Clinical trial NCT04739761: A Study of T-DXd in Participants With or Without Brain Metastasis Who Have Previously Treated Advanced or Metastatic HER2 Positive Breast Cancer
Official title: An Open-Label, Multinational, Multicenter, Phase 3b/4 Study of Trastuzumab Deruxtecan in Patients With or Without Baseline Brain Metastasis With Previously Treated Advanced/Metastatic HER2-Positive Breast Cancer (DESTINY-Breast12)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Trastuzumab deruxtecan
Human epidermal growth factor receptor 2 Positive Breast Cancer
Brain Metastasis
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo
First posted: 2021-02-05
Enrollment: 506
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Objective Response Rate (ORR) in Cohort 1 (Participants Without Brain Metastasis at Baseline)
timeFrame: From first dose (Day 1) to progression of disease (up to 2 years 7 months)
measure: Progression-free Survival (PFS) Rate at 12 Months in Cohort 2 (Participants With Brain Metastasis at Baseline)
timeFrame: At 12 months
Secondary outcomes:
measure: Survival Rate at 12 Months
timeFrame: At 12 Months
measure: Objective Response Rate in Cohort 2 (Participants With Brain Metastasis at Baseline)
timeFrame: From first dose (Day 1) to progression of disease (up to 2 years 7 months)
measure: Duration of Response (DoR)
timeFrame: From the date of first documented confirmed response until date of documented progression (up to 2 years 7 months)
measure: Time to Progression
timeFrame: From first dose (Day 1) to progression of disease (up to 2 years 7 months)
measure: Duration of Treatment on Subsequent Lines of Therapy
timeFrame: From the date of first dose of a subsequent therapy until date of last dose of therapy (up to 2 years 7 months)
measure: Second Progression-Free Survival Rate at 12 Months
timeFrame: At 12 Months
measure: Incidence of New Symptomatic Central Nervous System (CNS) Metastasis During Treatment Without CNS Metastasis at Baseline (Cohort 1)
timeFrame: From first dose (Day 1) to end of treatment (up to 2 years 7 months)
measure: Time to Next Progression (CNS or Extracranial) or Death
timeFrame: From date of first documented isolated CNS progression to the date of the next documented disease progression (up to 2 years 7 months)
measure: Site (CNS vs Extracranial vs Both) of Next Progression
timeFrame: 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)
measure: Central Nervous System Progression-free Survival Rate at 12 Months in Participants With Brain Metastasis at Baseline (Cohort 2)
timeFrame: At 12 Months
measure: Time to New CNS Lesions in Participants With Brain Metastasis at Baseline (Cohort 2)
timeFrame: From first dose (Day 1) to the date of documented new CNS lesions (up to 2 years 7 months)
measure: Central Nervous System Objective Response Rate in Participants With Brain Metastasis at Baseline by ICR (Cohort 2)
timeFrame: From first dose (Day 1) until CNS progression of disease (up to 2 years 7 months)
measure: Central Nervous System Duration of Response in Participants With Brain Metastasis at Baseline (Cohort 2)
timeFrame: From date of first documented confirmed CNS response until CNS progression of disease (up to 2 years 7 months)
measure: 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)
timeFrame: 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
measure: Number of Participants With Neurologic Assessment in Neuro-Oncology Scale (NANO Scale)
timeFrame: 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
measure: Cognitive Functions Tests: Paired Associates Learning (PAL) First Attempt Memory Score (PALFAMS)
timeFrame: Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)
measure: Cognitive Functions Tests: Paired Associates Learning Total Errors Adjusted (PALTEA)
timeFrame: Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)
measure: Cognitive Functions Tests: Reaction Time (RTI)
timeFrame: Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)
measure: Cognitive Functions Tests: Spatial Working Memory (SWM)
timeFrame: Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)
measure: Cognitive Functions Tests: Spatial Working Memory Strategy (SWMS)
timeFrame: Baseline, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, and Cycle 17 Day 1 (21 days cycle)
measure: St. George's Respiratory Questionnaire - Idiopathic (SGRQ-I) Pulmonary Fibrosis Version in Participants With Interstitial Lung Disease (ILD)/Pneumonitis
timeFrame: 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)
measure: MD Anderson Symptom Inventory Brain Tumor-Specific Items in Brain Metastasis at Baseline Participants
timeFrame: 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)
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
measure: Number of Participants With Investigator-assessed ILD/Pneumonitis
timeFrame: From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
measure: Number of Participants With ILD Clinical Symptoms Resolution Among ILD/Pneumonitis Participants Who Have Been Treated With High Dose Steroid
timeFrame: From first dose until end of safety follow-up (47 days post last dose) (up to 2 years 7 months)
Other outcomes:
Locations:
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Durham
country: United States
facility: Research Site
state: North Carolina
city: Adelaide
country: Australia
facility: Research Site
city: Auchenflower
country: Australia
facility: Research Site
city: Clayton
country: Australia
facility: Research Site
city: Heidelberg
country: Australia
facility: Research Site
city: St Leonards
country: Australia
facility: Research Site
city: Subiaco
country: Australia
facility: Research Site
city: Anderlecht
country: Belgium
facility: Research Site
city: Bruges
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Liège
country: Belgium
facility: Research Site
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Copenhagen
country: Denmark
facility: Research Site
city: Herlev
country: Denmark
facility: Research Site
city: Odense C
country: Denmark
facility: Research Site
city: Helsinki
country: Finland
facility: Research Site
city: Tampere
country: Finland
facility: Research Site
city: Turku
country: Finland
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Dresden
country: Germany
facility: Research Site
city: Erlangen
country: Germany
facility: Research Site
city: Essen
country: Germany
facility: Research Site
city: Frankfurt
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Kiel
country: Germany
facility: Research Site
city: Mannheim
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Münster
country: Germany
facility: Research Site
city: Tübingen
country: Germany
facility: Research Site
city: Cork
country: Ireland
facility: Research Site
city: Dublin
country: Ireland
facility: Research Site
city: Dublin
country: Ireland
facility: Research Site
city: Ancona
country: Italy
facility: Research Site
city: Bergamo
country: Italy
facility: Research Site
city: Catania
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Prato
country: Italy
facility: Research Site
city: Isehara
country: Japan
facility: Research Site
city: Kawasaki-shi
country: Japan
facility: Research Site
city: Sapporo-shi
country: Japan
facility: Research Site
city: Shinagawa-ku
country: Japan
facility: Research Site
city: Yokohama-shi
country: Japan
facility: Research Site
city: Den Haag
country: Netherlands
facility: Research Site
city: Maastricht
country: Netherlands
facility: Research Site
city: Bergen
country: Norway
facility: Research Site
city: Oslo
country: Norway
facility: Research Site
city: Oslo
country: Norway
facility: Research Site
city: Gdańsk
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Opole
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Porto
country: Portugal
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Bilbao (Vizcaya)
country: Spain
facility: Research Site
city: Granada
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Salamanca
country: Spain
facility: Research Site
city: Santander
country: Spain
facility: Research Site
city: Santiago De Compostela-Coruña
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Göteborg
country: Sweden
facility: Research Site
city: Lund
country: Sweden
facility: Research Site
city: Uppsala
country: Sweden
facility: Research Site
city: Basel
country: Switzerland
facility: Research Site
city: Bellinzona
country: Switzerland
facility: Research Site
city: Lausanne
country: Switzerland
facility: Research Site
city: Luzern
country: Switzerland
facility: Research Site
city: Edinburgh
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Head, Breast Center, Ludwig-Maximilians-University of Munich Department of Obstetrics and Gynecology Marchioninistr. 15, 81377 Munich, Germany
name: Nadia Harbeck, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Associate Chief, Division of Breast Oncology, Susan F. Smith Center for Women's Cancers Director, Metastatic Breast Cancer Program, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215
name: Nancy U. Lin, MD
role: PRINCIPAL_INVESTIGATOR
References: