Trastuzumab Deruxtecan in Participants With HER2-overexpressing Advanced or Metastatic Colorectal Cancer (DESTINY-CRC02)

A Phase 2, Multicenter, Randomized, Study of Trastuzumab Deruxtecan in Participants With HER2-overexpressing Locally Advanced, Unresectable or Metastatic Colorectal Cancer (DESTINY-CRC02)

This study will evaluate the efficacy, safety, and pharmacokinetics of Trastuzumab deruxtecan (T-DXd) in participants with human epidermal growth factor 2 (HER2)-overexpressing locally advanced, unresectable, or metastatic colorectal cancer (mCRC).

Study Overview

• Status: Active, not recruiting
• Conditions: Advanced Colorectal Cancer
• Intervention / Treatment: Drug: DS-8201a 5.4 mg/kg Q3W; Drug: DS-8201a 6.4 mg/kg Q3W

Detailed Description

This 2-stage study will evaluate participants with locally advanced, unresectable, or metastatic HER2-overexpressing colorectal cancer (CRC) (immunohistochemistry [IHC] 3+ or IHC 2+/ in situ hybridization [ISH]+) of v-raf murine sarcoma viral oncogene homologue B1 (BRAF) wild-type and either rat sarcoma viral oncogenes homologue (RAS) wild-type or mutant tumor type, previously treated with standard therapy. In the first stage, participants will be randomized 1:1 with 2 doses of T-DXd. After Stage 1 enrollment is complete, all further eligible participants will be registered to T-DXd administered IV in Stage 2. Participants will receive the assigned dose of T-DXd until progression of disease or the participant meets one of the discontinuation criteria.

• Study Type: Interventional
• Enrollment (Actual): 122
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Bedford Park, Australia
    • Flinders Medical Centre (Fmc)
  • Blacktown, Australia
    • Blacktown Hospital
  • Brisbane, Australia
    • Royal Brisbane & Women's Hospital
  • Clayton, Australia
    • Monash Medical Centre
  • Melbourne, Australia
    • Peter MacCallum Cancer Centre
• Belgium
  • Bruxelles, Belgium
    • UCL St-Luc
  • Edegem, Belgium
    • UZ Antwerpen
  • Gent, Belgium
    • Universitair Ziekenhuis Gent
• France
  • Lyon Cedex 03, France
    • Hôpital Edouard Herriot
  • MONTPELLIER Cedex 5, France
    • ICM-Val d'Aurelle
  • Nantes, France
    • University Hospital of Nantes
  • Paris, France
    • Hopital St Antoine
  • Toulouse, France
    • CHU Toulouse
• Italy
  • Milano, Italy
    • Fondazione Irccs Istituto Nazionale Dei Tumori
  • Milano, Italy
    • Asst Grande Ospedale Metropolitano Niguarda
  • Padova, Italy
    • Istituto Oncologico Veneto IRCCS
  • Vicenza, Italy
    • Azienda ULSS 8 Berica
• Japan
  • Aichi, Japan
    • Aichi Cancer Center Hospital
  • Chiba, Japan
    • National Cancer Center Hospital East
  • Ehime, Japan
    • National Hospital Organization Shikoku Cancer Center
  • Fukuoka, Japan
    • National Hospital Organization Kyushu Cancer Center
  • Hokkaido, Japan
    • Hokkaido University Hospital
  • Kanagawa, Japan
    • Kanagawa Cancer Center
  • Osaka, Japan
    • Kindai University Hospital
  • Osaka, Japan
    • National Hospital Organization Osaka National Hospital
  • Tokyo, Japan
    • National Cancer Center Hospital
  • Tokyo, Japan
    • The Cancer Institute Hospital of Jfcr
• Korea, Republic of
  • Goyang-si, Korea, Republic of
    • National Cancer Center (NCC)
  • Gyeonggi-do, Korea, Republic of
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Samsung Medical Center
  • Seoul, Korea, Republic of
    • Severance Hospital Yonsei University Health System
• Spain
  • Barcelona, Spain
    • Hospital Clínico y Provincial de Barcelona
  • Barcelona, Spain
    • Hospital Universitari Vall dHebron
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre
  • Pamplona, Spain
    • Clinica Universitaria de Navarra
• Taiwan
  • Taichung, Taiwan
    • China Medical University Hospital
  • Tainan, Taiwan
    • National Cheng Kung University Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
  • Taoyuan, Taiwan
    • Chang Gung Memorial Hospital-Linkou
• United Kingdom
  • Manchester, United Kingdom
    • The Christie
• United States
  • Kentucky
    • Louisville, Kentucky, United States, 40217
      • Norton Cancer Institute Audubon
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon (Tennessee Oncology - Nashville)
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

KEY Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for randomization/registration into the study:

1. Adults aged ≥20 years in Japan, Taiwan, and Korea, or those aged ≥18 years in other countries, at the time the Informed Consent Forms (ICFs) are signed.
2. Pathologically-documented, unresectable, recurrent, or metastatic colorectal adenocarcinoma. Participants must have v-raf murine sarcoma viral oncogene homologue B1 (BRAF) wild-type cancer and rat sarcoma viral oncogenes homologue (RAS) status identified in primary or metastatic site.

3. The following therapies should be included in prior lines of therapy:

   1. Fluoropyrimidine, oxaliplatin, and irinotecan, unless contraindicated
   2. Anti-epidermal growth factor receptor (EGFR) treatment, if RAS wild-type and if clinically indicated
   3. Anti-vascular endothelial growth factor (VEGF) treatment, if clinically indicated
   4. Anti-programmed death ligand 1 (PD-(L)-1) therapy, if the tumor is microsatellite instability (MSI)-high/deficient mismatch repair (dMMR), or tumor mutational burden (TMB)-high, if clinically indicated
4. Confirmed human epidermal growth factor 2 (HER2)-overexpressing status assessed by central laboratory and defined as immunohistochemistry (IHC) 3+ or IHC 2+/ in situ hybridization (ISH) +.
5. Presence of at least one measurable lesion assessed by the Investigator per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
7. Has left ventricular ejection fraction (LVEF) ≥50% within 28 days before randomization/registration.

KEY Exclusion Criteria:

Participants who meet any of the following criteria will be disqualified from entering the study:

1. Medical history of myocardial infarction (MI) within 6 months before randomization/registration, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV). Participants with troponin levels above the upper limit of normal (ULN) at Screening (as defined by the manufacturer), and without any MI-related symptoms, should have a cardiologic consultation before randomization/registration to rule out MI.
2. Has a corrected QT interval corrected with Fridericia's formula (QTcF) prolongation to >470 msec (female participants) or >450 msec (male participants) based on the average of the Screening triplicate 12-lead electrocardiograms (ECGs).
3. Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
4. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the randomization/registration, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.).
5. Any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, Sjögren syndrome, sarcoidosis, etc.) where there is documented, or a suspicion of, pulmonary involvement at the time of Screening.
6. Prior pneumonectomy.
7. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive brain metastases may be included in the study. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole-brain radiotherapy and randomization/registration.
8. Participants with leptomeningeal carcinomatosis.
9. Has known human immunodeficiency virus (HIV) infection.

10. Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral infection within 28 days before study randomization/registration. Participants with past or resolved hepatitis B virus (HBV) infection are eligible if hepatitis B surface antigen (HBsAg) negative (-) and antibody to hepatitis B core antigen (anti-HBc) positive (+).

    Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).

11. Previous treatment with a DXd-containing antibody-drug conjugate (ADC).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: T-DXd 5.4 mg/kg Q3W; Participants will be randomized to receive intravenous T-DXd administered at a dose of 5.4 mg/kg every 3 weeks (Q3W).	Drug: DS-8201a 5.4 mg/kg Q3W; DS-8201a for injection will be administered intravenously (IV) at a dose of 5.4 mg/kg every 3 weeks (Q3W); Other Names: T-DXd
Experimental: T-DXd 6.4 mg/kg Q3W; Participants will be randomized to receive intravenous T-DXd administered at a dose of 6.4 mg/kg every 3 weeks (Q3W).	Drug: DS-8201a 6.4 mg/kg Q3W; DS-8201a for injection will be administered intravenously (IV) at a dose of 6.4 mg/kg every 3 weeks (Q3W); Other Names: T-DXd

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Objective Response Rate (ORR) Based on Blinded Independent Central Review Following IV Administration of T-DXd in Participants With Human Epidermal Growth Factor Receptor 2-overexpressing Metastatic Colorectal Cancer	Confirmed objective response rate (ORR), defined as the number (percentage) of participants with complete response (CR) or partial response (PR), were assessed by blinded independent central review (BICR) based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR was defined as the disappearance of all target lesions and PR was defined as at least a 30% decrease in the sum of diameters of target lesions.	6 months post-dose administration to data cut off, up to 20 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Confirmed Objective Response Rate by Investigator Following Intravenous Administration of T-DXd in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Overexpressing Metastatic Colorectal Cancer	6 months post-dose administration to data cut off, up to 40 months
Duration of Response Following Intravenous Administration of T-DXd in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Overexpressing Metastatic Colorectal Cancer	6 months post-dose administration to data cut off, up to 40 months
Disease Control Rate Following Intravenous Administration of T-DXd in Participants With Human Epidermal Growth Factor Receptor 2 (HER2) -Overexpressing Metastatic Colorectal Cancer	6 months post-dose administration to data cut off, up to 40 months
Clinical Benefit Rate Following Intravenous Administration of T-DXd in Participants With Human Epidermal Growth Factor Receptor 2 (HER2) -Overexpressing Metastatic Colorectal Cancer	6 months post-dose administration to data cut off, up to 40 months
Progression Free Survival Following Intravenous Administration of T-DXd in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Overexpressing Metastatic Colorectal Cancer	6 months post-dose administration to data cut off, up to 40 months
Overall Survival Following Intravenous Administration of T-DXd in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Overexpressing Metastatic Colorectal Cancer	6 months post-dose administration to data cut off, up to 40 months
Percentage of Participants Reporting Treatment-emergent Adverse Events Following Intravenous Administration of T-DXd in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Overexpressing Metastatic Colorectal Cancer	Baseline up to 40 months
Change From Baseline in Patient-Reported Outcomes (PROs) in European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30)	Baseline up to 40 months
Change From Baseline in Patient-Reported Outcomes (PROs) in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Colorectal Cancer 29 (QLQ-CR29)	Baseline up to 40 months
Patient-Reported Outcomes (PROs) in the EuroQol Questionnaire (EQ) of 5 Dimensions (5D) on a Standardized 5- Level (5L) Descriptive Health Status Scale (EQ-5D-5L)	Baseline up to 40 months
Patient-Reported Outcomes (PROs) in Patient's Global Impression of Treatment Tolerability (PGI-TT)	Baseline up to 40 months
Patient-Reported Outcomes (PROs) in Patient Global Impression of Symptom Severity (PGIS)	Baseline up to 40 months
Patient-Reported Outcomes (PROs) in Patient Global Impression of Change (PGIC) Scores	Baseline up to 40 months
Inpatient Healthcare Resource Utilization	Baseline up to 40 months
Serum Concentration of T-DXd	Baseline up to 40 months
Serum Concentration of Total Anti-Human Epidermal Growth Factor Receptor 2 (HER2) Antibody	Baseline up to 40 months
Serum Concentration of Active Metabolite MAAA-1181a	Baseline up to 40 months
Percentage of Participants Positive for Treatment-emergent Anti-drug Antibodies (ADAs) and Neutralizing Antibodies (NAb) in Participants Who Were Administered T-DXd	Baseline up to 40 months

Collaborators and Investigators

• Sponsor: Daiichi Sankyo
• Collaborators: AstraZeneca
• Investigators: Study Director: Global Clinical Leader, Daiichi Sankyo

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2021
• Primary Completion (Actual): November 1, 2022
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: January 19, 2021
• First Submitted That Met QC Criteria: February 4, 2021
• First Posted (Actual): February 9, 2021

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Metastatic Colorectal Cancer; Advanced Colorectal Cancer; DS-8201a; T-DXd; Trastuzumab deruxtecan; HER2 Overexpressing Colorectal Cancer; BRAF Wild-Type Status
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Immunoconjugates; Camptothecin; Trastuzumab deruxtecan
• Other Study ID Numbers: DS8201-A-U207; 2020-004782-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https:// vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No