Phase I Study Investigating the Safety of Stereotactic Body Radiotherapy (SBRT) With Anti-PD1 and Anti-IL-8 for the Treatment of Multiple Metastases in Advanced Solid Tumors and Melanoma
Nivolumab (and other agents affecting the anti-programmed death-1 \[anti-PD-1\] pathway) have demonstrated anti-tumor activity in multiple tumor types. Combinations of immune-oncology (IO) agents with complimentary mechanisms as well as radiation represent a promising strategy to improve response rates to immunotherapy and overcome resistance. In this phase I/Ib study, radiation will be used in combination with IO agents nivolumab and anti-IL-8 (BMS-986253) to assess toxicity by organ system and then assess the preliminary efficacy of the treatment regimen. In Part 1, the study will determine the safe doses of radiation by organ site in conjunction with nivolumab and BMS-986253. In Part 2, the treatment regimen will be investigated in melanoma, prioritizing acral melanoma, to describe the response rate to treatment as well as other clinical and safety outcomes. The study will also provide the opportunity to evaluate changes in the tumor microenvironment induced by the treatment.
• SAFETY COHORT
‣ Patients with advanced/metastatic/unresectable solid tumors progressed on standard therapies. Patients with melanoma and RCC will make up approximately 30% of total cohort.
⁃ Patients with 1-4 tumor sites that can be irradiated safely
⁃ Age \> or equal 18 years
⁃ ECOG performance status 0 or 1
⁃ Patients must have normal organ and marrow function as defined below:
• Leukocytes ≥ 3000/mcL;
∙ absolute neutrophil count ≥ 1500/mcL;
∙ Platelets ≥ 100,000/mcL;
∙ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN) ;
∙ Total bilirubin ≤ 1.5 × ULN (except participants with Gilbert's Syndrome who must have normal direct bilirubin)
∙ Serum creatinine ≤ 1.5 × ULN Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non- nodal lesions and short axis for nodal lesions) as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam
⁃ Ability to understand and the willingness to sign a written informed consent document.
⁃ Reproductive status
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study treatment.
∙ Women must not be breastfeeding.
∙ WOCBP must agree to follow instructions for method(s) of contraception (Appendix 5) for the duration of study treatment plus 5 half-lives of nivolumab plus 30 days (duration of ovulatory cycle), for a total of 155 days post treatment completion. Local laws and regulations may require use of alternative and/or additional contraception methods.
∙ WOCBP who are continuously not heterosexually active are also exempt from contraceptive requirements, but should still undergo pregnancy testing as described in this section.
∙ Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception (Appendix4) during combination treatment with study treatment BMS-986253 and nivolumab, plus 5 half-lives of nivolumab (∼125 days), plus 90 days (duration of sperm turnover), for a total of 215 days post-treatment completion. In addition, male participants must be willing to refrain from sperm donation during this time.
• EFFICACY COHORT
‣ Patients with anti-PD1/PDL1 refractory melanoma
⁃ Patients with 1-4 tumor sites that can be irradiated safely
⁃ Age ≥ 18 years
⁃ ECOG performance status 0 or 1
⁃ Patients must have normal organ and marrow function as defined above for safety cohort
⁃ Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non- nodal lesions and short axis for nodal lesions) as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam
⁃ Ability to understand and the willingness to sign a written informed consent document.