This study is designed to primarily evaluate the safety and efficacy of U3-1402 in
participants with advanced or metastatic colorectal cancer (CRC) who have received at least 2
prior lines of therapy and will explore clinical benefit according to human epidermal growth
factor receptor 3 (HER3) tumor expression level in otherwise refractory tumors.
- Subject has provided written informed consent prior to the start of any study specific
- Subjects ≥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
- Must be resistant, refractory, or intolerant to at least 2 prior lines of systemic
therapy, that must include all of the following agents:
- 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: Subjects 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 IHC and exploratory biomarkers, defined as:
1. Pre-treatment tumor biopsy. Subjects 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
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 subject 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
- 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/mm3 or ≥100 × 109/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/mm3 or ≥1.5 × 109/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
- 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
2. any autoimmune, connective tissue or inflammatory disorder with pulmonary
involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) OR prior
- 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
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,
- 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 subject to
participate in the study or which would jeopardize compliance with the protocol.
Screening for chronic conditions is not required.