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
Medical History and Concurrent Diseases
Patients who are receiving any other investigational agents.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab and BMS-986253
Subjects with an active, known or suspected autoimmune disease. Subjects 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.
Single group
nivolumab
DrugNivolumab (BMS-936558-01), 480 mg intravenous (every 4 weeks) Treatment must be within 7 days of the last dose of radiation.
BMS-986253
DrugBMS-986253 (Anti-IL-8), 2,400 mg intravenous (every 2 weeks) Treatment must be within 7 days of the last dose of radiation.
Stereotactic Body Radiotherapy (SBRT)
RadiationStereotactic Body Radiotherapy (SBRT) (varying doses) SBRT: Initial Dose fractionation of 3 or 5 fractions of radiation as determined by the location of the metastases to be irradiated, to at least 1 but no more than 4 metastatic lesions. There will be a minimum of 40 hours between treatments for an individual metastasis. SBRT must be completed within a 14-day window, separate from the screening phase. Treatment with nivolumab and BMS-986253 must be within 7 days of the last dose of radiation.
Rate of Dose Limiting Toxicities (DLT)
The rate of Dose Limiting Toxicities (DLT) that are determined to be definitely, probably or possibly attributed to SBRT or one or both of the immunotherapies. Patients receiving one of more fractions of SBRT are evaluable for DLT. Toxicities include grade 3 or higher adverse events, by organ system, by Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
Incidence of grade 3 or higher adverse events
Incidence of grade 3 or higher adverse events, by organ system, per CTCAEv5.0, determined to be definitely, probably or possibly attributed to SBRT or one or both of the immunotherapies.
Objective Response
The proportion of patients that experience a Complete Response (CR) or Partial Response (PR) per RECIST v1.1. Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Progression-free survival (PFS)
The duration of time from first day of treatment until disease progression or date of death from any cause will be estimated with a 90% confidence interval. Progression as defined by RECIST v1.1 for target lesions: Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions: Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Overall survival (OS)
Overall survival (OS) (of the cohort) which is defined as elapsed time from date of first treatment until date of death.
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