MC# 20-24 - A Multi-Center, Open-Label, Phase II Study to Evaluate Safety and Efficacy of U3-1402 in Subjects with Advanced or Metastatic Colorectal Cancer (CRC)

  • Agent(s): U3-1402
  • Disease Type(s): Colorectal
  • Phase(s): II
  • Drug Classification(s): Targeted Therapy, Antibody Drug Conjugate
  • Molecular Target(s): HER3

Mechanism of Action

U3-1402 is an antibody-drug conjugate (ADC) composed of patritumab, a monoclonal antibody directed against the human epidermal growth factor receptor HER3 (ErbB3), linked to the topoisomerase I inhibitor DX 8951, a semisynthetic, water-soluble derivative of camptothecin.  The patritumab moiety targets and binds to HER3 where DX 8951 inhibits topoisomerase I activity by stabilizing the complex between topoisomerase I and DNA and inhibiting religation of DNA breaks, thereby inhibiting DNA replication and triggering apoptotic cell death.

Purpose

In this study, the sponsor and investigators want to learn:

  • The safety and tolerability of U3-1402
  • How much of U3-1402 is absorbed into the blood and how fast it is removed
  • If research tests can be used in the future to predict who will benefit from U3-1402
  • How proteins that indicate the status of your disease are affected with use of U3-1402
  • If your body develops proteins that work against U3-1402
  • If U3-1402 prevents or delays tumor growth
Inclusion Criteria
  1. Sign and date the ICF prior to the start of any study-specific qualification procedures
  2. Male or female subjects ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old)
  3. Pathological or histological confirmation and documentation of colon or rectum adenocarcinoma with advanced or metastatic disease
  4. Must be resistant, refractory, or intolerant to at least 2 prior lines of therapy, that must include all of the following agents:
    1. Fluoropyrimidine
    2. Irinotecan
    3. Platinum agents (eg, oxaliplatin)
    4. An anti-EGFR agent, if clinically indicated
    5. An anti-VEGF agent, if clinically indicated (eg, bevacizumab)
    6. An immune checkpoint inhibitor, if clinically indicated (eg, microsatellite instability-high [MSI-H] status)
    7. A BRAF inhibitor, if clinically indicated (eg, BRAF V600E positive)
  5. Has at least 1 measurable lesion confirmed by BICR as per RECIST v1.1
  6. Willing to provide a required pre-treatment tumor biopsy and an additional archival tissue sample for the 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 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 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 tumor biopsies per cohort have been collected, the Sponsor will provide written notification of a change to the requirement.
  7. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1
  8. Life expectancy ≥3 months
  9. Has adequate bone marrow reserve and organ function, based on local laboratory data, defined as within 14 days prior to Cycle 1 Day 1:

Parameter

Laboratory Value

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

SCr OR CrCl

SCr ≤ 1.5 × 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

PT or PT-INR and aPTT/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

aPTT = activated partial thromboplastin time; CrCl = creatinine clearance; INR = international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time; SCr = serum creatinine; ULN = upper limit of normal

  1. If the subject is a female of childbearing potential, she must have a negative serum pregnancy test at screening and must be willing to use a highly effective form of birth control, upon enrollment during the Treatment Period, and for 7 months following the last dose of study drug.  A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy) with surgery at least 1 month before the first dose or confirmed by follicle-stimulating hormone (FSH) test.
  2. Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration
  3. If male, the subject must be surgically sterile or willing to use highly effective contraception upon enrollment, during the treatment period, and for at least 4 months following the last dose of study drug
  4. Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and for at least 4 months after the final study drug administration
  5. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions
Exclusion Criteria
  1. Any history of ILD (including pulmonary fibrosis or radiation pneumonitis), has current ILD, or is suspected to have such disease by imaging during screening
  2. Clinically severe pulmonary compromise (based on Investigator’s assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:
    1. any underlying pulmonary disorder (eg, 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 complete pneumonectomy.
  3. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1 Day 1.  Subjects who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study.
  4. Evidence of leptomeningeal disease
  5. Evidence of clinically active spinal cord compression or brain metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.  Subjects with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study.  Subjects must have a stable neurologic status for at least 2 weeks prior to Cycle 1 Day 1.
  6. 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. Monoclonal antibodies other than immune checkpoint inhibitors, such as bevacizumab (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 of radiation <28 days or palliative radiation therapy <14 days;
    7. Chloroquine /Hydroxychloroquine ≤14 days
  7. Prior treatment with an anti-HER3 antibody and/or ADC that consists of an exatecan derivative that is any topoisomerase I inhibitor (eg, trastuzumab deruxtecan)
  8. 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.  Subjects with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the Sponsor (Medical Monitor or designee).
  9. 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
  10. Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1, including:
    1. QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation interval of >470 ms for females and >450 ms for males within 28 days;
    2. Left ventricular ejection fraction (LVEF) <50% by either echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within 28 days;
    3. Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg;
    4. Myocardial infarction within 6 months;
    5. New York Heart Association (NYHA) Classes 2 to 4 (See Section 13.5) within 28 days;
    6. Uncontrolled angina pectoris within 6 months;
    7. Cardiac arrhythmia requiring antiarrhythmic treatment within 28 days
  11. Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1
    1. Subjects with past or resolved hepatitis B virus (HBV) infection are eligible if:
      1. Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody positive; OR
      2. HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load is documented to be ≤2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation with normal transaminases values (in the absence of liver metastasis); OR
      3. HBsAg positive and HBV DNA viral load is documented to be ≤2000 IU/mL in the absence of anti-viral therapy and during the previous 12 weeks prior to the viral load evaluation for subjects with liver metastasis and abnormal transaminases with a result of AST/ALT <3 × ULN
    2. Subjects with a history of hepatitis C infection will be eligible for enrollment only if the viral load according to local standards of detection is documented to be below the level of detection in the absence of anti-viral therapy during the previous 12 weeks (ie, sustained viral response according to the local product label but no less than 12 weeks, whichever is longer)
  12. Subject with any human immunodeficiency virus (HIV) infection
  13. 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.
  14. Has history of hypersensitivity to either the drug substances or inactive ingredients in the drug product
  15. Female who is pregnant or breastfeeding or intends to become pregnant during the study
  16. Has a concomitant medical condition that would increase the risk of toxicity, in the opinion of the Investigator
  17. Has clinically significant corneal disease

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT04479436

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Re: MC# 20-24