Zanzalintinib for Metastatic Clear Cell Renal Cell Carcinoma With Bone Metastases

Exclusion Criteria

• •1. Prior treatment with zanzalintinib for RCC.
• •2. Receipt of any small molecule kinase inhibitor (including investigational) or vascular endothelial growth factor (VEGF)-targeted therapy within 2 weeks before the first dose of study treatment.
• •3. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Note: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of enrollment. Note: Base of skull lesions without definitive evidence of dural or brain parenchymal involvement are allowed.
• •4. Participants requiring whole brain radiotherapy (WBRT).
• •5. Incomplete healing from prior radiotherapy as determined by the treating radiation oncologist or treating investigator.
• •6. Participation in an experimental drug study within 28 days of study enrollment.
• •7. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
• •8. Pregnant and lactating women are excluded from this study because zanzalintinib is an investigational product with 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 with zanzalintinib, breastfeeding should be discontinued if the mother is treated with zanzalintinib.
• •9. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Cycle 1, Day 1.
• •10. Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation); Clinically significant hematuria, hematemesis, or hemoptysis of \>0.5 tsp (2.5ml) of red blood or other history of significant bleeding within 12 weeks before first dose of study treatment.
• •11. Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding.
• •12. Evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
• •13. Concomitant anticoagulation with coumarin agents, direct thrombin inhibitors, factor Xa inhibitor betrixaban, or platelet inhibitors. Other anticoagulants are allowed.
• •1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
• •2. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen.
• •ii. Participants with known brain metastases and who are taking prophylactic low-dose aspirin for cardioprotection or low-dose (prophylactic-dose) low molecular weight heparin are eligible.
• •Note: Subjects must have discontinued oral anticoagulants within 3 days or 5 half-lives prior to first dose of study treatment, whichever is longer.
• •14. Previously identified allergy or hypersensitivity to components of the treatment.
• •15. Malignancy that requires anti-cancer directed therapy within the last 3 years. Exceptions include those cancers that are considered cured by local therapy (e.g. Basal cell carcinoma, squamous cell carcinoma, ductal carcinoma in situ of breast, bladder, or cervix) or other cancers that have low malignant potential and do not require systemic therapy (e.g. Gleason grade \<6 prostate adenocarcinoma).
• •16. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.
• •18. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Note: Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of enrollment. Note: Base of skull lesions without definitive evidence of dural or brain parenchymal involvement are allowed.
• •19. Any complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment.
• •20. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• •1. Congestive heart failure New York Heart Association Class 3 or 4, class 2 or higher, unstable angina pectoris, new-onset angina, serious cardiac arrhythmias (e.g., ventricular flutter, ventricular fibrillation, Torsades de pointes).
• •2. Uncontrolled hypertension defined as sustained blood pressure (BP) \> 140 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment.
• •3. Stroke (including transient ischemic attack (TIA)), myocardial infarction, or other clinically significant arterial thrombotic and/or ischemic event within 6 months before first dose of study treatment.
• •4. Pulmonary embolism (PE) or deep vein thrombosis (DVT) or prior clinically significant venous events within 3 months before first dose of study treatment.
• •Note: Subjects with a diagnosis of DVT within 6 months are allowed if asymptomatic and stable at screening and are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen.
• •Note: Subjects who don't require prior anticoagulation therapy may be eligible but must be discussed and approved by the Principal Investigator.
• •5. Prior history of myocarditis.
• •6. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
• •i. Tumors invading the GI-tract from external viscera. ii. Active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or acute pancreatitis.
• •iii. Acute obstruction of the bowel, gastric outlet, or pancreatic or biliary duct within 6 months before first dose unless cause of obstruction is definitively managed and subject is asymptomatic.
• •iv. Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment.
• •v. Known gastric or esophageal varices. vi. Ascites, pleural effusion, or pericardial fluid requiring drainage in last 4 weeks.
• •21. Clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose of study treatment.
• •22. Symptomatic cavitating pulmonary lesion(s) or endobronchial disease (asymptomatic or radiated lesions allowed).
• •23. Lesions invading major blood vessel including, but not limited to, inferior vena cava, pulmonary artery, or aorta. Note: Subjects with intravascular tumor extension (e.g., tumor thrombus in renal vein or inferior V. cava) may be eligible following Principal Investigator approval.
• •24. Other clinically significant disorders that would preclude safe study participation.
• •1. Active infection requiring systemic treatment. Note: Prophylactic antimicrobial treatments (antibiotics, antimycotic, antiviral) are allowed.
• •2. Known infection with acute or chronic hepatitis B or C, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness except for subjects meeting all of the following criteria: (1) on stable anti-retroviral therapy; (2) Cluster of differentiation 4 positive (CD4+) T cell count ≥ 200/µL; and (3) an undetectable viral load. Note: HIV testing will be performed at screening if and as required by local regulation. Note: To be eligible, participants taking Cytochrome P450, family (CYP) inhibitors (e.g., zidovudine, ritonavir, cobicistat, didanosine) or Cytochrome P450, family 3 (CYP3) inducers (efavirenz) must change to a different regimen not including these drugs 7 days prior to initiation of study treatment. Anti-retroviral therapies (ART) must have been received for at least 4 weeks prior to the first dose. Note: CD4+ T cell counts, and viral load are monitored per standard of care by the local health care provider.
• •3. Serious non-healing wound/ulcer/bone fracture. Note: non-healing wounds or ulcers are permitted if due to tumor-associated skin lesions.
• •i. Complete healing of intra-abdominal abscess must be confirmed before the first dose of study treatment d. Malabsorption syndrome. e. Pharmacologically uncompensated, symptomatic hypothyroidism. f. Moderate to severe hepatic impairment (Child-Pugh B or C). g. Requirement for hemodialysis or peritoneal dialysis. h. History of solid organ or allogeneic stem cell transplant.
• •25. Major surgery (as defined in Section 6.6.2.3; e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks prior to first dose of study treatment. Prior laparoscopic surgeries (i.e. nephrectomy) within 4 weeks prior to first dose of study treatment. Minor surgery (e.g., simple excision, tooth extraction) within 5 days before first dose of study treatment. Complete wound healing from major or minor surgery must have occurred at least prior to first dose of study treatment.
• •26. Corrected QT interval calculated by the Fridericia formula (QTcF) \> 480 ms within 14 days per electrocardiogram (ECG) before first dose of study treatment.
• •Note: Triplicate ECG evaluations will be performed and the average of these 3 consecutive results for QTcF will be used to determine eligibility.
• •27. History of psychiatric illness likely to interfere with ability to comply with protocol requirements or give informed consent.
• •28. Patients who are ineligible for CT contrast AND who are unable to undergo MRI for any reason.
• •29. Inability to swallow tablets or ingest a suspension either orally or by a nasogastric (NG) or gastrostomy (PEG) tube.
• •30. Other conditions, which in the opinion of the Investigator, would compromise the safety of the participant or the participant's ability to complete the study.