Inclusion Criteria:
1. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
2. Part A: Histological diagnosis of one of the following unresectable locally advanced or metastatic solid tumors:
- Non-squamous cell carcinoma subtypes, such as adenocarcinoma
- Squamous cell carcinoma subtype
- Breast cancer (subtypes based on estrogen/progesterone receptor and HER2 testing according to American Society of Clinical Oncology - College of American Pathologists guidelines):
- Triple-negative breast cancer
- HR+, HER2- subtype
- Esophageal, esophagogastric junction, and gastric cancer:
- Adenocarcinoma subtype
- Other histologies, if approved by the Medical Monitor, which may include: head and neck squamous cell carcinoma; cervical cancer; bladder cancer; squamous cell carcinoma subtype of esophageal, esophagogastric junction, and gastric cancer; HER2+ breast cancer
3. Part B Cohorts - Histological diagnosis of one of the following unresectable locally advanced or metastatic solid tumors:
- Cohort B1: CRC, all subtypes
- Cohort B2: NSCLC
- Non-squamous cell carcinoma subtypes, such as adenocarcinoma
- Squamous cell carcinoma subtype
- Cohorts B3 and B4: Cohort-specific disease indications may include those listed for Part A
4. Participants must have disease that is considered to be noncurative and meet the appropriate criteria below:
- Part A only: Participants have progressed on, were intolerant to, or have a contraindication to prior SOC treatments, with no satisfactory SOC treatment options available.
- Part B only:
- Participants must have previously progressed on, were intolerant to, or have a contraindication to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, bevacizumab, and for those with RAS wild-type tumors, an anti-epidermal growth factor receptor (EGFR)-directed monoclonal antibody in advanced disease setting.
- Participants with actionable biomarkers must have been treated with at least one prior appropriate biomarker-directed therapy.
- If any of these therapies was given in the adjuvant setting, disease must have progressed within 6 months after completing therapy.
- Cohort B2 (NSCLC):
- Participants must have previously progressed on, were intolerant to, or have a contraindication to platinum-based chemotherapy and a programmed cell death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibody (given concurrently or sequentially with chemotherapy) in advanced disease setting.
- Participants with actionable biomarkers must have been treated with at least one prior appropriate targeted therapy.
- If any of these therapies was given in the adjuvant setting, disease must have progressed within 6 months after completing therapy.
- Cohorts B3 and B4: Criteria will be specified based on the disease indications selected.
5. Participants must have measurable disease as defined per RECIST v1.1
Exclusion Criteria:
1. Previously treated with an antibody-drug conjugate (ADC) with a topoisomerase-1 (TOP1) inhibitor payload. Exception: Participants with NSCLC or breast cancer may have received up to one prior ADC with a TOP1 inhibitor payload
2. History of anaphylactic reaction to TOP1 inhibitors (e.g., irinotecan) or TOP1 inhibiting ADCs
3. Life expectancy < 12 weeks
4. Prior solid organ transplant
5. Symptomatic ascites or pleural effusion
6. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
7. Known history of another primary solid or hematologic malignancy (other than that under study), unless the participant has undergone potentially curative therapy with no evidence of recurrence for at least 2 years and approved by the Medical Monitor