Phase II Trial of Ivonescimab in Previously Treated Patients With Advanced Clear Cell Renal Cell Carcinoma

Eligibility Criteria

• 1. Participants must not have any other malignancies within the past 2 years except for in situ carcinoma of any site, or adequately treated (without recurrence post-resection or postradiotherapy) carcinoma of the cervix or basal or squamous cell carcinomas of the skin, ductal carcinoma in situ of the breast or low-risk early stage prostate adenocarcinoma with negligible risk of metastasis or death.
• 2. Major surgical procedures or serious trauma within 4 weeks prior to enrollment, or plans for major surgical procedures within 4 weeks after the first dose (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to enrollment.
• 3. Current hypertension with systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg after adequate oral antihypertensive therapy.
• 4. History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to enrollment, including but not limited to:
• * Nasal bleeding /epistaxis. Bloody nasal discharge is allowed.
• * Hematuria associated with urinary obstruction. Microhematuria or macrohematuria not associated with urinary obstruction are allowed.
• * Radiologically documented evidence of major blood vessel encasement with narrowing of the vessel that the investigator determines will pose a significantly increased risk of bleeding.
• 5. History of major diseases prior to enrollment, specifically:
• * Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association \[NYHA\] classification . grade 2) or vascular disease (eg, aortic aneurysm at risk of rupture) that required hospitalization within 12 months prior to randomization, or other cardiac impairment that may affect the safety evaluation of the study drug (eg, poorly controlled arrhythmias, myocardial ischemia)
• * History of esophageal gastric varices, severe ulcers, wounds that do not heal, abdominal fistula, intra-abdominal abscesses, or acute gastrointestinal bleeding within 6 months prior to enrollment.
• 6. History of arterial thromboembolic event, venous thromboembolic event of Grade 3 and above as specified in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to enrollment.
• * Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks prior to enrollment.
• * History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection) within 6 months prior to enrollment.
• 7. Symptomatic CNS metastases, leptomeningeal disease, CNS metastases with hemorrhagic features, CNS metastasis ≥ 1.5 cm, CNS radiation within 7 days prior to enrolmment, or potential need for CNS radiation within the first cycle of ivonescimab.
• 8. Active or prior history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic inflammatory diarrhea).
• 9. Participants who are receiving any other investigational agents.
• 10. Active autoimmune disease requiring systemic therapy (e.g., with disease modifying drugs, prednisone \>10 mg daily or equivalent, immunosuppressant therapy) within 2 years prior to enrollment. However the following will be allowed:
• * Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is permitted.
• * Intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections is permitted.
• 11. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• 12. Severe infection within 4 weeks prior to enrollment, including but not limited to comorbidities requiring hospitalization, severe sepsis, or severe pneumonia; active infection (as determined by the investigator) requiring systemic anti-infective therapy within 2 weeks prior to enrollment (excluding antiviral therapy for hepatitis B or C).
• 13. Uncontrolled pleural effusions, pericardial effusions, or ascites that is clinically symptomatic. Participants managed with indwelling catheters (e.g., PleurX) are allowed.
• 14. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ivonescimab or other agents used in study. This includes known history of severe hypersensitivity to other monoclonal antibodies.
• 15. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• 16. Participants with active hepatitis B are required to have stable or declining levels of hepatitis B DNA by polymerase chain reaction (PCR) on appropriate anti-viral therapy with acceptable tolerability for one month prior to enrollment. All patients with active hepatitis C (hepatitis C virus \[HCV\] antibody positive with HCV RNA levels above the lower limit of detection) are excluded.
• 17. Pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE version 5.0.
• 18. Pregnant women are excluded from this study because ivonescimab is a bispecific agent 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 ivonescimab, breastfeeding should be discontinued if the mother is treated with ivonescimab.
• 19. Participant is breastfeeding or plans to breastfeed during the study.
• 20. Participants with persistent grade ≥ 2 adverse events per NCI CTCAE v5.0 from prior systemic therapies that would confound timely detection of immune-related adverse events due to ivonescimab or otherwise hinder patient participation in the clinical trial.
• 21. History or current evidence of any condition (medical \[including adverse events from prior anticancer therapy, disorders secondary to tumor\], surgical or psychiatric \[including substance abuse\]), or laboratory abnormality that might confound the results of the study, interfere with the participants participation for the full duration of the study, might lead to higher medical risk and/or is not in the best interest of the patient to participate, in the opinion of the treating investigator