Clinical trial NCT04479436: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: Metastatic Colorectal Cancer
U3-1402
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2020-07-21
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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. Participants 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.

Eligibility criteria: 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
  * 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 archival tissue sample for the 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. An additional archival tissue sample collected greater than 3 months prior to screening must be available and of sufficient quantity, as defined above, at the time of screening. If an archival tissue sample (collected greater than 3 months prior to screening) 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-treatment tumor biopsy. When at least 10 treatment tumor biopsies 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:

  * 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 complete pneumonectomy.
* 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. Participants who require use of bronchodilators, inhaled or topical 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 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.
* 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.
* 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.

  1. Participants with past or resolved hepatitis B virus (HBV) infection are eligible 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 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
     * 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 participants with liver metastasis and abnormal transaminases with a result of AST/ALT \<3 × ULN.
  2. Participants 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).
* Participant with any human immunodeficiency virus (HIV) infection.
* Any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses, active infection), 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.

Primary outcomes:
measure: Objective Response Rate (ORR) As Assessed By Blinded Independent Central Review (BICR) Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: From Baseline (Day 0) to data cut off (up to approximately 16.5 months)
Secondary outcomes:
measure: Duration of Response (DoR) As Assessed by Blinded Independent Central Review (BICR) and Investigator Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: From Baseline (Day 0) to data cut off (up to approximately 16.5 months)
measure: Objective Response Rate (ORR) As Assessed by Investigator Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: From Baseline (Day 0) to data cut off (up to approximately 16.5 months)
measure: Disease Control Rate (DCR) by Blinded Independent Central Review (BICR) and Investigator Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: From Baseline (Day 0) to data cut off (up to approximately 16.5 months)
measure: Time to Tumor Response (TTR) As Assessed by Blinded Independent Central Review (BICR) and Investigator Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: From Baseline (Day 0) to data cut off (up to approximately 16.5 months)
measure: Progression-free Survival (PFS) Assessed by Blinded Independent Central Review (BICR) and Investigator Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: From Baseline (Day 0) to data cut off (up to approximately 16.5 months)
measure: Overall Survival (OS) Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: From Baseline (Day 0) to data cut off (up to approximately 16.5 months)
measure: Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) and Other Safety Parameters During the Study
timeFrame: From Baseline (Day 0) to data cut off (up to approximately 16.5 months)
measure: Number of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline)
timeFrame: At Baseline, and post-Baseline. Post-Baseline including any of the following timepoints- Cycle 1, Days 1&8; Cycles 2&4 and every 2 cycles thereafter, Day 1 (each cycle, 21 days), and at EOT (~16.5 months).
measure: Number of Participants Who Have Treatment-emergent Anti-Drug Antibody (ADA)
timeFrame: At Baseline, and post-Baseline. Post-Baseline including any of the following timepoints- Cycle 1, Days 1&8; Cycles 2&4 and every 2 cycles thereafter, Day 1 (each cycle, 21 days), and at EOT (~16.5 months).
measure: Pharmacokinetic Parameter Maximum Serum Concentration (Cmax) Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: At baseline (-8 hour to 0 hour), pre-infusion, and 15 minutes, 1 hour, 2 hour, 4 hour, and 8 hour post-infusion of Cycle 1 and Cycle 3 (each cycle is 21 days)
measure: Pharmacokinetic Parameter Maximum Serum Concentration (Cmax) of MAAA-1181a Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: At baseline (-8 hour to 0 hour), pre-infusion, and 15 minutes, 1 hour, 2 hour, 4 hour, and 8 hour post-infusion of Cycle 1 and Cycle 3 (each cycle is 21 days)
measure: Pharmacokinetic Parameter Time to Reach Maximum Serum Concentration (Tmax) Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: At baseline (-8 hour to 0 hour), pre-infusion, and 15 minutes, 1 hour, 2 hour, 4 hour, and 8 hour post-infusion of Cycle 1 and Cycle 3 (each cycle is 21 days)
measure: Pharmacokinetic ParameterTrough Serum Concentration (Ctrough) Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: At baseline (-8 hour to 0 hour), pre-infusion, and 15 minutes, 1 hour, 2 hour, 4 hour, and 8 hour post-infusion of Cycle 1 and Cycle 3 (each cycle is 21 days)
measure: Pharmacokinetic ParameterTrough Serum Concentration (Ctrough) of MAAA-1181a Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: At baseline (-8 hour to 0 hour), pre-infusion, and 15 minutes, 1 hour, 2 hour, 4 hour, and 8 hour post-infusion of Cycle 1 and Cycle 3 (each cycle is 21 days)
measure: Pharmacokinetic of Area Under the Serum Concentration-Time Curve Up to Last Quantifiable Time (AUClast) and During Dosing Interval (AUCtau) Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: At baseline (-8 hour to 0 hour), pre-infusion, and 15 minutes, 1 hour, 2 hour, 4 hour, and 8 hour post-infusion of Cycle 1 and Cycle 3 (each cycle is 21 days)
measure: Pharmacokinetic of Area Under the Serum Concentration-Time Curve Up to Last Quantifiable Time (AUClast) and During Dosing Interval (AUCtau) of MAAA-1181a Following Administration of U3-1402 In Participants With Advanced or Metastatic Colorectal Cancer
timeFrame: At baseline (-8 hour to 0 hour), pre-infusion, and 15 minutes, 1 hour, 2 hour, 4 hour, and 8 hour post-infusion of Cycle 1 and Cycle 3 (each cycle is 21 days)
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology
state: Arkansas
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern Medical Faculty Foundation NMFF Hematology Oncology
state: Illinois
city: Baltimore
country: United States
facility: John Hopkins Sidney Kimmel Comprehensive Cancer Center
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Omaha
country: United States
facility: Nebraska Cancer Specialists
state: Nebraska
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Germantown
country: United States
facility: West Cancer Center
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon
state: Tennessee
city: Dallas
country: United States
facility: Mary Crowley Cancer Research
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center University of Texas
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists
state: Utah
city: Fairfax
country: United States
facility: Virgina Cancer Specialists
state: Virginia
city: Edegem
country: Belgium
facility: UZ Antwerpen
city: Leuven
country: Belgium
facility: UZ Leuven
city: Dijon
country: France
facility: Centre Georges-Franois Leclerc
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: Hospital St Antoine
city: Milano
country: Italy
facility: Asst Grande Ospedale Metropolitano Niguarda
city: Nagoya-shi
country: Japan
facility: Aichi Cancer Center Hospital
state: Nagoya-shi, Aichi-ken
city: Osaka-shi
country: Japan
facility: National Hospital Organization - Osaka National Hospital (ONH)
state: Osaka-shi, Osaka-fu
city: Osaka
country: Japan
facility: Kindai University Hospital
state: Osakasayama Shi
city: Chiba
country: Japan
facility: National Cancer Center Hospital East
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital Of JFCR
city: Ostrów Wielkopolski
country: Poland
facility: Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu
state: Poznan
city: Poznań
country: Poland
facility: Szpital Kliniczny Przemienienia Pańskiego.University Hospital, Chemotherapy Department
city: Warszawa
country: Poland
facility: M Sklodowska Curie Memorial Cancer Center
city: Warszawa
country: Poland
facility: M Sklodowska Curie Memorial Cancer Center
city: Barcelona
country: Spain
facility: Hospital del Mar - Institut Hospital del Mar d'Investigacions Mediques IMIM
city: Barcelona
country: Spain
facility: VHIO Valle de Hebron Instituto de Oncologia
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro, CIOCC
city: Sabadell
country: Spain
facility: Consorci Corporació Sanitària Parc Taulí de Sabadell
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: London
country: United Kingdom
facility: Royal Marsden Hospital NHS
city: London
country: United Kingdom
facility: Sarah Cannon Research Institute UK
city: London
country: United Kingdom
facility: Royal Marsden Hospital NHS
city: London
country: United Kingdom
facility: Sarah Cannon
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References: