A Phase II Study of Zanzalintinib for Metastatic Clear Cell Renal Cell Carcinoma With Bone Metastases in Patients Previously Treated With Immune Checkpoint Inhibitors
This is a single-institution, phase 2 trial of zanzalintinib plus investigator-choice bone-strengthening agent in patients with metastatic renal cell carcinoma (RCC) with bone metastases whose disease has advanced on 1-3 prior lines of therapy, including at least one immune oncology-based (IO) therapy in the adjuvant or first-line metastatic setting.
• Participants must have unresectable advanced or metastatic RCC with a predominant clear cell histologic component .
• At least three bone metastases are present and detectable on bone scan, and at least one bone metastasis is NOT planned to be treated with radiation therapy.
• Previously treated with 1-3 prior lines of therapy in at least one of the following settings:
∙ Metastatic setting; must have received combination therapy containing either programmed cell death protein 1 (PD-1) inhibitor/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor or PD-1 inhibitor/vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitors (TKI).
‣ Adjuvant setting; must have received pembrolizumab and have had documented progression of disease within 1 year of the first dose of pembrolizumab .
• Age ≥18 years.
• Has seen a dentist within 90 days prior to enrollment and been cleared to receive bone-strengthening agents.
• Availability of a representative formalin fixed, paraffin embedded tumor specimen or fresh frozen tissue specimen that enables the definitive diagnosis of RCC, accompanied by an associated pathology report. If stored specimens are not available, an optional biopsy may be performed and specimens can be collected by surgical resection or biopsy of the primary tumor or biopsy or resection of a metastatic lesion.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Demonstrates adequate organ function as defined below within 14 days prior to first study treatment:
∙ Absolute neutrophil count (ANC) \>=1,500/ μL (without granulocyte colony stimulating factor support within 2 weeks prior to Cycle 1, Day 1).
‣ Platelets ≥100,000/ μL (without transfusion within 2 weeks prior to Cycle 1, Day 1).
‣ White Blood Cell count (WBC) counts ≥ 2500/μL.
‣ Lymphocyte count ≥ 500/μL.
‣ Hemoglobin ≥9.0 g/dL.
∙ Participants may be transfused or receive erythropoietic treatment to meet this criterion:
‣ Serum bilirubin ≤ 1.5 x upper limit of normal (ULN). Participants with known Gilbert disease who have serum bilirubin level \<= 3 x ULN may be enrolled.
‣ Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) ≤2.5 X institutional upper limit of normal.
‣ Alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase (SGPT) ≤2.5 X institutional upper limit of normal.
‣ Alkaline phosphatase ≤2.5 X institutional upper limit of normal. For participants with documented liver metastases: AST and/or ALT ≤ 5 x ULN. For participants with documented liver or bone metastases: alkaline phosphatase ≤ 5 x ULN.
∙ Creatinine ≤ 1.5 x within institutional upper limit of normal OR creatinine clearance ≥ 40 mL/min by institutional standard AND urine protein-creatinine ratio (UPCR) 1mg/mg.
∙ International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN. This applies only to participants who are not receiving therapeutic anticoagulation; participants receiving therapeutic anticoagulation should be on a stable dose.
∙ Serum ionized calcium above lower limit of normal and ≤ 1.5 x ULN.
• If any Grade ≥1 toxicities occurred in relation to prior treatment, patients must have recovered to baseline or ≤ Grade 1 unless adverse events are clinically insignificant or stable on supportive medication if needed.
⁃ Ability to understand and the willingness to sign a written informed consent document.
⁃ Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
⁃ For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
⁃ Individuals with a history of hepatitis C virus (HCV) infection must have been treated and cured. For individuals with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
⁃ Sexually active fertile subjects and their partners must agree to use highly effective method of contraception (defined in Appendix 4) during the course of the study and for the following durations after the last dose of treatment (whichever is later). An additional contraceptive method, such as a barrier method (e.g., condom), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods.
⁃ a. Through 186 days after the last dose of zanzalintinib for women of childbearing potential (WOCBP) or through 96 days after the last dose of zanzalintinib for men.
⁃ Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman \> 45 years-of-age in the absence of other biological or physiological causes. In addition, females \< 55 years-of-age must have a serum follicle stimulating hormone (FSH) level \> 40 milli-international units per millilitre (mIU/mL) to confirm menopause). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff. Exception: women who are not postmenopausal (12 months of amenorrhea) or surgically sterile (absence of ovaries and/or uterus).