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 study specific procedures.
• Participants ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old).
• Pathological/histological confirmation of advanced or metastatic colon or rectal adenocarcinoma.

• Must be resistant, refractory, or intolerant to at least 2 prior lines of systemic therapy, 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 (eg, RAS/BRAF wildtype)
  • An anti-VEGF agent, unless contraindicated (eg, bevacizumab) Note: Participants with known microsatellite instability-high (MSI-H) status must have received treatment with an immune checkpoint inhibitor unless contraindicated.
• 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 required archival and pre-treatment tumor biopsy for assessment of HER3 expression levels by immunohistochemistry and exploratory biomarkers, defined as:

  1. Pre-treatment tumor biopsy. Participants may be exempted from the requirement to provide a pre-treatment tumor biopsy if archival tumor tissue was collected within 3 months of screening during or after treatment with the last prior cancer treatment and is of sufficient quantity (2 cores or 20 slides with adequate tumor tissue content).
  2. Archival tissue must be available and of sufficient quantity, as defined above, at the time of screening. If archival tissue is not available, a participant may be included provided the pre-treatment tumor biopsy is obtained and after discussion and agreement from Sponsor (Medical Monitor or designee).
  3. Consent to provide on-study tumor biopsy. When at least 10 on-study have been collected, the Sponsor will provide written notification of a 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 local laboratory data defined as follows within 14 days prior to Cycle 1 Day 1:

The following Parameters / Laboratory values:

Platelet count: ≥100,000/mm^3 or ≥100 × 10^9/L (platelet transfusions are not allowed 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 limit of normal (ULN), OR CrCl ≥ 30 mL/min as calculated using the Cockcroft- Gault equation or measured CrCl; confirmation of CrCl is only required when creatinine is >1.5 × ULN

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

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

Serum albumin: ≥2.5 g/dL

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

Exclusion Criteria:

• Any history of interstitial lung disease (including pulmonary fibrosis or radiation pneumonitis), has current interstitial lung disease (ILD), or is suspected to have such 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, pleural effusion)
  2. any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) OR prior pneumonectomy.
• Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent or any form of immunosuppressive therapy prior to Cycle 1 Day 1. Participants who require use of bronchodilators, inhaled steroids, or local steroid injections may be included in the study.
• Evidence of leptomeningeal disease.
• Has 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 5 half-lives, whichever is longer;
  3. Immune checkpoint inhibitor therapy <21 days;
  4. Major surgery (excluding placement of vascular access) <4 weeks;
  5. Radiotherapy treatment to >30% of the bone marrow or with a wide field of radiation <28 days or palliative radiation therapy <14 days;
  6. Chloroquine/hydroxychloroquine ≤14 days.
• Prior treatment with an anti-HER3 antibody and/or antibody drug conjugate (ADC) that consists 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 Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 Grade ≤1 or baseline. Participants with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the Sponsor (Medical Monitor or designee).
• 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-situ disease, 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 serologic evidence of viral infection within 28 days of Cycle 1 Day 1. Participants will be eligible for enrollment only if the viral load, according to local standards of detection, is documented to be low or undetectable in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation.
• Any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses, active infection [including human immunodeficiency virus (HIV)]), psychiatric illness/social situations, geographical factors, substance abuse, or other factors which in the Investigator's opinion makes it undesirable for the participant to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required.