Phase 2 Study of Ivonescimab in Patients With Cutaneous Squamous Cell Carcinoma

Inclusion Criteria:

• Ability to understand and willingness to sign informed consent form prior toinitiation 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 prostatewithout neuroendocrine differentiation or small cell histology.

• Documented prostate cancer progression as documented by PSA progressionaccording to PCWG3 criteria.

• Surgically or medically castrated, with serum testosterone level <50 ng/dL.

• Refractory or naïve to anti-PD-1 therapy (Cohort 1). There is no limit on the numberof prior lines of therapy. NOTE: Detailed information regarding duration of prioranti-PD-1 therapy and the extent of progression at the time of anti-PD-1 therapydiscontinuation will be collected.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 1).

• Cohort 1: measurable disease per the RECIST v1.1 or Measurable by mRECIST for skincancer or Global Assessment or Papillary/Ulceration Response Assessment orPathological Assessment or WHO Criteria for Response Assessment in CutaneousSquamous Cell Carcinoma, as appropriate (Appendix 4).

• Adequate organ and marrow function as defined below within 28 days of studytreatment initiation:

• Hemoglobin >9.0 g/dL

• Absolute neutrophil count ≥1500/mL

• Platelets ≥100,000/mL

• Total bilirubin ≤1.5 institutional upper limit of normal (ULN). DocumentedGilbert syndrome is allowed if total bilirubin is ≤3 × ULN.

• AST/alanine transaminase ≤2.5 × institutional ULN. Transaminases up to 3 × ULNin the presence of liver metastases.

• Serum creatinine ≤1.5 × ULN OR measured or calculated creatinine clearance (CrCl; glomerular filtration rate can also be used in place of creatinine orCrCl) ≥60 mL/min for participants with creatinine levels >1.5 × institutionalULN (CrCl should be calculated per institutional standard).

• Urine protein <2+ or 24-hour urine protein quantification <1.0 g

• For participants not receiving therapeutic anticoagulation: internationalnormalized ratio or activated partial thromboplastin time ≤1.5 × ULN. Forpatients receiving therapeutic anticoagulation: stable anticoagulant regimen.

• Albumin >2.5 mg/dL.

• Participants must have adequate washout from prior therapy at the time of studytreatment initiation: 4 weeks from major surgery; 4 weeks from antibody-basedtherapy; 2 weeks or 5 half-lives (whichever is shorter) from any targeted therapy orsmall molecule therapy; 3 weeks or 5 half-lives (whichever is shorter) fromchemotherapy or 6 weeks in the case of certain therapies (e.g., extensiveradiotherapy, mitomycin C, and nitrosoureas); 4 weeks from radiation therapy; and atleast 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 inantihypertensive medication within 7 days of Day 1 Cycle 1.

• Women of childbearing potential (WOCBP) should have a negative urine or serumpregnancy within 72 hours prior to study treatment initiation. If the urine test ispositive or cannot be confirmed as negative, a serum pregnancy test will berequired.

• WOCBP must agree to use adequate contraception during the study treatment period andfor 120 days after completion of study treatment. A woman is considered to be ofchildbearing potential if she is postmenarcheal, has not reached a postmenopausalstate (≥12 continuous months of amenorrhea with no identified cause other thanmenopause), and is not permanently infertile due to surgery (i.e., removal ofovaries, fallopian tubes, and/or uterus) or another cause as determined by theinvestigator (e.g., Müllerian agenesis). Should a woman become pregnant or suspectshe is pregnant while she or her partner is participating in this study, she shouldinform her treating physician immediately.

• Male participants of childbearing potential must agree to use adequate contraceptionduring the study treatment period and for 120 days after completion of studytreatment.

Exclusion Criteria:

• Patients who have previously been treated with PD-1/PD-L1 inhibitors and requiredpermanent discontinuation, or systemic immunosuppression due to irAEs.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to ivonescimab.

• Pregnant or breastfeeding.

• Participants with an active, known or suspected autoimmune disease. Participantswith type I diabetes mellitus, hypothyroidism only requiring hormone replacement,skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemictreatment, or conditions not expected to recur in the absence of an external triggerare permitted to enroll.

• Known history of positive test for human immunodeficiency virus or known acquiredimmunodeficiency 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 illnessrequiring hospitalization.

• Unresolved toxicities from prior therapy (defined as having not resolved to NCICTCAE v.5.0 Grade ≤1 or baseline) or any other toxicity that is deemed irreversibleby the investigator. Exceptions include endocrinopathies from prior therapy ordisease and successfully treated (such as hypothyroidism, diabetes mellitus),alopecia, vitiligo, and Grade ≤2 peripheral neuropathy.

• Major blood vessel invasion.

• Major surgical procedures or serious trauma within 4 weeks prior to study treatmentinitiation, or plans for major surgical procedures within 4 weeks after the firstdose of study treatment (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days priorto study treatment initiation.

• Unstable angina, myocardial infarction, congestive heart failure (New York HeartAssociation [NYHA] classification Grade ≥2) or vascular disease (e.g., aorticaneurysm at risk of rupture) that required hospitalization within 12 months prior tostudy treatment initiation, or other cardiac impairment that may affect the safetyevaluation of the study drug (e.g., poorly controlled arrhythmias, myocardialischemia).

• History of esophageal gastric varices, severe ulcers, wounds that do not heal,abdominal fistula, intra-abdominal abscesses, or acute gastrointestinal bleedingwithin 6 months prior to study treatment initiation.

• History of arterial thromboembolic event, venous thromboembolic event of Grade ≥3 asspecified in NCI CTCAE v5.0, transient ischemic attack, cerebrovascular accident,hypertensive crisis, or hypertensive encephalopathy within 6 months prior to studytreatment initiation.

• Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks prior tostudy treatment initiation.

• History of perforation of the gastrointestinal tract and/or fistula, history ofgastrointestinal obstruction (including incomplete intestinal obstruction requiringparenteral nutrition), extensive bowel resection (partial colectomy or extensivesmall bowel resection) within 6 months prior to study treatment initiation.

• Treatment with a live, attenuated vaccine within 4 weeks prior to study treatmentinitiation, or anticipation of need for such a vaccine during the course of thestudy.

• 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 withcooperation with the requirements of the study.

• Inability to comply with the study and follow-up procedures.

• Participants who are receiving any other investigational agents.

• Participants with psychiatric illness/social situations that would limit compliancewith study requirements.