Ivonescimab for the Treatment of Metastatic or Recurrent Endometrial Cancer and Cervical Cancer

Inclusion Criteria

• Histologically confirmed metastatic/recurrent endometrial or cervical cancer that has progressed after treatment with at least one platinum-based regimen * Endometrial cancer histologies can include: endometrioid, serous, clear cell, dedifferentiated undifferentiated, mixed epithelial, adenocarcinoma not otherwise specified (NOS), and carcinosarcoma * Cervical cancer histologies can include: squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma
• Measurable disease per RECIST v 1.1 criteria
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2
• All patients must have received at least 1 line of platinum-based therapy. Prior PD1 or VEGF therapy is allowed
• Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP ≤ 160/90 mmHg
• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (≥ 1.5 x 103/uL)
• Platelets ≥ 100,000/uL
• Hemoglobin ≥ 9.0 g/dL
• International normalized ratio (INR) ≤ 1.5
• Creatinine clearance (CrCl) ≥ 50 mL/min using the Cockcroft-Gault formula
• Urine protein < 2+ (or 24 hour urine protein quantification < 1.0 g)
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x ULN may be enrolled)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN for participants with liver metastases)
• Thyroid-stimulating hormone (TSH) within normal limits. If TSH is not within normal range despite no symptoms of thyroid dysfunction, normal free T4 level is required
• Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 x ULN, and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (unless abnormalities are unrelated to coagulopathy, or prophylactic coagulation
• Age ≥ 18 years at the time of informed consent
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS) directed therapy shows no evidence of progression. Patients with treated brain metastasis should be excluded if they have any evidence of bleeding, or if they have large lesions at risk of bleeding ie > 1.5cm. Patients should also be off corticosteroids at the time of enrollment. Patients with untreated brain metastasis are excluded
• Not pregnant and not nursing. If with childbearing potential, should have a negative urine pregnancy test at the time of screening
• Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 120 days after the last dose of the ivonescimab
• Must have clinical IMPACT data available, if data is not available, must have adequate tissue to available for clinical IMPACT. Patient will consent to 12-245 at enrollment if not previously completed
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

Exclusion Criteria

• 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
• Patient not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy
• 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: * Gastrointestinal bleeding * Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots) Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed * Nasal bleeding /epistaxis (bloody nasal discharge is allowed) * Need for new therapeutic anticoagulant therapy within 14 days prior to enrollment ** Note: Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that is not stable prior to randomization is not allowed. The use of full-dose anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution
• History of major diseases before enrollment, specifically: * Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association [NYHA] classification ≥ grade 2) or vascular disease that required hospitalization within 12 months prior to enrollment, 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 before enrollment * History of arterial thromboembolic event, venous thromboembolic event, , transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 6 months prior to enrollment * Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks before 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
• Imaging during the screening period shows that the patient has: * Radiologically documented evidence of major blood vessel invasion or encasement by cancer * Radiographic evidence of intratumor cavitation
• Has participated in a study of an investigational agent and/or received cancer directed study therapy within 4 weeks prior to start of study treatment
• Prolongation of corrected QT interval (QTc) interval to > 480 msec
• Active/Acute hepatitis B infection * Note: Patients with chronic hepatitis B virus (HBV) infection with active disease who meet the criteria for anti HBV therapy should require the patient be on a suppressive antiviral therapy prior to initiation of cancer therapy
• Active/acute hepatitis C infection * Note: Patients who are hepatitis C virus (HCV) antibody (Ab) positive but HCV ribonucleic acid (RNA) negative due to prior treatment or natural resolution should be eligible
• Known intolerance to either of the study drugs (or any of the excipients)
• History of organ allograft (subject has had an allogenic tissue/solid organ transplant)
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 10 mg/d of prednisone or equivalent) may be approved after consultation with the study principal investigator (PI) or Co-PI
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis
• Patient with any prior immune related events (immune-related adverse events [irAE]) grade 3 or higher that resulted in discontinuing or significant delay of dosing of immunotherapy
• Has received a live-virus vaccination within 30 days of planned treatment start