To determine safety of stereotactic body radiation therapy (SBRT) in presence of ICB in
patients with advanced unresectable melanoma. Toxicity will be deemed acceptable if the rate
of Grade 3+ adverse events (CTC v4) is ≤ 33%, with relevant AEs defined as either of the
following occurring between the start of SBRT and 12 weeks following SBRT completion:
- Any grade 3-5 metabolic or hematological toxicity that is related, probably related or
possibly related to nivolumab or SBRT.
- Any grade 3-5 non-hematological toxicity that is related, probably related or possibly
related to SBRT.
Secondary Endpoints:
• To determine whether SBRT results in a clinical abscopal effect on unirradiated lesions.
The hypothesized rate of abscopal effect is >14%.
Exploratory Correlative studies:
- In select patients for whom TCRseq reveals clonal expansion in non-irradiated tumor and
serial blood specimens, the relevance of such expansion to tumor-specific responses will
be investigated using mutation-associated neoantigens (MANAFEST) assays.
- Serial stool specimens will be studied to correlate potential changes in microbiome with
abscopal effect.
- To determine whether SBRT promotes clonal expansion of melanoma-specific T-cells, in
both peripheral blood and within TME of non-irradiated lesions.
- To determine whether TCR clonal expansion correlates with clinically observed abscopal
response.
- To identify additional immunological biomarkers in the non-irradiated (abscopal) TME
using intratumoral gene expression profiling to assess for induction and upregulation of
a Type I IFN signature among responders1-3. IHC in TME will be used to characterize
modulation of immune cell populations pre- and post-SBRT, and to assess correlation of
PD-L1 and other immune-checkpoint receptor expression with responsiveness to SBRT and
changes in TME post-SBRT.
Inclusion Criteria:
- Signed Written Informed Consent
- Willing and able to provide informed consent
- Age ≥ 18 years
- Target Population
- Histological confirmation of melanoma
- Advanced unresectable (AJCC Stage III or IV) disease (cutaneous, mucosal, acral or
ocular)
- Stable disease or progression (RECIST 1.1) after anti-PD-1 monotherapy (≥ 16 weeks and
≥ 2 CT assessments). The maximum time period off anti-PD-1 monotherapy, prior to
protocol therapy, cannot exceed 2 months.
- Prior systemic treatment regimen in the advanced/metastatic setting is allowed (BRAF
inhibitor, chemotherapy, cytokine/biologic therapy or clinical trial)
- Prior treatment with anti-CTLA-4 checkpoint inhibitor is allowed
- Minimum of 2 or more measurable lesions by RECIST 1.1, with at least 1 lesion
accessible for clinical, US, or CT-guided needle biopsy. If 2 lesions, then one of
those must measure 4cm in maximum diameter and be amenable for biopsy; this lesion
will be utilized for abscopal effect determination as well. Otherwise, if 3 or more
lesions are present, one lesion will receive SBRT, 2nd lesion will be used for
radiographic abscopal response assessment, and 3rd lesion will be used for pre- and
post-treatment biopsies.
- ECOG Performance Status of 0-1
Exclusion Criteria:
- Target Disease Exceptions
- Prior radiation within 6 months of enrollment (excluding brain metastases), or at any
time to one of the 3 lesions for treatment/assessment
- If patient has >1 lesion which requires immediate/urgent management with RT due to
present or impending clinical consequences (uncontrolled pain, risk of loss of
function), such a patient will not be enrolled on this trial
- Medical History and Concurrent Diseases
- Major toxicity from prior anti-PD-1 which precludes continuation of anti-PD-1
therapy.
- Pregnancy or inability to use contraception (if childbearing age)
- Any active or recent history of a known or suspected autoimmune disease or recent
history of a syndrome that required systemic corticosteroids (> 10 mg daily
prednisone equivalent) or immunosuppressive medications except for syndromes
which would not be expected to recur in the absence of an external trigger.
Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due
to autoimmune thyroiditis only requiring hormone replacement are permitted to
enroll. Patients with psoriasis not requiring active, systemic treatment are
allowed.
- Any condition requiring systemic treatment with corticosteroids (> 10 mg daily
prednisone equivalents) or other immunosuppressive medications within 14 days
prior to first dose of study drug. Inhaled steroids and adrenal replacement
steroid doses up to 10 mg daily prednisone equivalents are permitted in the
absence of active autoimmune disease
- Uncontrolled adrenal insufficiency
- Requirement for anti-coagulation with Coumadin, low molecular weight heparin and
anti-thrombin inhibitors will be accepted if anticoagulation has been stable for
at least 4 weeks and no recent history of prior bleeding complications.
- Prior malignancy active within the previous 3 years except for locally curable
cancers that have been apparently cured such as basal or squamous cell skin
cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast or
low risk Gleason 6 prostate cancer
- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS); Any positive test for hepatitis B or
hepatitis C virus indicating acute or chronic infection
- Known medical condition (e.g., a condition associated with diarrhea or acute
diverticulitis) that, in the investigator's opinion, would increase the risk
associated with study participation or study drug administration or interfere
with the interpretation of safety results
- Major surgery (i.e., nephrectomy) less than 28 days prior to the first dose of
study drug
- Anti-cancer therapy less than 14 days prior to the first dose of study drug or
palliative, focal radiation therapy less than 14 days prior to the first dose of
study drug
- Presence of any toxicities attributed to prior immunotherapy, other than
alopecia, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before
administration of study drug
- Physical and Laboratory Test Findings: Any of the following laboratory test findings:
- WBC < 2,000/mm3
- Neutrophils < 1,500/mm3
- Platelets < 100,000/mm3
- AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
- Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
total bilirubin < 3.0 mg/dL)
- Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40
mL/min (measured or calculated by Cockroft-Gault formula)
- Allergies and Adverse Drug Reaction: History of severe hypersensitivity reaction to
any monoclonal antibody or study drug components
- Other Exclusion Criteria
- Prisoners or subject who are involuntarily incarcerated
- Not suitable for SBRT treatment
- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical illness
