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.
This is a study of SBRT in combination with nivolumab and BMS-986253, a monoclonal antibody (mAb) against human interleukin-8 (IL-8), conducted in humans with advanced solid tumors. This study will evaluate the safety profile, tolerability and preliminary efficacy of SBRT in combination with BMS-986253 and nivolumab in participants with advanced solid tumors and then specifically in melanoma, focused on acral melanoma. The study will be conducted in 2 parts. Part 1 will evaluate the safety, tolerability of different doses of SBRT in combination with nivolumab (480 mg) and BMS-986253 (2400mg) every 2 weeks (Q2W) in participants with advanced solid tumors. This phase will begin with a cohort of participants who will receive a 2,400 mg flat dose of BMS-986253 Q2W combined with 480 mg flat dose of nivolumab Q4W along with SBRT (the dose is dependent on the irradiating organ). Part 2 will assess preliminary efficacy of SBRT in combination with nivolumab and BMS-986253 in participants with advanced/metastatic/unresectable melanoma, focusing on acral melanoma, who progressed on anti-PD-(L)1 therapy. This study aims to determine that safe doses will be found using ablative doses of SBRT with concurrent IO agents. Additional safety, tolerability and preliminary efficacy information in specific patient population will be gathered. Twenty participants with anti-PD-(L)1 refractory advanced/unresectable/metastatic melanoma, focusing on acral melanoma, will be enrolled into efficacy phase. Note: The Sponsor-Investigator/Study Principal Investigator of this trial is Yana Najjar, MD at the University of Pittsburgh/UPMC. The Sponsor-Investigator of this trial at University of Chicago is Steven Chmura MD, PhD The primary outcome measure, "Preliminary Estimate of the Response Rate to SBRT/Nivolumab/BMS986253 for Part II," was added to the ClinicalTrials.gov record after it was identified that this outcome had inadvertently not been entered during the initial registration process. This outcome was included in the original study protocol and has been a pre-specified primary objective for Part II since study inception. The update was made solely to align the ClinicalTrials.gov record with the approved protocol and does not represent a change to the study design, objectives, or planned analyses.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Nivolumab (BMS-936558-01), 480 mg intravenous (every 4 weeks) Treatment must be within 7 days of the last dose of radiation.
BMS-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) (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.
University of Chicago Medical Center
Chicago, Illinois, United States
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States
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.
Time frame: Up to 8 weeks after start of immunotherapeutic treatment
Response rate to SBRT/Nivolumab/BMS98625
Response to combination therapy and primary endpoint is ORR measured by RECIST v1.1 criteria.
Time frame: Up to 1 year from treatment initiation, assessed every 8 weeks.
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.
Time frame: Up to 1 year after start of immunotherapeutic treatment
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.
Time frame: Up to 3 years
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.
Time frame: Up to 3 years
Overall survival (OS)
Overall survival (OS) (of the cohort) which is defined as elapsed time from date of first treatment until date of death.
Time frame: Up to 3 years
Local tumor control (RECIST v1.1)
The total disappearance of the primary tumor and neighboring lymph node metastases without any local recurrence on long-term follow-up, per RECIST version 1.1. Complete response per RECIST v1.1 is the disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm.
Time frame: Up to 3 years
Local tumor control (irRECIST)
The total disappearance of the primary tumor and neighboring lymph node metastases without any local recurrence on long-term follow-up, by immune-related RECIST (irRECIST). Immune Complete Response (iCR) is the complete resolution of non-nodal lesions and \< 10 mm short-axis for lymph nodes. No confirmation necessary.
Time frame: Up to 3 years
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