A Study to Evaluate U3-1402 in Subjects With Advanced or Metastatic Colorectal Cancer

Inclusion Criteria:

• Participant has provided written informed consent prior to the start of any studyspecific procedures.

• Participants ≥18 years (follow local regulatory requirements if the legal age ofconsent for study participation is >18 years old).

• Pathological/histological confirmation of advanced or metastatic colon or rectaladenocarcinoma.

• Must be resistant, refractory, or intolerant to at least 2 prior lines of systemictherapy, that must include all of the following agents:

• Fluoropyrimidine

• Irinotecan

• Platinum agents (e.g, oxaliplatin)

• An anti-epidermal growth factor receptor (EGFR) agent, if clinically indicated

• An anti-VEGF agent, if clinically indicated (eg, bevacizumab)

• An immune checkpoint inhibitor (eg, microsatellite instability-high [MSI-H]status)

• A BRAF inhibitor, if clinically indicated (eg, BRAF V600E positive)

• Has at least 1 measurable lesion confirmed by blinded independent central review (BICR) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1.

• Willing to provide a required pre-treatment tumor biopsy and an additional archivaltissue sample for the assessment of HER3 expression levels by immunohistochemistryand exploratory biomarkers, defined as:

1. Pre-treatment tumor biopsy. Participants may be exempted from the requirementto provide a pre-treatment tumor biopsy if archival tumor tissue was collectedwithin 3 months of screening during or after treatment with the last priorcancer treatment and is of sufficient quantity (2 cores or 20 slides withadequate tumor tissue content).

2. An additional archival tissue sample collected greater than 3 months prior toscreening must be available and of sufficient quantity, as defined above, atthe time of screening. If an archival tissue sample (collected greater than 3months prior to screening) is not available, a subject may be included providedthe pre-treatment tumor biopsy is obtained and after discussion and agreementfrom Sponsor (Medical Monitor or designee).

3. Consent to provide on-treatment tumor biopsy. When at least 10 treatment tumorbiopsies have been collected, the Sponsor will provide written notification ofa change to the requirement.

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

• Life expectancy ≥3 months.

• Has adequate bone marrow reserve and organ function at baseline based on locallaboratory data defined as follows within 14 days prior to Cycle 1 Day 1:

• Platelet count: ≥100,000/mm^3 or ≥100 × 10^9/L (platelet transfusions are notallowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility)

• Hemoglobin: ≥9.0 g/dL (transfusion and/or growth factor support is allowed)

• Absolute neutrophil count: ≥1500/mm^3 or ≥1.5 × 10^9/L

• Serum creatinine (SCr) OR creatinine clearance (CrCl): SCr ≤ 1.5 × upper limitof normal (ULN), OR CrCl ≥ 30 mL/min as calculated using the Cockcroft- Gaultequation or measured CrCl; confirmation of CrCl is only required whencreatinine is >1.5 × ULN

• Alanine aminotransferase /aspartate aminotransferase: ≤3 × ULN (if livermetastases are present, ≤5 × ULN)

• Total bilirubin: ≤1.5 × ULN if no liver metastases (<3 × ULN in the presence ofdocumented Gilbert's syndrome [unconjugated hyperbilirubinemia] or livermetastases)

• Serum albumin: ≥2.5 g/dL

• Prothrombin time (PT) or PT-international normalized ratio (INR) and activatedpartial thromboplastin time (aPTT) / partial thromboplastin time (PTT): ≤1.5 ×ULN except for subjects on coumarin- derivative anticoagulants or other similaranticoagulant therapy, who must have PT-INR within therapeutic range as deemedappropriate by the Investigator

Exclusion Criteria:

• Any history of interstitial lung disease (including pulmonary fibrosis or radiationpneumonitis), has current interstitial lung disease (ILD), or is suspected to havesuch disease by imaging during screening.

• Clinically severe pulmonary compromise (based on Investigator's assessment)resulting from intercurrent pulmonary illnesses including, but not limited to:

1. any underlying pulmonary disorder (e.g., pulmonary emboli, severe asthma,severe chronic obstructive pulmonary disease, restrictive lung disease, pleuraleffusion)

2. any autoimmune, connective tissue or inflammatory disorder with pulmonaryinvolvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis)

• OR prior complete pneumonectomy.

• Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone orequivalent anti-inflammatory activity or any form of immunosuppressive therapy priorto Cycle 1 Day 1. Participants who require use of bronchodilators, inhaled ortopical steroids, or local steroid injections may be included in the study.

• Evidence of leptomeningeal disease.

• Evidence of clinically active spinal cord compression or brain metastases

• Inadequate washout period prior to Cycle 1 Day 1 of U3-1402:

1. Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7 days;

2. Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s)from a previous cancer treatment regimen or clinical study <14 days or 5half-lives, whichever is longer;

3. Monoclonal antibodies other than immune checkpoint inhibitors, such asbevacizumab (anti-VEGF) and cetuximab (anti-EGFRs) <28 days;

4. Immune checkpoint inhibitor therapy <21 days;

5. Major surgery (excluding placement of vascular access) <4 weeks;

6. Radiotherapy treatment to >30% of the bone marrow or with a wide field ofradiation <28 days or palliative radiation therapy <14 days;

7. Chloroquine/hydroxychloroquine ≤14 days.

• Prior treatment with an anti-HER3 antibody and/or antibody drug conjugate (ADC) thatconsists of an exatecan derivative that is any topoisomerase I inhibitor (e.g,trastuzumab deruxtecan).

• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute CommonTerminology Criteria for Adverse Events (NCI-CTCAE) v5.0 Grade ≤1 or baseline.

• Had primary malignancies other than CRC within 3 years prior to Cycle 1 Day 1,except adequately resected non-melanoma skin cancer, curatively treated in-situdisease, or other solid tumors curatively treated.

• Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1.

• Known Hepatitis B and/or Hepatitis C infection, such as those with serologicevidence of viral infection within 28 days of Cycle 1 Day 1.

1. Participants with past or resolved hepatitis B virus (HBV) infection areeligible if:

• Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) positive; OR
• HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load isdocumented to be ≤2000 IU/mL in the absence of anti-viral therapy andduring the previous 12 weeks prior to the viral load evaluation withnormal transaminases values (in the absence of liver metastasis); OR
• HBsAg positive and HBV DNA viral load is documented to be ≤2000 IU/mL inthe absence of anti-viral therapy and during the previous 12 weeks priorto the viral load evaluation for participants with liver metastasis andabnormal transaminases with a result of AST/ALT <3 × ULN.

2. Participants with a history of hepatitis C infection will be eligible forenrollment only if the viral load according to local standards of detection isdocumented to be below the level of detection in the absence of anti-viraltherapy during the previous 12 weeks (ie, sustained viral response according tothe local product label but no less than 12 weeks, whichever is longer).

• Participant with any human immunodeficiency virus (HIV) infection.

• Any evidence of severe or uncontrolled systemic diseases (including active bleedingdiatheses, active infection), psychiatric illness/social situations, geographicalfactors, substance abuse, or other factors which in the Investigator's opinion makesit undesirable for the participant to participate in the study or which wouldjeopardize compliance with the protocol. Screening for chronic conditions is notrequired.