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
detectable levels of IL-8 in the serum. 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 and detectable levels of IL-8 in the serum. 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 and RCC who progressed on
anti-PD-(L)1 therapy and have detectable levels of IL-8 in the serum.
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 and RCC and with serum IL-8 above the
lower limit of quantitation (LLOQ) will be enrolled into efficacy phase.
This proposal is intended to incorporate SBRT as a direct therapeutic which is in contrast
with other proposals evaluating response at distant sites after isolated metastasis
radiation. With this intent, the results of this study will be directly applicable to
potential expansion cohorts and ongoing clinical need.
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. Patients who have detectable serum IL-8 (> 10 pg/mL) at baseline
4. Age > or equal 18 years
5. ECOG performance status 0 or 1
6. 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
7. Ability to understand and the willingness to sign a written informed consent
document.
8. 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 or RCC.
2. Patients with 1-4 tumor sites that can be irradiated safely
3. Patients who have detectable serum IL-8 (> 10 pg/mL) at baseline
4. Age ≥ 18 years
5. ECOG performance status 0 or 1
6. Patients must have normal organ and marrow function as defined above for safety
cohort
7. 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
8. 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 randomization 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) 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 MIs OR two or more coronary revascularization
procedures 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
