Clinical Trials /

Trastuzumab Deruxtecan in Participants With HER2-overexpressing Advanced or Metastatic Colorectal Cancer

NCT04744831

Description:

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).

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: DS8201-A-U207
  • SECONDARY ID: 2020-004782-39
  • NCT ID: NCT04744831

Conditions

  • Advanced Colorectal Cancer

Interventions

DrugSynonymsArms
DS-8201a 5.4 mg/kg Q3WT-DXdT-DXd 5.4 mg/kg Q3W
DS-8201a 6.4 mg/kg Q3WT-DXdT-DXd 6.4 mg/kg Q3W

Purpose

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).

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.
    

Trial Arms

NameTypeDescriptionInterventions
T-DXd 5.4 mg/kg Q3WExperimentalParticipants will be randomized to receive intravenous T-DXd administered at a dose of 5.4 mg/kg every 3 weeks (Q3W).
  • DS-8201a 5.4 mg/kg Q3W
T-DXd 6.4 mg/kg Q3WExperimentalParticipants will be randomized to receive intravenous T-DXd administered at a dose of 6.4 mg/kg every 3 weeks (Q3W).
  • DS-8201a 6.4 mg/kg Q3W

Eligibility Criteria

        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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in Confirmed Objective Response Rate by Blinded Independent Central Review Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Human epidermal growth factor receptor 2-overexpressing Metastatic Colorectal Cancer
Time Frame:The first 80 participants have 12 weeks of follow-up or have discontinued the treatment for the Interim Analysis (IA), 6 months after the last participant is registered for the primary analysis
Safety Issue:
Description:Confirmed objective response rate (ORR), defined as the proportion of participants with complete response (CR) or partial response (PR), will be 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.

Secondary Outcome Measures

Measure:Change in Confirmed Objective Response Rate by Investigator Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Human epidermal growth factor receptor 2 (HER2)-overexpressing Metastatic Colorectal Cancer
Time Frame:The first 80 participants have 12 weeks of follow-up or have discontinued the treatment for the Interim Analysis (IA) and 6 months after the last participant is registered for the primary analysis
Safety Issue:
Description:Confirmed objective response rate (ORR), defined as the proportion of participants with complete response (CR) or partial response (PR), will be assessed by the Investigator 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.
Measure:Change in Duration of Response Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Human epidermal growth factor receptor 2 (HER2)-overexpressing Metastatic Colorectal Cancer
Time Frame:The first 80 participants have 12 weeks of follow-up or have discontinued the treatment for the Interim Analysis (IA) and 6 months after the last participant is registered for the primary analysis
Safety Issue:
Description:Duration of response (DoR) is defined as the time from the initial response (complete response [CR] or partial response [PR]) until documented tumor progression or death from any cause. DoR is only defined for participants who achieved confirmed CR or PR. 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.
Measure:Change in Disease Control Rate Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Human Epidermal Growth Factor Receptor 2 (HER2) -Overexpressing Metastatic Colorectal Cancer
Time Frame:The first 80 participants have 12 weeks of follow-up or have discontinued the treatment for the Interim Analysis (IA) (DCR) and 6 months after the last participant is registered for the primary analysis (DCR, CBR)
Safety Issue:
Description:Disease control rate (DCR) is the sum of complete response (CR), partial response (PR), and stable disease (SD) rates. CR was defined as disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD); at least a 20% increase in the sum of diameters of target lesions. DCR based on Investigator assessments Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
Measure:Change in Clinical Benefit Ratio Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Human Epidermal Growth Factor Receptor 2 (HER2) -Overexpressing Metastatic Colorectal Cancer
Time Frame:The first 80 participants have 12 weeks of follow-up or have discontinued the treatment for the Interim Analysis (IA) (DCR) and 6 months after the last participant is registered for the primary analysis (DCR, CBR)
Safety Issue:
Description:Clinical Benefit Ratio (CBR), defined as the proportion of participants who achieved complete response (CR), partial response (PR), and stable disease (SD) for at least 6 months. CR was defined as disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD); at least a 20% increase in the sum of diameters of target lesions. CBR based on the blinded independent central review (BICR) and CBR based on Investigator assessments Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
Measure:Change in Progression Free Survival Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Human epidermal growth factor receptor 2 (HER2)-overexpressing Metastatic Colorectal Cancer
Time Frame:The first 80 participants have 12 weeks of follow-up or have discontinued the treatment for the Interim Analysis (IA) (PFS) and 6 months after the last participant is registered for the primary analysis (PFS, OS)
Safety Issue:
Description:Progression-Free Survival (PFS), defined as the time from date of randomization/registration until first objective radiographic tumor progression or death from any cause, based on the blinded independent central review (BICR) and Investigator assessment according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
Measure:Change in Overall Survival Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Human epidermal growth factor receptor 2 (HER2)-overexpressing Metastatic Colorectal Cancer
Time Frame:The first 80 participants have 12 weeks of follow-up or have discontinued the treatment for the Interim Analysis (IA) (PFS) and 6 months after the last participant is registered for the primary analysis (PFS, OS)
Safety Issue:
Description:Overall Survival (OS), defined as the time from date of randomization/registration until death from any cause.
Measure:The Percentage of Participants Reporting Treatment-emergent Adverse Events Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Human epidermal growth factor receptor 2 (HER2)-overexpressing Metastatic Colorectal Cancer
Time Frame:12 weeks after the first 80 participants are randomized for Interim Analysis (IA), up to approximately 18 months.
Safety Issue:
Description:Treatment-emergent Adverse Events (TEAEs)
Measure:The Percentage of Participants Reporting Treatment-emergent Adverse Events Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Human epidermal growth factor receptor 2 (HER2)-overexpressing Metastatic Colorectal Cancer
Time Frame:6 months after the last participant is registered for the primary analysis, up to approximately 30 months.
Safety Issue:
Description:Treatment-emergent Adverse Events (TEAEs)
Measure: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)
Time Frame:6 months after the last participant is registered or later
Safety Issue:
Description:The EORTC QLQ-C30 consists of 30 questions assessing global health-related quality of life, five aspects of subject functioning (physical, emotional, role, cognitive, and social), three symptom scales (fatigue, nausea and vomiting, and pain), and six single-items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All of the scales and single-item measures range in score from 0 to 100. Higher scores for functioning scales and global health status indicate a better level of functioning while higher scores on the symptom and single-item scales indicate a higher level of symptoms.
Measure: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)
Time Frame:6 months after the last participant is registered or later
Safety Issue:
Description:The EORTC QLQ-CR29 consists of functional scales (Body Image, Future projections, Weight, Sexual interest) and symptom scales (urinary frequency, blood and mucus in stool, stool frequency, urinary incontinence, dysuria, abdominal pain, buttock pain, bloating, dry mouth, hair loss, taste, flatulence, fecal incontinence, sore skin, embarrassment, impotence, dyspareunia). All scales and single-item measurements range from 0 to 100. A higher score on a functional scale indicates better functioning. A higher score for a symptom scale/item indicates higher symptomatology and problem level.
Measure: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)
Time Frame:6 months after the last participant is registered or later
Safety Issue:
Description:The EQ-5D questionnaire is made up for two components; health state description and evaluation. The EQ-5D-5L is the health state description for measuring health status. The descriptive system comprises the 5 dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The participants self-rate each dimension on a 5-point, categorical scale: no problems, slight problems, moderate problems, severe problems, and extreme problems.
Measure:Patient-Reported Outcomes (PROs) in Patient's Global Impression of Treatment Tolerability (PGI-TT)
Time Frame:6 months after the last participant is registered or later
Safety Issue:
Description:The PGI-TT item is included to assess how a patient perceives the overall tolerability of the study treatment over the past 7 days. This is a single-item questionnaire, and patients will rate the bother associated with any treatment-related symptoms using response options on a 5-point scale ranging from 1 (Not at all) to 5 (Very much); 1-Not at all, 2-A little bit, 3-Somewhat, 4-Quite a bit, 5-Very much. Higher scores indicate a worse outcome.
Measure:Patient-Reported Outcomes (PROs) in Patient Global Impression of Symptom Severity (PGIS)
Time Frame:6 months after the last participant is registered or later
Safety Issue:
Description:The PGIS item is included to assess how a patient perceives the overall severity of cancer symptoms over the past 7 days. This is a single-item questionnaire, and patients will choose the response that best describes the severity of their overall cancer symptoms with options on a 6-point scale ranging from 1 (No symptoms) to 6 (Very Severe); 1-No Symptoms, 2-Very Mild, 3-Mild, 4-Moderate, 5-Severe, 6-Very Severe. Higher scores indicate a worse outcome.
Measure:Patient-Reported Outcomes (PROs) in Patient Global Impression of Change (PGIC) Scores
Time Frame:6 months after the last participant is registered or later
Safety Issue:
Description:The PGIC item is included to assess how a patient perceives their overall change in health status since the start of study treatment. This is a single-item questionnaire, and patients will choose from response options on a 7-point scale ranging from 1 (Much Better) to 7 (Much worse); 1- Much Better, 2-Moderately Better, 3-A Little Better, 4-About the Same, 5-A Little Worse, 6-Moderately Worse, 7-Much Worse. Higher scores indicate a worse outcome.
Measure:Inpatient Healthcare Resource Utilization
Time Frame:6 months after the last participant is registered or later
Safety Issue:
Description:Healthcare resource use will be captured/collected, including inpatient admissions, intensive care unit admissions, and length of stay in hospital.
Measure:Serum Concentration of Trastuzumab Deruxtecan (T-DXd)
Time Frame:6 months after the last participant is registered or later
Safety Issue:
Description:
Measure:Serum Concentration of Total Anti-Human Epidermal Growth Factor Receptor 2 (HER2) Antibody
Time Frame:6 months after the last participant is registered or later
Safety Issue:
Description:
Measure:Serum Concentration of Active Metabolite MAAA-1181a
Time Frame:6 months after the last participant is registered or later
Safety Issue:
Description:
Measure:Percentage of Participants Positive for Treatment-emergent Anti-drug Antibodies (ADAs) and Neutralizing antibodies (NAb) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd)
Time Frame:6 months after the last participant is registered or later
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Daiichi Sankyo, Inc.

Trial Keywords

  • Metastatic Colorectal Cancer
  • HER2 Overexpressing Colorectal Cancer
  • BRAF Wild-Type Status
  • DS-8201a
  • Trastuzumab deruxtecan
  • Advanced Colorectal Cancer
  • T-DXd

Last Updated

May 12, 2021