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

Metastatic Colorectal Cancer Clinical Trial

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 Details — Status: Terminated

Administrative data

• NCT number: NCT04479436
• Other study ID #: U31402-A-U202
• Secondary ID: 2019-004418-32
• Status: Terminated
• Phase: Phase 2
• Start date: September 14, 2020
• Est. completion date: February 3, 2022

Study information

• Verified date: January 2023
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 40
• Est. completion date: February 3, 2022
• Est. primary completion date: February 3, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• Patritumab Deruxtecan
U3-1402 will be dosed at 5.6 mg/kg as an intravenous (IV) infusion administered on Day 1 of each 21-day cycle.

Locations

Country	Name	City	State
Belgium	UZ Antwerpen	Edegem
Belgium	UZ Leuven	Leuven
France	Centre Georges-Franois Leclerc	Dijon
France	CHU Nantes	Nantes
France	Hospital St Antoine	Paris
Italy	Asst Grande Ospedale Metropolitano Niguarda	Milano
Japan	National Cancer Center Hospital East	Chiba
Japan	Aichi Cancer Center Hospital	Nagoya-shi	Nagoya-shi, Aichi-ken
Japan	Kindai University Hospital	Osaka	Osakasayama Shi
Japan	National Hospital Organization - Osaka National Hospital (ONH)	Osaka-shi	Osaka-shi, Osaka-fu
Japan	The Cancer Institute Hospital Of JFCR	Tokyo
Poland	Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im. Karola Marcinkowskiego w Poznaniu	Ostrów Wielkopolski	Poznan
Poland	Szpital Kliniczny Przemienienia Panskiego.University Hospital, Chemotherapy Department	Poznan
Poland	M Sklodowska Curie Memorial Cancer Center	Warszawa
Poland	M Sklodowska Curie Memorial Cancer Center	Warszawa
Spain	Hospital del Mar - Institut Hospital del Mar d'Investigacions Mediques IMIM	Barcelona
Spain	VHIO Valle de Hebron Instituto de Oncologia	Barcelona
Spain	Hospital Universitario HM Sanchinarro, CIOCC	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Consorci Corporació Sanitària Parc Taulí de Sabadell	Sabadell
Spain	Hospital Universitario Virgen del Rocio	Sevilla
United Kingdom	Royal Marsden Hospital NHS	London
United Kingdom	Royal Marsden Hospital NHS	London
United Kingdom	Sarah Cannon	London
United Kingdom	Sarah Cannon Research Institute UK	London
United States	Emory University	Atlanta	Georgia
United States	University of Colorado Hospital	Aurora	Colorado
United States	John Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	Northwestern Medical Faculty Foundation NMFF Hematology Oncology	Chicago	Illinois
United States	Mary Crowley Cancer Research	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Virgina Cancer Specialists	Fairfax	Virginia
United States	Highlands Oncology	Fayetteville	Arkansas
United States	West Cancer Center	Germantown	Tennessee
United States	MD Anderson Cancer Center University of Texas	Houston	Texas
United States	Sarah Cannon	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Nebraska Cancer Specialists	Omaha	Nebraska
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University	Saint Louis	Missouri
United States	Utah Cancer Specialists	Salt Lake City	Utah
United States	Moffitt Cancer Center	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.

Countries where clinical trial is conducted

United States,  Belgium,  France,  Italy,  Japan,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	From baseline up to disease progression by BICR, death, lost to follow up, or withdrawal of consent by subject (whichever occurs first), up to approximately 27 months
Secondary	Duration of Response (DOR) As Assessed by Blinded Independent Central Review (BICR) Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer	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.	From baseline up to disease progression by BICR, death, lost to follow up, or withdrawal of consent by subject (whichever occurs first), up to approximately 27 months
Secondary	Objective Response Rate (ORR) As Assessed by Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer	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.	From baseline up to disease progression, death, lost to follow up, or withdrawal of consent by subject (whichever occurs first), up to approximately 27 months
Secondary	Duration of Response (DoR) As Assessed by Investigator Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer	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.	From baseline up to disease progression, death, lost to follow up, or withdrawal of consent by subject (whichever occurs first), up to approximately 27 months
Secondary	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	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	From baseline up to disease progression by BICR, death, lost to follow up, or withdrawal of consent by subject (whichever occurs first), up to approximately 27 months
Secondary	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	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	From baseline up to disease progression by BICR, death, lost to follow up, or withdrawal of consent by subject (whichever occurs first), up to approximately 27 months
Secondary	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	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	From baseline until disease progression by BICR, death, lost to follow up, or withdrawal of consent by subject (whichever occurs first), assessed up to 27 months
Secondary	Overall Survival (OS) Following Administration of U3-1402 In Participants with Advanced or Metastatic Colorectal Cancer	OS defined as the time from the start of study treatment to the date of death due to any cause.	From baseline up to the date of death due to any cause or 27 months, whichever is earlier.
Secondary	Summary of Reported Treatment-emergent Adverse Events (TEAEs) and other safe parameters during the study	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	From baseline up to Day 40 post last dose, approximately 27 months
Secondary	Proportion of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline)	The immunogenicity of U3-1402 will be assessed.	From baseline up to 3 months post end of treatment, up to approximately 27 months
Secondary	Proportion of Participants Who Have Treatment-emergent ADA	The immunogenicity of U3-1402 will be assessed.	From baseline up to 3 months post end of treatment, up to approximately 27 months
Secondary	Pharmacokinetic (PK) of Maximum Serum Concentration (Cmax) of analytes of U3-1402 Following Administration In Participants with Advanced or Metastatic Colorectal Cancer	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	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 through Cycle 8 (each cycle is 21 days)
Secondary	Pharmacokinetic of Time to Reach Maximum Serum Concentration (Tmax) of analytes of U3-1402 Following Administration In Participants with Advanced or Metastatic Colorectal Cancer	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	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 through Cycle 8 (each cycle is 21 days)
Secondary	Pharmacokinetic of Trough Serum Concentration (Ctrough) of analytes of U3-1402 Following Administration In Participants with Advanced or Metastatic Colorectal Cancer	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	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 through Cycle 8 (each cycle is 21 days)
Secondary	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	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	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 through Cycle 8 (each cycle is 21 days)