A Study of T-DXd in Participants With or Without Brain Metastasis Who Have Previously Treated Advanced or Metastatic HER2 Positive Breast Cancer

Phase 3Active Not RecruitingNCT04739761

AstraZeneca506 enrolled

Overview

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).

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

506

Conditions

Breast Cancer

Interventions

Trastuzumab DeruxtecanDRUG

Participants will receive T-DXd administered using an IV bag containing 5% (w/v) dextrose injection infusion solution.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

Inclusion: * Participants should have pathologically documented breast cancer that is: unresectable/advanced or metastatic; confirmed HER2-positive status expression as determined according to American Society of Clinical Oncology/College of American Pathologists guidelines * Participant must have either: no evidence of BM, or untreated BM on screening contrast brain magnetic resonance imaging/ computed tomography (MRI/CT) scan, not needing immediate local therapy or previously-treated stable or progressing BM * Participants with BMs must be neurologically stable * For participants requiring radiotherapy due to BMs, there should be an adequate washout period before day of first dosing: * ≥ 7 days since stereotactic radiosurgery or gamma knife * ≥ 21 days since whole brain radiotherapy * Eastern Cooperative Oncology Group performance status 0-1 * Previous breast cancer treatment: radiologic or objective evidence of disease progression on or after HER2 targeted therapies and no more than 2 lines/regimens of therapy in the metastatic setting * Participant with the following measurable: at least 1 lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter with CT or MRI and is suitable for accurate repeated measurements; or following Non-measurable diseases: Non-measurable, bone-only disease that can be assessed by CT or MRI or X-Ray. Lytic or mixed lytic bone lesions that can be assessed by CT or MRI or X-ray in the absence of measurable disease as defined above is acceptable; Participants with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible; and Non-measurable CNS disease (Cohort 2 only) * Adequate organ and bone marrow function within 14 days before the day of first dosing as defined in the protocol * Left ventricular ejection fraction ≥ 50% within 28 days before enrollment * Negative pregnancy test (serum) for women of childbearing potential Exclusion Criteria * Known or suspected leptomeningeal disease * Prior exposure to tucatinib treatment * Refractory nausea and vomiting, chronic gastrointestinal disease, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of T-DXd * History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence * Based on screening contrast brain MRI/CT scan, participants must not have any of the following: any untreated brain lesions \> 2.0 cm in size; ongoing use of systemic corticosteroids for control of symptoms of BMs; any brain lesion thought to require immediate local therapy; have poorly controlled (\> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to BMs not withstanding CNS-directed therapy * Has spinal cord compression * Known active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1. Participants with past or resolved hepatitis B virus infection are eligible, if negative for hepatitis B surface antigen and positive for anti-hepatitis B core antigen * Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA * Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals * Receipt of live, attenuated vaccine within 30 days prior to the first dose of T-DXd * Participants with a medical history of myocardial infarction within 6 months before screening, symptomatic congestive heart failure (New York Heart Association Class II to IV) * History of (non-infectious) 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 and any autoimmune, connective tissue or inflammatory disorders * Prior exposure, without adequate treatment washout period before the day of first dosing, to chloroquine/hydroxychloroquine: \< 14 days * Anticancer chemotherapy: immunotherapy (non-antibody-based therapy), retinoid therapy, hormonal therapy: \< 3 weeks * \< 6 weeks for nitrosoureas or mitomycin * Antibody-based anticancer therapy: \< 4 weeks * Any concurrent anticancer treatment. Concurrent use of hormonal therapy for noncancer- related conditions is allowed * Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline * Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation, radiation to the chest, or to more than 30% of the bone marrow within 4 weeks before the first dose of study intervention * Participants with prior exposure to immunosuppressive medication within 14 days prior to first study dose * Participants with a known hypersensitivity to study intervention or any of the excipients of the product or other monoclonal antibodies

Locations (81)

Outcomes

Primary Outcomes

Objective Response Rate (ORR) in Cohort 1 (Participants Without Brain Metastasis at Baseline)

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.

Time frame: From first dose (Day 1) to progression of disease (up to 2 years 7 months)

Progression-free Survival (PFS) Rate at 12 Months in Cohort 2 (Participants With Brain Metastasis at Baseline)

The PFS rate is the percentage of participants alive and free of disease progression at 12 months, estimated by the Kaplan-Meier method.

Time frame: At 12 months

Secondary Outcomes

Survival Rate at 12 Months

Survival rate is the percentage of participants alive at 12 months, estimated by the Kaplan-Meier method.

Time frame: At 12 Months

Objective Response Rate in Cohort 2 (Participants With Brain Metastasis at Baseline)

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 frame: From first dose (Day 1) to progression of disease (up to 2 years 7 months)

Duration of Response (DoR)

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.

Time frame: From the date of first documented confirmed response until date of documented progression (up to 2 years 7 months)

Time to Progression

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.

Data from ClinicalTrials.gov

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Research Site

Boston, Massachusetts, United States

Research Site

Durham, North Carolina, United States

Research Site

Adelaide, Australia

Research Site

Auchenflower, Australia

Research Site

Clayton, Australia

Research Site

Heidelberg, Australia

Research Site

St Leonards, Australia

Research Site

Subiaco, Australia

Research Site

Anderlecht, Belgium

Research Site

Bruges, Belgium

...and 71 more locations

Time frame: From first dose (Day 1) to progression of disease (up to 2 years 7 months)

Duration of Treatment on Subsequent Lines of Therapy

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.

Time frame: From the date of first dose of a subsequent therapy until date of last dose of therapy (up to 2 years 7 months)

Second Progression-Free Survival Rate 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.

Time frame: At 12 Months

Incidence of New Symptomatic Central Nervous System (CNS) Metastasis During Treatment Without CNS Metastasis at Baseline (Cohort 1)

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 frame: From first dose (Day 1) to end of treatment (up to 2 years 7 months)

Time to Next Progression (CNS or Extracranial) or Death

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.

Time frame: From date of first documented isolated CNS progression to the date of the next documented disease progression (up to 2 years 7 months)

Site (CNS vs Extracranial vs Both) of Next Progression

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.

Time frame: 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)

Central Nervous System Progression-free Survival Rate at 12 Months in Participants With Brain Metastasis at Baseline (Cohort 2)

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 frame: At 12 Months

Time to New CNS Lesions in Participants With Brain Metastasis at Baseline (Cohort 2)

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.

Time frame: From first dose (Day 1) to the date of documented new CNS lesions (up to 2 years 7 months)

Central Nervous System Objective Response Rate in Participants With Brain Metastasis at Baseline by ICR (Cohort 2)

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.

Time frame: From first dose (Day 1) until CNS progression of disease (up to 2 years 7 months)

Central Nervous System Duration of Response in Participants With Brain Metastasis at Baseline (Cohort 2)

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.

Time frame: From date of first documented confirmed CNS response until CNS progression of disease (up to 2 years 7 months)

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)

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.

Time frame: 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

Number of Participants With Neurologic Assessment in Neuro-Oncology Scale (NANO Scale)

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.

Time frame: 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

Cognitive Functions Tests: Paired Associates Learning (PAL) First Attempt Memory Score (PALFAMS)

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.