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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Advanced Colorectal Cancer

Intervention / Treatment
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* Drug: DS-8201a 5.4 mg/kg Q3W
* Drug: DS-8201a 6.4 mg/kg Q3W


Participation Criteria
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Eligibility Criteria
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KEY Inclusion Criteria: Participants must meet all of the following criteria to be eligible for randomization/registration into the study: 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. 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. The following therapies should be included in prior lines of therapy: Fluoropyrimidine, oxaliplatin, and irinotecan, unless contraindicated Anti-epidermal growth factor receptor (EGFR) treatment, if RAS wild-type and if clinically indicated Anti-vascular endothelial growth factor (VEGF) treatment, if clinically indicated 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 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) +. Presence of at least one measurable lesion assessed by the Investigator per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. 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: 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. 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). 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. 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.). 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. Prior pneumonectomy. 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. Participants with leptomeningeal carcinomatosis. Has known human immunodeficiency virus (HIV) infection. 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). Previous treatment with a DXd-containing antibody-drug conjugate (ADC).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T-DXd 5.4 mg/kg Q3W<br>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<br>* DS-8201a for injection will be administered intravenously (IV) at a dose of 5.4 mg/kg every 3 weeks (Q3W)<br>* Other names: T-DXd;|
| Experimental: T-DXd 6.4 mg/kg Q3W<br>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<br>* DS-8201a for injection will be administered intravenously (IV) at a dose of 6.4 mg/kg every 3 weeks (Q3W)<br>* Other names: T-DXd;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 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 | 
| 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 | 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. | 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 | 
| 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 | 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. | 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) | 
| 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 | 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. | 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) | 
| 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 | 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. | 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) | 
| Change in Overall Survival Following Intravenous Administration of Trastuzumab Deruxtecan in Participants With Human epidermal growth factor receptor 2 (HER2)-overexpressing Metastatic Colorectal Cancer | Overall Survival (OS), defined as the time from date of randomization/registration until death from any cause. | 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) | 
| 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 | Treatment-emergent Adverse Events (TEAEs) | 12 weeks after the first 80 participants are randomized for Interim Analysis (IA), up to approximately 18 months. | 
| 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 | Treatment-emergent Adverse Events (TEAEs) | 6 months after the last participant is registered for the primary analysis, up to approximately 30 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) | 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. | 6 months after the last participant is registered or later | 
| 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) | 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. | 6 months after the last participant is registered or later | 
| 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) | 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. | 6 months after the last participant is registered or later | 
| Patient-Reported Outcomes (PROs) in Patient's Global Impression of Treatment Tolerability (PGI-TT) | 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. | 6 months after the last participant is registered or later | 
| Patient-Reported Outcomes (PROs) in Patient Global Impression of Symptom Severity (PGIS) | 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. | 6 months after the last participant is registered or later | 
| Patient-Reported Outcomes (PROs) in Patient Global Impression of Change (PGIC) Scores | 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. | 6 months after the last participant is registered or later | 
| Inpatient Healthcare Resource Utilization | Healthcare resource use will be captured/collected, including inpatient admissions, intensive care unit admissions, and length of stay in hospital. | 6 months after the last participant is registered or later | 
| Serum Concentration of Trastuzumab Deruxtecan (T-DXd) |  | 6 months after the last participant is registered or later | 
| Serum Concentration of Total Anti-Human Epidermal Growth Factor Receptor 2 (HER2) Antibody |  | 6 months after the last participant is registered or later | 
| Serum Concentration of Active Metabolite MAAA-1181a |  | 6 months after the last participant is registered or later | 
| Percentage of Participants Positive for Treatment-emergent Anti-drug Antibodies (ADAs) and Neutralizing antibodies (NAb) in Participants Who Were Administered Trastuzumab Deruxtecan (T-DXd) |  | 6 months after the last participant is registered or later | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Colorectal Cancer, Metastatic Colorectal Cancer, HER2 Overexpressing Colorectal Cancer, BRAF Wild-Type Status, DS-8201a, Trastuzumab deruxtecan, T-DXd