STING Agonist (IMSA101) and Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy with Nivolumab for the Treatment of Stage IV Renal Cell Carcinoma in Patients who Progressed on Immunotherapy, SPARK Trial

Inclusion Criteria

• Metastatic (American Joint Committee on Cancer [AJCC] stage IV) clear cell renal cell carcinoma patients
• Previously treated with anti-CTLA4 and anti-PD-1 regimen (e.g. nivolumab and ipilimumab or botensilimab/balstilimab) for at least 2 cycles and eligible to continue anti-PD-1 monotherapy (or currently on anti-PD-1 monotherapy) with oligoprogression
• Oligoprogressive disease (1-3 progressing lesions) that are all amenable to radiation including one lesion suitable for IMSA101 injection within 6 months of completion of anti-CTLA4 and anti-PD-1 combination therapy
• Karnofsky performance status (KPS) of at least 80%
• Life expectancy of at least 6 months
• Patients with favorable, intermediate and poor risk categories will be eligible for the study. Patients must be categorized according to favorable versus intermediate/poor risk status at registration. International Metastatic RCC Database Consortium (IMDC) must be used to determine prognostic factors
• Age ≥ 18 years
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
• Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria

• Prior high-grade toxicity from anti-CTLA4 and anti-PD-1 deemed to place the patient at high risk for toxicity recurrence with nivolumab (Nivo) alone
• Prior STING agonist use
• Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalent) 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
• Progression in > 3 lesions
• Sites of progression not amenable to the safe administration of SAbR. Patients with progressive ultracentral/central chest lesions will be excluded
• Patients must have at least one site of disease that can be safely injected with IMSA101. Lung metastases are excluded
• Anticoagulation is not allowed, if it cannot be held to ensure safe intratumoral injections
• 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 that may require systemic therapy or is perceived to potentially affect patient life expectancy
• Acute or chronic hepatitis B or hepatitis C
• Immunocompromised patients or patients with AIDS. HIV positive patients with normal CD4 counts on highly active antiretroviral therapy (HAART) are allowed
• 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
• Uncontrolled brain metastasis or leptomeningeal disease. Subjects with previously treated brain or central nervous system (CNS) metastases are eligible provided that the subject has recovered from any acute effects of radiotherapy and is not requiring steroids and that stereotactic radiosurgery was completed at least 2 weeks prior to study drug administration
• White blood cell (WBC) < 2,000/mm^3
• Neutrophils < 1,000/mm^3
• Platelets < 50,000/mm^3
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (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)
• Estimated creatinine clearance < 30 mL/min
• History of allergic reactions attributed to nivolumab
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements
• Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants