associated with inhibition of ovulation (oral, intravaginal or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable); intrauterine device; intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence for 23 weeks (30 days plus the time required for nivolumab and urelumab to undergo five half-lives) after the last dose of investigational drug.
• •12. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of treatment.
• •13. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception.
• •14. Patients must be at least 18 years old.