Ph II Study of Enfortumab Vedotin in Patients With Advanced or Metastatic CRC or HCC

Inclusion Criteria: * Participants must have histologically confirmed CRC or HCC that is metastatic or unresectable and have progressive disease or intolerance after standard front-line therapies as defined below: Participants with CRC (cohort 1): Participants must have had progressive disease or intolerance after at least 2 but no more than 3 prior lines of systemic therapy in advanced or metastatic setting. Prior lines of therapy should include fluoropyrimidine (5-fluorouracil or capecitabine), oxaliplatin, and irinotecan with or without anti EGFR antibody for RAS/RAF wild-type CRC or bevacizumab unless contraindicated. For patients with microsatellite instability high (MSI-H) CRC, previous lines of therapy should include a PD-1/PD-L1 immune checkpoint inhibitor in additional to the chemotherapy agents mentioned above. Adjuvant chemotherapy with radiographic progression greater than 12 months after the last dose is not considered as a line of therapy. Participants with HCC (cohort 2): Participants must have had progressive disease or intolerance after at least 1 but no more than 2 prior lines of systemic therapy in advanced or metastatic setting. Prior lines of therapy should include a PD-1/PD-L1 immune checkpoint inhibitor or a multikinase inhibitor, which was administered either alone or in combination. * Participants must have measurable disease according to RECIST v1.1. Lesions in a prior radiation field must have progressed subsequent to radiotherapy to be considered measurable. * Participants must have had progression or recurrence of CRC or HCC during or following receipt of most recent therapy. * Legally an adult according to local regulation at the time of signing informed consent, and minimum age of 18 years * ECOG performance status ≤1 * Participants must have adequate organ and marrow function as defined below: 1. Absolute neutrophil count (ANC) ≥ 1500/mm3 2. Platelet count ≥100 × 109/L 3. Hemoglobin ≥9 g/dL 4. Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert's disease 5. Creatinine clearance (CrCl) ≥30 mL/min as estimated per institutional standards 6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN or ≤ 5 x ULN for subjects with liver metastases 7. Liver function status should be Child-Pugh (CP) Class A. * Tumor tissue samples must be available for submission prior to study treatment. * Participants must have an anticipated life expectancy of ≥3 months as assessed by the investigator. * The effects of enfortumab vedotin on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 4 months after the last dose. 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. * Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: * Radiotherapy or major surgery or chemotherapy, biologics, investigational agents, and/or immunotherapy that is not completed 2 weeks prior to first dose of study drug. * Ongoing sensory or motor neuropathy Grade ≥2. Ongoing clinically significant toxicity (Grade 2 or higher) associated with prior treatment (including systemic therapy, radiotherapy or surgery). * Active central nervous system (CNS) metastases. Participants with treated CNS metastases are permitted on study if all the following are true: i. CNS metastases have been clinically stable for at least 6 weeks prior to screening and baseline scans show no evidence of new or enlarged metastasis ii. If requiring steroid treatment for CNS metastases, the patient is on a stable dose ≤20 mg/day of prednisone or equivalent for at least 2 weeks iii. Participant does not have leptomeningeal disease * Prior enrollment in an enfortumab vedotin study or prior treatment with other MMAE-based ADCs. * History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Participants with nonmelanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed. * Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of first dose of enfortumab vedotin. Routine antimicrobial prophylaxis is permitted. * Patients with a positive hepatitis B surface antigen and/or antihepatitis B core antibody. Patients with a negative polymerase chain reaction (PCR) assay (HBV DNA is less than 10 IU/ml) are permitted with appropriate antiviral prophylaxis. * Active hepatitis C infection or known human immunodeficiency virus (HIV) infection. Patients who have been treated for hepatitis C infection are permitted if they have negative HCV RNA test (less than 15 IU/ml) and have documented sustained virologic response of ≥12 weeks. * Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of enfortumab vedotin. * Known hypersensitivity to enfortumab vedotin or to any excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate, and polysorbate 20) * Participants with active keratitis or corneal ulcerations. Patients with superficial punctate keratitis are allowed if the disorder is being adequa