Clinical Trials /

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

NCT04479436

Description:

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.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate U3-1402 in Subjects With Advanced or Metastatic Colorectal Cancer
  • Official Title: A Multi-Center, Open-Label, Phase 2 Study to Evaluate Safety and Efficacy of U3-1402 in Subjects With Advanced or Metastatic Colorectal Cancer (CRC)

Clinical Trial IDs

  • ORG STUDY ID: U31402-A-U202
  • SECONDARY ID: 2019-004418-32
  • NCT ID: NCT04479436

Conditions

  • Metastatic Colorectal Cancer

Interventions

DrugSynonymsArms
U3-1402Cohort 1: HER3 High (IHC 3+, 2+)

Purpose

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.

Detailed Description

      There will be 2 cohorts with enrollment in 2 parts. Subjects will be treated on Day 1 of each
      21-day cycle (every 3 weeks) with U3-1402 5.6 mg/kg intravenous (IV). The estimated treatment
      period is approximately 8 months and the follow-up period is approximately 4 months.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1: HER3 High (IHC 3+, 2+)ExperimentalCohort 1 participants will have high tumor expression levels of human epidermal receptor 3 (HER3)
  • U3-1402
Cohort 2: HER3 Low/Negative (IHC 1+, 0)ExperimentalCohort 2 participants will have low or negative tumor expression levels of human epidermal receptor 3 (HER3) expression levels
  • U3-1402

Eligibility Criteria

        Inclusion Criteria:

          -  Subject has provided written informed consent prior to the start of any study specific
             procedures.

          -  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
             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: 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
                  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 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/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

        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 subject to
             participate in the study or which would jeopardize compliance with the protocol.
             Screening for chronic conditions is not required.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR) As Assessed By Blinded Independent Central Review Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:From baseline up to disease progression or other protocol-defined reasons, up to approximately 27 months
Safety Issue:
Description:ORR defined as the proportion of participants with a best overall response of confirmed complete response (CR) or partial response (PR) as assessed by blinded independent central review.

Secondary Outcome Measures

Measure:Duration of Response (DOR) As Assessed by Blinded Independent Central Review Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:From baseline up to disease progression or other protocol-defined reasons, up to approximately 27 monthss
Safety Issue:
Description:DOR defined as the time from the first documented response (CR or PR) to the date of disease progression or death due to any cause.
Measure:Objective Response Rate (ORR) As Assessed by Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:From baseline up to disease progression or other protocol-defined reasons, up to approximately 27 months
Safety Issue:
Description:ORR defined as the proportion of participants with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) as assessed by Investigator.
Measure:Duration of Response (DoR) As Assessed by Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:From baseline up to disease progression or other protocol-defined reasons, up to approximately 27 months
Safety Issue:
Description:DoR defined as the time from the first documented response (complete response [CR] or partial response [PR]) to the date of disease progression or death due to any cause.
Measure:Disease Control Rate (DCR) by Blinded Independent Central Review and Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:From baseline up to disease progression or other protocol-defined reasons, up to approximately 27 months
Safety Issue:
Description:DCR is defined as the proportion of participants who achieved a confirmed best overall response (BOR) of complete response (CR), partial response (PR), or stable disease (SD) as assessed by blinded independent central review or by the Investigator
Measure:Time to Tumor Response (TTR) As Assessed by Blinded Independent Central Review and Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:From baseline up to disease progression or other protocol-defined reasons, up to approximately 27 months
Safety Issue:
Description:TTR defined as the time from the start of study treatment to the date of the first documentation of objective response (complete response [CR] or partial response [PR]) that is subsequently confirmed by Blinded Independent Central Review or by the Investigator
Measure:Progression-free Survival (PFS) Assessed by Blinded Independent Central Review and Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:From baseline until disease progression or other protocol defined reason, assessed up to 27 months
Safety Issue:
Description:PFS is defined as the time from the start of study treatment to the date of the first documentation of objective PD or death due to any cause, whichever is earlier
Measure:Overall Survival (OS) Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:From baseline up to the date of death due to any cause or 27 months, whichever is earlier.
Safety Issue:
Description:OS defined as the time from the start of study treatment to the date of death due to any cause.
Measure:Summary of Reported Treatment-emergent Adverse Events (TEAEs) and other safe parameters during the study
Time Frame:From baseline up to Day 40 post last dose, approximately 27 months
Safety Issue:
Description:Incidence of TEAEs, serious adverse events, adverse events of special interests (interstitial lung disease; and elevation of aminotransferases and total bilirubin), Eastern Cooperative Oncology Group performance status, vital sign measurements, standard clinical laboratory parameters will be assessed
Measure:Pharmacokinetic (PK) of Maximum Serum Concentration (Cmax) of analytes of U3-1402 Following Administration In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:At baseline, pre- and post-infusion of cycle 1 through Cycle 8 (approximately 24 weeks)
Safety Issue:
Description:Plasma concentrations at each time point and PK parameters Cmax of U3-1402 (ADC, total anti-HE antibody, and MAAA-1181a) will be assessed in the full PK sampling cohort
Measure:Pharmacokinetic of Time to Reach Maximum Serum Concentration (Tmax) of analytes of U3-1402 Following Administration In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:At baseline, pre- and post-infusion of cycle 1 through Cycle 8 (approximately 24 weeks)
Safety Issue:
Description:Plasma concentrations at each time point and PK parameters Tmax of U3-1402 (ADC, total anti-HE antibody, and MAAA-1181a) will be assessed in the full PK sampling cohort
Measure:Pharmacokinetic of Trough Serum Concentration (Ctrough) of analytes of U3-1402 Following Administration In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:At baseline, pre- and post-infusion of cycle 1 through Cycle 8 (approximately 24 weeks)
Safety Issue:
Description:Plasma concentrations at each time point and PK parameters Ctrough of U3-1402 (ADC, total anti-HE antibody, and MAAA-1181a) will be assessed in the full PK sampling cohort
Measure:Pharmacokinetic of Area Under the Serum Concentration-Time Curve Up to Last Quantifiable Time (AUClast) and During Dosing Interval (AUCtau) of analytes of U3-1402 Following Administration In Participants with Advanced or Metastatic Colorectal Cancer
Time Frame:At baseline, pre- and post-infusion of cycle 1 through Cycle 8 (approximately 24 weeks)
Safety Issue:
Description:Plasma concentrations at each time point and PK parameters AUClast and AUCtau of U3-1402 (ADC, total anti-HE antibody, and MAAA-1181a) will be assessed in the full PK sampling cohort

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Daiichi Sankyo, Inc.

Trial Keywords

  • Metastatic Colorectal Cancer
  • U3-1402

Last Updated

July 19, 2020