• Participant must have at least 1 lesion, not previously irradiated, amenable to core biopsy and must consent to provide a pretreatment biopsy tissue sample. An archival tumor tissue sample obtained within 6 months of consent and after progression during/after treatment with the participant's most recent cancer therapy regimen is also acceptable.

• Participants ages ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is \>18 years).

• At least 1 measurable lesion on computed tomography (CT) or magnetic resonance imaging (MRI) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), as assessed by the investigator.

• Documentation of radiological disease progression on or after the previous standard-of-care regimen in the advanced/metastatic setting.

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

• Pathologically or cytologically documented EC of any histological carcinoma subtype or endometrial carcinosarcoma, irrespective of microsatellite instability or mismatch repair status.

• Relapse or progression after a platinum-containing systemic treatment and an immune checkpoint inhibitor (ICI)-containing regimen (combined or sequential). Subjects with actionable target tumor mutation should have been previously treated with targeted therapy, with a maximum of 3 prior lines of therapy for endometrial carcinoma or carcinosarcoma. Neoadjuvant/adjuvant therapy may count as 1 line of therapy if the subject progressed within 6 months after completion of therapy.

• Pathologically or cytologically documented unresectable or metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx, excluding nasopharynx, nasal cavity and paranasal sinuses, and unknown primary.

• Has disease progression after platinum-based and ICI treatment, whether administered in combination or separately. Subjects with actionable target tumor mutation should have been previously treated with targeted therapy, with a maximum of 2 prior therapy lines for unresectable or metastatic HNSCC.

• Participants without radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrating a \>90-degree abutment or encasement of a major blood vessel.

• Participants with no prior history of Grade ≥3 bleeding as per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 within 28 days prior to the start of study drug related to the current head and neck cancer may be included in the study.

• Documented p16 status for oropharyngeal cancer (historical results are acceptable if available).

∙ Additional Inclusion Criterion for PDAC Participants

∙ 1\. Pathologically or cytologically documented unresectable or metastatic pancreatic adenocarcinoma that has relapsed or progressed after 1 prior line of gemcitabine-based systemic therapy in the locally advanced/metastatic setting or after 2 lines of therapy if the subject has actionable target tumor mutation and has been previously treated with targeted therapy. No prior treatment with topoisomerase I inhibitors, such as irinotecan or topotecan.

• Pathologically or cytologically documented unresectable or metastatic CRC with microsatellite stable status.

• Relapse or progression after 1 prior line of systemic therapy including a fluoropyrimidine plus oxaliplatin with or without anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb) or anti-epidermal growth factor receptor mAb therapy, as clinically indicated, or relapse or progression after 2 lines of therapy if the subject has received targeted therapy.

• Note: Prior adjuvant/neoadjuvant systemic cytotoxic chemotherapy will count as 1 line of prior systemic therapy if there is documented disease progression during therapy or within 6 months of chemotherapy completion.

• No prior treatment with topoisomerase I inhibitors, such as irinotecan or topotecan.

• Pathologically or cytologically documented unresectable or metastatic HCC (fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible) or noninvasive diagnosis of HCC as per the American Association for the Study of Liver Diseases (AASLD) criteria in subjects with a confirmed diagnosis of cirrhosis.

• Relapse or progression after 1 prior line of an ICI-containing regimen (combination or monotherapy) in the locally advanced/metastatic setting, with a maximum of 2 prior lines. Subjects with actionable target tumor mutation should have been previously treated with targeted therapy.

• Barcelona Clinic Liver Cancer (BCLC) Stage B or C.

• Liver function status should be Child-Pugh (CP) Class A.

• Albumin-Bilirubin (ALBI) Grade 1 within 7 days prior to the first dose of study drug.

• Participants with large esophageal varices at risk of bleeding must be treated with conventional medical intervention: beta blockers or endoscopic treatment.

• Pathologically or cytologically documented unresectable or metastatic Ad-eso/GEJ/Gastric that has relapsed or progressed after 1 prior line of systemic therapy in the locally advanced/metastatic setting. Subjects with PD-(L)1+ or MSI-H/dMMR should receive ICI treatment if ICIs are standard of care in the country, unless the subject is ineligible for ICI treatment.

• If the participant has known history of HER2 positivity (defined by IHC 3+ or IHC 2+ and in situ hybridization \[ISH\] positive, as classified by American Society of Clinical Oncology - College of American Pathologists \[ASCO CAP\]) or actionable target, the subject must have been previously treated with a targeted therapy.

• Pathologically or cytologically documented unresectable or metastatic UC of the bladder, renal pelvis, ureter, or urethra. Participants with histological variants are allowed if urothelial histology is predominant. Small cell/neuroendocrine tumors are not allowed even if mixed histology.

• Relapse or progression after at least 1 prior line of ICI-containing systemic therapy, and 1 prior line of systemic chemotherapy, given in combination with other anticancer therapy or separately, with a maximum of 3 prior therapy lines.

‣ At least 1 line of therapy should include enfortumab vedotin in countries where enfortumab vedotin is approved and available.

⁃ Perioperative systemic therapies will be counted as 1 line of therapy.

⁃ To meet inclusion criteria requirement of prior ICI-containing therapy, use in the perioperative or metastatic setting will suffice.

⁃ Subjects with actionable target tumor mutation should have been previously treated with targeted therapy.

⁃ The same regimen administered twice in different disease settings will be counted as 1 line of prior therapy.

• Histologically confirmed unresectable or metastatic CC that was previously treated with ≥1 prior line of systemic therapy in the locally advanced or metastatic setting. Subjects with actionable target tumor mutation should have been previously treated with targeted therapy.

• Participants should receive prior anti-programmed death 1/programmed death-ligand 1 treatment and/or tisotumab vedotin if those are standard of care in the country, unless the subject is ineligible for these treatments.

• Histologically confirmed high-grade serous OVC, high-grade endometrioid OVC, primary peritoneal cancer, or fallopian tube cancer that was previously treated with at least 1 line of platinum-based therapy and bevacizumab unless the subject is ineligible for treatment with bevacizumab.

• Participant is no longer considered eligible for platinum-based therapy per the investigator's opinion or has progressed less than 180 days after the last dose of platinum therapy.

• Participant is not considered primary platinum refractory and has not progressed during platinum treatment or within 4 weeks after the completion of platinum treatment.

• Subjects with actionable target tumor mutation should have been previously treated with targeted therapy.

• Pathologically or cytologically documented unresectable or metastatic BTC (intra- or extrahepatic cholangiocarcinoma or gallbladder carcinoma).

• Relapse or progression after at least 1 prior line of systemic therapy, or 2 prior lines of systemic therapy if the participant has an actionable target and has received targeted therapy.

• Histological subtypes other than ampullary cancer, small cell cancer, lymphoma, sarcoma, neuroendocrine tumors, mixed tumor histology, and/or mucinous cystic neoplasms (Please note that the histological subtypes listed here are not allowed.)

• Pathologically or cytologically documented unresectable or metastatic BC.

• Low HER2 expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested), according to ASCO-CAP 2018 HER2 testing guidelines, based on most recent testing, regardless of hormonal status.

• Progression on or after treatment with trastuzumab deruxtecan (T-DXd).

• Relapse or progression after at least 2 and a maximum of 3 prior lines of systemic therapy. Subjects with metastatic hormone receptor (HR)+ BC who have received endocrine-based therapy and have received at least 2 and a maximum of 3 prior lines of additional systemic therapy in the metastatic setting. Subjects with actionable target tumor mutation should have been previously treated with targeted therapy.

• Pathologically or cytologically documented unresectable or metastatic BC.

• Negative for HER2 expression, defined as IHC 0 (ISH- or untested) according to ASCO-CAP 2018 HER2 testing guidelines, based on the most recent testing, regardless of hormonal status.

• Relapse or progression after at least 2 and a maximum of 3 prior lines of systemic therapy. Participants with metastatic HR+ BC who have received endocrine-based therapy and have received at least 2 and a maximum of 3 prior lines of additional systemic therapy in the metastatic setting. Subjects with actionable target tumor mutation should have been previously treated with targeted therapy.

• Histologically or cytologically confirmed cutaneous (acral and non-acral) melanoma.

• Disease progression while on or after having received treatment with ≥1 prior line of ICI based therapy. Prior anti-PD-(L)1 therapy in the adjuvant setting may be counted as 1 line if there is recurrence within 12 weeks of the last dose. If the subject had BRAF mutated melanoma or other actionable target tumor mutation, they must have had disease progression on targeted therapy as well.

∙ Participants who meet any of the following criteria will be disqualified from entering the study:

• Prior treatment with orlotamab, enoblituzumab, or other B7-homologue 3 (B7-H3)-targeted agents, including I-DXd.

• Prior discontinuation of an antibody drug conjugate (ADC) that consists of an exatecan derivative (eg, T-DXd) due to treatment-related toxicities.

• Clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, defined as untreated or symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms.

• Inadequate treatment washout period before enrollment as specified in the protocol.