A Study of T-DXd in Participants With or Without Brain Metastasis Who Have Previously Treated Advanced or Metastatic HER2 Positive Breast Cancer
- Registration Number
- NCT04739761
- Lead Sponsor
- AstraZeneca
- Brief Summary
This is open-label, multicenter, international study, assessing the efficacy and safety of Trastuzumab deruxtecan (T-DXd) in participants with or without brain metastasis (BMs), with previously-treated advanced/metastatic HER2-positive breast cancer whose disease has progressed on prior anti-HER2-based regimens and who received no more than 2 lines/regimens of therapy in the metastatic setting (excluding tucatinib).
- Detailed Description
Approximately 500 eligible participants will be enrolled into 1 of 2 cohorts (250 participants in each cohort) according to the presence or absence of BMs at baseline. Cohort 1 will include participants without BM at baseline and Cohort 2 will consist of participants with BM at baseline.
After study intervention discontinuation, all participants will undergo an end-of-treatment visit (within 7 days of discontinuation) and will be followed up for safety assessments 40 (+ up to 7) days after the discontinuation of all study intervention.
All participants will be followed up for survival status and duration of treatment on subsequent therapies after intervention discontinuation every 3 months (± 14 days) from the date of the safety follow-up until death, withdrawal of consent, or the end of the study, as per defined in the protocol.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 506
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Trastuzumab Deruxtecan Trastuzumab Deruxtecan Participants with or without BM at baseline will receive intravenous (IV) T-DXd, 5.4 mg/kg, every 3 weeks (21-day cycle) until Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) defined radiological progression outside central nervous system, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.
- Primary Outcome Measures
Name Time Method Objective Response Rate (ORR) in Cohort 1 (Participants Without Brain Metastasis at Baseline) From first dose (Day 1) to progression of disease (up to 2 years 7 months) The ORR is defined as the percentage (%) of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Progression-free Survival (PFS) Rate at 12 Months in Cohort 2 (Participants With Brain Metastasis at Baseline) At 12 months The PFS rate is the percentage of participants alive and free of disease progression at 12 months, estimated by the Kaplan-Meier method.
- Secondary Outcome Measures
Name Time Method Duration of Treatment on Subsequent Lines of Therapy From the date of first dose of a subsequent therapy until date of last dose of therapy (up to 2 years 7 months) Duration of treatment on subsequent therapy is defined as the time from the date of first dose of a subsequent therapy until date of the last dose of that therapy.
Duration of Response (DoR) From the date of first documented confirmed response until date of documented progression (up to 2 years 7 months) Duration of response is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1 as assessed by ICR or death due to any cause.
Survival Rate at 12 Months At 12 Months Survival rate is the percentage of participants alive at 12 months, estimated by the Kaplan-Meier method.
Objective Response Rate in Cohort 2 (Participants With Brain Metastasis at Baseline) From first dose (Day 1) to progression of disease (up to 2 years 7 months) The ORR is defined as the percentage of participants who have a confirmed CR or confirmed PR, as determined by ICR per RECIST 1.1.
Time to Progression From first dose (Day 1) to progression of disease (up to 2 years 7 months) Time to progression by RECIST 1.1 per ICR is defined as the time from the date of the first dose of study intervention to the date of documented disease progression.
Second Progression-Free Survival Rate at 12 Months At 12 Months Second progression-free survival rate is the percentage of participants alive and free from a second progression on next-line treatment at 12 months, estimated by the Kaplan-Meier method. The second progression is defined as the earliest progression event subsequent to the first anti-cancer therapy after the initial progression.
Incidence of New Symptomatic Central Nervous System (CNS) Metastasis During Treatment Without CNS Metastasis at Baseline (Cohort 1) From first dose (Day 1) to end of treatment (up to 2 years 7 months) The incidence rate is defined as proportion of participants with new symptomatic CNS metastases during treatment period in participants without symptomatic CNS metastasis at baseline.
Time to Next Progression (CNS or Extracranial) or Death From date of first documented isolated CNS progression to the date of the next documented disease progression (up to 2 years 7 months) The time to next progression is defined as the time from the date of the first documented isolated CNS progression to the date of the next documented disease progression (CNS or extracranial) per RECIST 1.1 or death and has been summarized descriptively in participants who have developed isolated CNS progression, receive local therapy, and continue on protocol therapy.
Site (CNS vs Extracranial vs Both) of Next Progression From the date of the first documented isolated CNS progression to the date of the next documented CNS disease progression (up to 2 years 7 months) Site of next progression (CNS \[CNS RECIST 1.1\] or extracranial \[systemic RECIST 1.1\] in participants who developed isolated CNS progression, received local therapy, and continued on protocol therapy.
Central Nervous System Progression-free Survival Rate at 12 Months in Participants With Brain Metastasis at Baseline (Cohort 2) At 12 Months Central nervous system progression free survival rate is the percentage of participants free from central nervous system progression at 12 months, estimated by the Kaplan-Meier method.
Time to New CNS Lesions in Participants With Brain Metastasis at Baseline (Cohort 2) From first dose (Day 1) to the date of documented new CNS lesions (up to 2 years 7 months) The time to new CNS lesions is defined as the time from the date of the first dose of study intervention to the date of documented new CNS lesions by RECIST 1.1 per ICR.
Central Nervous System Objective Response Rate in Participants With Brain Metastasis at Baseline by ICR (Cohort 2) From first dose (Day 1) until CNS progression of disease (up to 2 years 7 months) The CNS ORR is defined as the percentage of participants with measurable brain metastasis at baseline who have a confirmed CR or confirmed PR of brain lesions, as determined by ICR per CNS RECIST 1.1.
Central Nervous System Duration of Response in Participants With Brain Metastasis at Baseline (Cohort 2) From date of first documented confirmed CNS response until CNS progression of disease (up to 2 years 7 months) The CNS DoR is defined as the time from the date of first documented confirmed CNS response until date of documented CNS progression per CNS RECIST 1.1 as assessed by ICR or death due to any cause.
Number of Participants With Best on Treatment Visit Response on the European Organization for the Research and Treatment of Cancer 30-Item Core Quality of Life Questionnaire (EORTC QLQ-C30) Time from first dose up to 47 days after last dose, or prior to starting any subsequent therapy, or for up to 2 years 7 months, whichever occurred first The EORTC QLQ-C30 is a 30-item questionnaire for cancer assessment. Increased scores indicate improvement; decreased scores indicate deterioration. Physical function: ≥+9= improvement, ≤-10=deterioration, otherwise=no change; Role functioning: ≤-6=deterioration, otherwise=no change; Social functioning: ≥+8=improvement, ≤-7=deterioration, otherwise=no change; Cognitive functioning: ≥+ 5=improvement, ≤- 4=deterioration, otherwise=no change; Global Health Status: ≥+2=improvement, ≤-8=deterioration, otherwise=no change; Fatigue: ≥+8=improvement, ≤-8=deterioration, otherwise=no change; Nausea and vomiting: ≤-11=deterioration, otherwise=no change; Appetite loss: ≤-14=deterioration, otherwise=no change; rest of scales: ≥+10=improvement, ≤-10=deterioration, otherwise=no change. Best on treatment response is best response category (improvement, no change, and deterioration) achieved by participants between first dose and 47 days after last dose, and prior to starting any anticancer therapy.
Number of Participants With Neurologic Assessment in Neuro-Oncology Scale (NANO Scale) Time from first dose up to 47 days after last dose, or prior to starting any subsequent therapy, or for up to 2 years 7 months, whichever occurred first The NANO scale is a clinician-reported assessment of neurologic functioning in neuro-oncology participants. The instrument captures 9 domains (gait, strength, ataxia, sensation, visual fields, facial strength, language, level of consciousness, and behavior) and was developed to provide a simple, objective assessment of neurologic function that would be combined with radiographic assessment to provide an overall outcome assessment for neuro-oncology participants in clinical trials and in daily practice. The soring scale for Gait consists of score range 0-3, Strength consists of score range 0-2, ataxia (upper extremity) consists of scale range 0-2 and sensation as 0. Higher scores indicate worse neurologic function. The response categories reported are changes from first post-baseline score to worst on-treatment score at any point of treatment.
Cognitive Functions Tests: Paired Associates Learning (PAL) First Attempt Memory Score (PALFAMS) Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle) The PAL is a computerized, self-completed cognitive test used to capture cognitive function, including attention, memory, and executive function. This gamified test included PAL and was a low-burden, highly sensitive, precise measure of cognitive function. The PALFAMS is the number of times a participant chose the correct box on their first attempt when recalling the pattern locations, calculated across all assessed trials. A higher number of events of selecting correct boxes indicates better cognitive function. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.
Cognitive Functions Tests: Paired Associates Learning Total Errors Adjusted (PALTEA) Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle) The PAL is a computerized, self-completed cognitive test used to capture cognitive function, including attention, memory, and executive function. This gamified test included PALTEA and was a low-burden, highly sensitive, precise measure of cognitive function. PALTEA is the number of times a participant chose the incorrect box for a stimulus on assessment problems, plus an adjustment for the estimated number of errors they would have made on any problems, attempts, and recalls they did not reach. A higher number of events of selecting incorrect boxes indicates worse cognitive function. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.
Cognitive Functions Tests: Reaction Time (RTI) Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle) This is a computerized, self-completed cognitive test used to capture cognitive function, including attention, memory, and executive function. This gamified test included Reaction Time Task (RTI) and was low-burden, highly sensitive, precise measures of cognitive function. RTI Median Five-Choice Movement Time: median time taken for a participant to release response button and select target stimulus after it flashed yellow on screen. Calculated across correct, assessed trials in which stimulus could appear in any one of five locations. RTI Median Five-Choice Reaction Time: median duration it took for a participant to release response button after presentation of target stimulus. Calculated across correct, assessed trials in which stimulus could appear in any one of five locations. Measured in milliseconds. Higher reaction times indicate worse cognitive function. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.
Cognitive Functions Tests: Spatial Working Memory (SWM) Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle) The SWM is a computerized cognitive test. The SWM Between Errors (SWMBE) is number of times a participant incorrectly revisits a box in which a token has previously been found, calculated across all 4, 6, and 8 token trials. SWM Between Errors 4 Boxes (SWMBE4), SWM Between Errors 6 Boxes (SWMBE6), and SWM Between Errors 8 Boxes (SWMBE8) are number of times a participant revisits a box in which a token has previously been found. These are calculated across all trials with 4 tokens only for SWMBE4, 6 tokens only for SWMBE6, and 8 tokens only for SWMBE8. SWM Total Errors is number of times a box is selected that is certain not to contain a token and therefore should not have been visited by participant. A higher number of incorrect revisit events to previously found token boxes indicates worse cognitive function, and a lower number of revisit events indicates better cognitive function. Here, baseline was last non-missing value prior to administration of first dose of study intervention.
Cognitive Functions Tests: Spatial Working Memory Strategy (SWMS) Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle) The SWM is a computerized cognitive test. The SWMS, the number of times a participant restarted search patterns from the same initial box, indicating their use of a planned strategy to find tokens. An increased number of events where search patterns started from the same initial box suggested participants were using a planned strategy to find tokens, which indicated better cognitive function. Here, a low score indicated high strategy use (1 = they always began the search from the same box). Conversely, high scores represented a decrease in events of beginning searches from the same box. Instead, starting from many different boxes suggested the participant was not using a consistent strategy, which indicated worse cognitive function. This was calculated across assessed trials with 6 tokens or more. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.
St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis From time of ILD/pneumonitis diagnosis (every week) until end of safety follow-up (47 days post last dose) (up to 2 years 7 months) The effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline brain metastasis was evaluated. The SGRQ-I is an idiopathic pulmonary fibrosis-specific version of the instrument developed and validated for use among participants with idiopathic pulmonary fibrosis, a type of ILD. The SGRQ-I was used to assess the HRQoL among participants who have been diagnosed with ILD/pneumonitis. It includes 34 of the original SGRQ items determined to be most reliable for assessing the HRQoL of participants with idiopathic pulmonary fibrosis. The instrument yields 3 domain scores (symptoms, activity, and impact) as well as a total score, with scores ranging from 0 to 100. Higher scores indicate greater impairment in HRQoL.
MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants Baseline, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 39 Day 1 (21 days cycle) The T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline brain metastasis was evaluated. The MDASI brain tumor module includes 9 symptoms specific to brain tumors (weakness on one side of the body, difficulty understanding, difficulty speaking, seizures, difficulty concentrating, problems with vision, change in appearance, change in bowel pattern (diarrhea or constipation), and irritability). These 9 items will be used to capture symptoms associated with brain metastasis for those diagnosed with brain metastasis. Each item is rated on an 11-point numeric rating scale on a scale of 0-10, with higher scores indicating greater symptom severity. Here, baseline was the last non-missing value prior to administration of the first dose of study intervention.
Number of Participants With Adverse Events (AEs) From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months) The safety and tolerability of the participants who received T-DXd was evaluated.
SAE=Serious adverse events; CTCAE=Common Terminology for Adverse EventsNumber of Participants With Investigator-assessed ILD/Pneumonitis From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months) The number of participants with ILD/Pneumonitis were by grouped term based on Investigator-reported preferred terms. No adjudication was performed.
Number of Participants With ILD Clinical Symptoms Resolution Among ILD/Pneumonitis Participants Who Have Been Treated With High Dose Steroid From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months) The number of participants with ILD clinical symptoms resolution in ILD/Pneumonitis participants who have been treated with high dose steroid (\>2 mg dexamethasone) were evaluated.
Trial Locations
- Locations (1)
Research Site
🇬🇧Edinburgh, United Kingdom