Ivonescimab for the Treatment of Patients with Locally Advanced, Unresectable and/or Metastatic Cutaneous Squamous Cell Cancer and Metastatic Castration-resistant Prostate Cancer

Inclusion Criteria

• Ability to understand and willingness to sign informed consent form prior to initiation of the study and any study procedures
• Age ≥ 18 years
• Has locally advanced surgically non-appropriate (unresectable and/or metastatic) cSCC (Cohort 1)
• Has metastatic CRPC (Cohort 2): * Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell histology * Documented prostate cancer progression as documented by prostate specific antigen (PSA) progression according to Prostate Cancer Working Group 3 (PCWG3) criteria * Surgically or medically castrated, with serum testosterone level < 50 ng/dL
• Refractory or naive to anti–PD-1 therapy (Cohort 1). There is no limit on the number of prior lines of therapy. NOTE: Detailed information regarding duration of prior anti-PD-1 therapy and the extent of progression at the time of anti-PD-1 therapy discontinuation will be collected
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Cohort 1: Measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 or measurable by mRECIST for skin cancer or Global Assessment or Papillary/Ulceration Response Assessment or Pathological Assessment or World Health Organization (WHO) Criteria for Response Assessment in Cutaneous Squamous Cell Carcinoma, as appropriate
• Life expectancy ≥ 3 months per treating physician's discretion
• Hemoglobin > 9.0 g/dL (within 28 days of study treatment initiation)
• Absolute neutrophil count ≥ 1500/mL (within 28 days of study treatment initiation)
• Platelets ≥ 100,000/mL (within 28 days of study treatment initiation)
• Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is ≤ 3 x ULN (within 28 days of study treatment initiation)
• Aspartate aminotransferase (AST)/alanine transaminase ≤ 2.5 x institutional ULN. Transaminases up to 3 x ULN in the presence of liver metastases (within 28 days of study treatment initiation)
• Measured or calculated creatinine clearance (creatinine clearance [CrCl]; glomerular filtration rate [GFR] can also be used in place of CrCl) ≥ 45 mL/min (CrCl should be calculated per institutional standard. GFR should be calculated according to the 2021 Chronic Kidney Disease Epidemiology Collaboration equation or institutional standard) (within 28 days of study treatment initiation)
• Urine protein < 2+ or 24-hour urine protein quantification < 1.0 g (within 28 days of study treatment initiation)
• For patients not receiving therapeutic anticoagulation: international normalized ratio or activated partial thromboplastin time ≤ 1.5 x ULN (within 28 days of study treatment initiation)
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen (within 28 days of study treatment initiation)
• Albumin > 2.5 mg/dL (within 28 days of study treatment initiation)
• Patients must have adequate washout from prior therapy at the time of study treatment initiation: 4 weeks from major surgery; 4 weeks from antibody-based therapy; 2 weeks or 5 half-lives (whichever is shorter) from any targeted therapy or small molecule therapy; 3 weeks or 5 half-lives (whichever is shorter) from chemotherapy or 6 weeks in the case of certain therapies (e.g., extensive radiotherapy, mitomycin C, and nitrosoureas); 4 weeks from radiation therapy; and at least 2 weeks from palliative radiotherapy
• Prior treatment with anti-VEGF therapy is allowed (Cohort 1)
• Adequately controlled blood pressure with 0 or 1 antihypertensive medication (defined as blood pressure ≤ 150/100 mmHg at screening and no changes in antihypertensive medication within 7 days of day 1 cycle 1
• Women of childbearing potential (WOCBP) should have a negative urine or serum pregnancy within 72 hours prior to study treatment initiation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• WOCBP must agree to use adequate contraception during the study treatment period and for 120 days after completion of study treatment. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Mullerian agenesis). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Male patients of childbearing potential must agree to use adequate contraception during the study treatment period and for 120 days after completion of study treatment

Exclusion Criteria

• Patients who have previously been treated with PD-1/PD-L1 inhibitors and required permanent discontinuation, or systemic immunosuppression due to immune-related adverse events (irAEs)
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ivonescimab
• Pregnant or breastfeeding
• Patients with an active, known or suspected autoimmune disease. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Known history of positive test for human immunodeficiency virus or known acquired immunodeficiency syndrome
• Known history of acute or chronic hepatitis B virus or hepatitis C virus infection
• Previous solid organ or allogeneic hematopoietic stem cell transplant
• Active infection requiring IV antibiotics or other uncontrolled intercurrent illness requiring hospitalization
• Unresolved toxicities from prior therapy (defined as having not resolved to National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.5.0 grade ≤ 1 or baseline) or any other toxicity that is deemed irreversible by the investigator. Exceptions include endocrinopathies from prior therapy or disease and successfully treated (such as hypothyroidism, diabetes mellitus), alopecia, vitiligo, and grade ≤ 2 peripheral neuropathy
• Radiologically documented evidence of major blood vessel invasion (e.g., aorta, central veins), or encasement by cancer (e.g., heart, trachea, esophagus), if poses a significant increased risk of bleeding, or intratumor cavitation
• Major surgical procedures or serious trauma within 4 weeks prior to study treatment initiation, or plans for major surgical procedures within 4 weeks after the first dose of study treatment (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to study treatment initiation
• Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association [NYHA] classification grade ≥ 2) or vascular disease (e.g., aortic aneurysm at risk of rupture) that required hospitalization within 12 months prior to study treatment initiation, or other cardiac impairment that may affect the safety evaluation of the study drug (e.g., 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 study treatment initiation
• History of arterial thromboembolic event, venous thromboembolic event of grade ≥ 3 as specified in NCI CTCAE v5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 6 months prior to study treatment initiation
• Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks prior to study treatment initiation
• 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 study treatment initiation
• Treatment with a live, attenuated vaccine within 4 weeks prior to study treatment initiation, or anticipation of need for such a vaccine during the course of the study
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer
• Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
• Inability to comply with the study and follow-up procedures
• Patients who are receiving any other investigational agents
• Patients with psychiatric illness/social situations that would limit compliance with study requirements