Safety of SBRT With Anti-PD1 and Anti-IL-8 for the Treatment of Multiple Metastases in Advanced Solid Tumors and Melanoma

NCT ID: NCT04572451

Last Updated: 2025-08-01

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-29
• Study Completion Date: 2027-05-31

Brief Summary

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.

Detailed Description

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

Conditions

Melanoma; Unresectable Solid Tumors; Neoplasms; Neoplasms by Histologic Type; Neoplasms by Site; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Nivolumab

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Nivolumab (Anti-PD-1) + BMS-986253 (Anti-IL-8) + SBRT

480 mg intravenous nivolumab (BMS-936558-01) every 4 weeks + 2,400 mg intravenous BMS-986253 (Anti-IL-8) every 2 weeks + Stereotactic Body Radiotherapy (SBRT)

Group Type: EXPERIMENTAL

nivolumab

Intervention Type: DRUG

Nivolumab (BMS-936558-01), 480 mg intravenous (every 4 weeks)

Treatment must be within 7 days of the last dose of radiation.

BMS-986253

Intervention Type: DRUG

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)

Intervention Type: 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.

Interventions

nivolumab

Nivolumab (BMS-936558-01), 480 mg intravenous (every 4 weeks)

Treatment must be within 7 days of the last dose of radiation.

Intervention Type: DRUG

BMS-986253

BMS-986253 (Anti-IL-8), 2,400 mg intravenous (every 2 weeks)

Treatment must be within 7 days of the last dose of radiation.

Intervention Type: DRUG

Stereotactic Body Radiotherapy (SBRT)

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.

Intervention Type: RADIATION

Other Intervention Names

Opdivo®; Anti-PD-1; Anti-IL-8

Eligibility Criteria

Inclusion Criteria

• SAFETY COHORT

1. Patients with advanced/metastatic/unresectable solid tumors progressed on standard therapies. Patients with melanoma and RCC will make up approximately 30% of total cohort.

2. Patients with 1-4 tumor sites that can be irradiated safely

3. Age > or equal 18 years

4. ECOG performance status 0 or 1

5. 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

6. Ability to understand and the willingness to sign a written informed consent document.

7. 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

1. Patients with anti-PD1/PDL1 refractory melanoma

2. Patients with 1-4 tumor sites that can be irradiated safely

3. Age ≥ 18 years

4. ECOG performance status 0 or 1

5. Patients must have normal organ and marrow function as defined above for safety cohort

6. 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

7. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

1. Known or suspected CNS metastases, with the following exceptions:

a) Subjects with controlled brain metastases will be allowed to enroll. Controlled brain metastases are defined as no radiographic progression for at least 4 weeks following 18 radiation and/or surgical treatment at the time of randomization. b) Subjects must be off steroids for at least 2 weeks prior to initiation of investigational therapy c) Subjects with signs or symptoms of brain metastases are not eligible unless brain metastases are ruled out by computed tomography or magnetic resonance imaging.

2. 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.
• Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:

i. Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent ii. Uncontrolled angina within the 3 months prior to consent iii. Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, torsades de pointes, or poorly controlled atrial fibrillation) within a month prior to consent iv. QTc prolongation > 480 msec v. History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, poorly controlled deep venous thrombosis, etc) vi. Cardiovascular disease-related requirement for daily supplemental oxygen vii. History of two or more coronary revascularization procedures within the 3 months prior to consent viii. Subjects with history of myocarditis, regardless of etiology

• A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
• Subjects with history of life-threatening toxicity related to prior immune therapy (eg. anti-CTLA-4 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 (eg, hormone replacement after endocrinopathy).
• Subject has been administered prior chemotherapy or immunotherapy at any time, and any with radiation therapy within 4 weeks prior to time of consent or who has not recovered (ie, ≤ Grade 1 or at baseline) from adverse events due to previously administered agent.

1. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.

2. Subjects with endocrinopathy which is adequately controlled with hormone replacement therapy are an exception to this criterion and may qualify for the study.

• If subject underwent major surgery, subject must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Subject has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• A known or underlying medical condition that, in the opinion of the investigator could make the administration of study drug hazardous to the subject or could adversely affect the ability of the subject to comply with or tolerate study therapy.
• Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated with the study drugs.
• Subjects who are unable to undergo venipuncture and/or tolerate venous access
• Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal therapy ≤ 7 days prior to initiation of study drug therapy
• Subjects who are on immunosuppressive therapy (systemic steroids 10mg and more daily use)
• Prisoners or subjects who are involuntarily incarcerated
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• Inability to comply with restrictions and prohibited activities and treatments

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

Yana Najjar

OTHER

Sponsor Role: lead

Responsible Party

Yana Najjar

Associate Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Yana Najjar, MD, FACP

Role: PRINCIPAL_INVESTIGATOR

UPMC Hillman Cancer Center

Locations

University of Chicago Medical Center

Chicago, Illinois, United States

Site Status: RECRUITING

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Danielle L Bednarz, BSN

Role: CONTACT

bednarzdl@upmc.edu

412-623-1191

Amy Rose, BSN

Role: CONTACT

kennaj@upmc.edu

412-647-8587

Facility Contacts

Robyn Hseu, RN

Role: primary

rdeneau1@bsd.uchicago.edu

Danielle L Bednarz, BSN

Role: primary

bednarzdl@upmc.edu

412-623-1191

Amy L Rose, BSN

Role: backup

kennaj@upmc.edu

412-647-8587

Other Identifiers

HCC 20-228

Identifier Type: -

Identifier Source: org_study_id