Cervical Cancer Clinical Trials

∙ Participants must meet all the following inclusion criteria to be eligible for participation in this study:

• Signed the informed consent form voluntarily and agreed to follow the program requirements.

• Either sex

• Age: ≥18 years

• Life expectancy of ≥3 months

• For Dose Escalation and Dose Finding: Documented locally advanced or metastatic HER2-expressing (IHC 1+ to 3+ and/or HER2 gene amplification or activating mutation \[see Table 17-5\] in tumor specimen by ISH or NGS) solid tumor(s) not amenable to curative surgery or radiation and has received at least 2 lines of standard therapy, including adjuvant/neoadjuvant treatment, or whose cancer is considered refractory to the standard of care or for which no standard treatment is available, including:

∙ Cohort 1: Participants with HER2 expression in endometrial cancers

‣ Cohort 2: Participants with HER2 expression in cervical cancers

‣ Cohort 3: Participants with HER2 expression in ovarian cancers, including fallopian tube cancer and primary peritoneal cancer

‣ Cohort 4: Participants with HER2 expression in urothelial cancers

‣ Cohort 5: Participants with HER2 expression in biliary tract cancers

‣ Cohort 6: Participants with HER2 expression in breast cancer

‣ Cohort 7: Participants with HER2 expression in lung cancer

‣ Cohort 8: Participants with HER2 expression in gastric, esophageal, or gastroesophageal junction (GEJ) cancers

‣ Cohort 9: Participants with HER2 expression in other solid tumors as approved by the medical monitor Note: For indications in which a HER2-directed therapy is approved, the approved treatment is recommended although not mandated, at the discretion of the investigator.

• Agree to provide most recent existing tumor samples (formalin-fixed paraffin-embedded \[FFPE\] tissue block or slides) from primary or metastatic sites for tissue-based IHC staining to centrally determine HER2 expression (see details in Section 7.1.1).

∙ In dose escalation and dose finding: archival tissue or fresh biopsy. If no archival tissue is available or it is not possible to obtain a fresh tissue biopsy, medical monitor approval is required to screen participant;

‣ In dose expansion: an FFPE block or slides from fresh biopsy or the most recent archival tissue is required.

• At least one measurable lesion based on RECIST (Response Evaluation Criteria in Solid Tumors) V1.1

• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1

• Toxicity of previous antitumor therapy has returned to Grade ≤1 as defined by the National Cancer Institute (NCI) CTCAE V5.0, except for alopecia and endocrinopathies controlled by replacement therapy that must be Grade ≤2

⁃ No serious cardiac dysfunction, left ventricular ejection fraction ≥50%

⁃ Adequate organ function before enrollment, defined as:

• Marrow function: Absolute neutrophil count (ANC) ≥1.5×10\^9/L, platelet (PLT) count ≥100×10\^9

• /L, hemoglobin (Hb) ≥9.0 g/dL \[blood transfusion, PLT transfusion, erythropoietin, hematopoiesis agents, and granulocyte colony-stimulating factor (G-CSF) use are not allowed 1 week prior to screening\]

∙ Hepatic function: Total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN) (≤3×ULN for participants with Gilbert's syndrome or liver metastasis at baseline), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) without liver metastasis ≤3.0×ULN, AST and ALT with liver metastasis ≤5.0×ULN

∙ Renal function:

‣ In dose escalation and dose finding: Creatinine (Cr) clearance ≥50 mL/minute (Cockcroft-Gault equation) or estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m\^2 (Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] equation)

⁃ In dose expansion: Cr clearance ≥40 mL/minute (Cockcroft-Gault equation) or eGFR ≥40 mL/min/1.73 m\^2 (CKD-EPI equation)

⁃ Coagulation parameters: International Normalized Ratio (INR) ≤1.5×ULN, and activated partial thromboplastin time (aPTT) ≤1.5×ULN, unless receiving anticoagulation therapy with prothrombin time and aPTT levels within the intended therapeutic range

⁃ Urine protein ≤2+ or ≤1000 mg/24 hours (in dose escalation and dose finding only)

⁃ Sexually active fertile participants and their partners must agree to use highly effective methods of contraception (defined in Appendix D) during the course of the study and for a washout period after the last dose of study treatment (7 months for women of childbearing potential and 4 months for men). An additional contraceptive method, such as a barrier method (eg, condom), is recommended.

⁃ Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and must be nonlactating. Female participants are considered WOCBP unless one of the following criteria are met: documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman \>45 years old in the absence of other biological or physiological causes). In addition, females \<55 years old must have a serum follicle stimulating hormone (FSH) level \>40 mIU/mL to confirm menopause. NOTE: Documentation may include review of medical records, medical examination, or medical history interview by study site staff. Additional Inclusion Criteria for Dose Expansion

⁃ For participants with urothelial carcinoma (Part A: Randomized Doses):

• Histologically confirmed advanced or unresectable HER2-expressing (as defined in Inclusion Criterion #5) urothelial carcinoma of the upper or lower urinary tract, not amenable to curative surgery or radiation. Mixed histological types are allowed if urothelial is the primary histology; however, small cell histology is excluded.

∙ Participants with progression or recurrence following receipt of an ADC (eg, enfortumab vedotin or disitamab vedotin) and anti-PD1/PD-L1 therapy (either as a combination regimen or as separate lines of therapy) in the advanced or metastatic setting. Patients treated with enfortumab/pembrolizumab in the localized muscle invasive setting will be eligible. Prior platinum therapy is allowed but not required.

⁃ Participants should have no more than 3 prior lines of systemic cytotoxic therapy (eg, ADC, chemotherapy) in the advanced or metastatic setting.

⁃ Multiple Indications (Part B: Basket Dosing):

⁃ Has documented locally advanced or metastatic HER2-expressing (as defined in Inclusion Criterion #5) solid tumor(s) not amenable to curative surgery or radiation and has received at least 2 lines of standard therapy, including adjuvant/neoadjuvant treatment, or whose cancer is considered refractory to the standard of care or for which no standard treatment is available, including:

∙ Participants with HER2 expression in endometrial cancer

∙ Participants with HER2 expression in cervical cancer

∙ Participants with HER2 expression in ovarian cancer, including fallopian tube cancer and primary peritoneal cancer

∙ Participants with HER2 expression in breast cancer, status post-trastuzumab deruxtecan

∙ Participants with HER2 expression in breast cancer, trastuzumab deruxtecan-naïve

∙ Participants with HER2 expression in gastric, esophageal, or GEJ cancers

⁃ Participants deemed at high-risk for infection, including those with an indwelling catheter or ostomy, must be willing to receive prophylactic G-CSF during their time on study (see Section 6.3.3.5).