This is a phase I study of combination immunotherapy with IFN-γ and the PD-1 inhibitor
nivolumab in patients with advanced solid tumors who have progressed on at least one prior
systemic therapy, which may include prior immunotherapy. Patients will be treated with a one
week induction phase (IP) of IFN-γ, followed by a combination phase (CP) with IFN-γ and
nivolumab for three cycles, followed by a single agent phase of only nivolumab for up to one
year. The study will primarily assess the safety and tolerability of the combination. Tumor
assessments will occur after three cycles of combination therapy, then every three cycles
thereafter. Secondary objectives including ORR, PFS, and OS will also be assessed, as will
various correlative analyses. Initial accrual will occur using a modified 6+6 design, and if
endpoints for safety (using DLT criteria) are met, expansion cohorts in RCC and UC will be
opened for up to 15 patients.
Inclusion Criteria:
1. Patients must have a histologically or cytologically confirmed metastatic solid tumor
that has shown clinical or pre-clinical evidence of responding to anti-PD-1 therapy or
the capacity to up-regulate PD-L1. These tumor types may include but may not be
limited to: RCC, UC, melanoma, non small cell lung cancer (NSCLC), small cell lung
cancer, squamous cell cancer of the head and neck (SCCHN), ovarian carcinoma, triple
negative breast cancer, gastric cancer, microsatellite instability expressing
(MSI-high) colon cancer, hepatocellular carcinoma, mesothelioma, gastrointestinal
stromal tumors, endometrial carcinoma, liposarcomas, chondrosarcomas, and uterine
sarcomas. Patients with solid tumor types not listed above may be enrolled at the
discretion of the Principal Investigator.
Note: Dose expansion phase will include two cohorts and consist of patients with
either metastatic UC or RCC, but must meet all other inclusion criteria.
2. All patients must have received at least one line of systemic therapy in the
metastatic setting. Prior immunotherapy is allowed, including prior treatment with
nivolumab or another PD-1 inhibitor, as long as the reason for discontinuation of a
prior PD-1 inhibitor was not for drug-related toxicity.
3. Patients must have measurable disease per RECIST criteria v. 1.1 as described in
detail in section 11.0.
4. Patients must have a site of disease that is amenable to pretreatment and on-treatment
core biopies. At least 3 formalin fixed, paraffin embedded (FFPE) slides at five
microns each may be collected at each biopsy. Determination of tissue accessibility
and quantity will be made by the consenting clinician. Patients must consent to the
two study-required biopsy procedures.
5. Age > 18 years.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
7. Patients must have normal organ and marrow function as defined below:
- Absolute neutrophil count > 1,500/mcL
- Platelets > 100,000/mcL
- Total bilirubin < 1.5 times the upper limit of normal (ULN), except patients with
Gilbert's syndrome in whom total bilirubin must be <3.0 mg/dL
- AST/ALT (SGOT/SGPT) < 3 times institutional normal limits
- Creatinine < 1.5 times the ULN OR Creatinine clearance > 40 mL/min (as measured
or calculated by Cockroft-Gault formula)
8. Ability to understand and willingness to sign a written informed consent and HIPAA
consent document.
Exclusion Criteria:
1. Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering
the study.
2. Patients may not have any active or recent history of a known or suspected autoimmune
disease or recent history of a syndrome that required systemic corticosteroids or
immunosuppressive medications, except for syndromes which would not be expected to
recur in the absence of an external trigger. Subjects with vitiligo, type I diabetes
mellitus, or residual hypothyroidism due to autoimmune thyroiditis only requiring
hormone replacement are permitted to enroll.
3. Any condition requiring systemic treatment with corticosteroids (> 10 mg daily
prednisone or equivalent) or other immunosuppressive medications within 14 days prior
to first dose of study drug. Inhaled or topical steroids and adrenal replacement
steroid doses > 10 mg daily prednisone or equivalent are permitted in the absence of
active autoimmune disease.
4. Patients may not be receiving any other investigational agents.
5. Patients with known active or symptomatic central nervous system (CNS) metastases
and/or carcinomatous meningitis. Asymptomatic, treated, and/or stable brain
metastases, as measured by subsequent radiologic evaluations at least two months
apart, are permitted.
6. History of allergic reactions attributed to compound of similar chemical or biologic
composition to the agent(s) used in this study.
7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that
would limit compliance with study requirements.
8. Known human immunodeficiency virus (HIV) positive or history of acquired immune
deficiency syndrome (AIDS) or AIDS-defining illness.
9. Known current or a history of hepatitis B or C virus, including chronic and dormant
states, unless disease has been treated and confirmed cleared.
10. Any medical condition that in the investigator's opinion could interfere with
interpretation of study or toxicity, or increase the risk to the patient related to
potential toxicity.
11. Major surgery within 4 weeks of initiation of study drug.
12. Pregnant or breast feeding. Refer to section 4.4 for further detail.
13. A second invasive malignancy requiring active treatment.
