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).
Recruiting
Phase 3
| Drug | Synonyms | Arms |
|---|---|---|
| Trastuzumab Deruxtecan | fam-trastuzumab deruxtecan-nxki | Trastuzumab Deruxtecan |
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.
| Name | Type | Description | Interventions |
|---|---|---|---|
| Trastuzumab Deruxtecan | Experimental | 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. |
|
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 trastuzumab, pertuzumab, or trastuzumab emtansine 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
- Persistent toxicities (Common Terminology Criteria for Adverse Events Grade >1) caused
by previous anticancer therapy, excluding alopecia
- 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
- < 1 week for tyrosine kinase inhibitor (TKIs) approved for the treatment of non-small
cell lung cancer - baseline CT scan must be completed after discontinuation of TKI
- Antibody-based anticancer therapy: < 4 weeks
- Any concurrent anticancer treatment. Concurrent use of hormonal therapy for noncancer-
related conditions is allowed
- 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
| Maximum Eligible Age: | 130 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Objective Response Rate (ORR) in Participants without BM at Baseline (Cohort 1) |
| Time Frame: | From screening until progression of disease [PD] (Up to 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the overall treatment effect of T- DXd in HER2-positive metastatic breast cancer (MBC) participants without baseline BM. An ORR is defined as the proportion of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by independent central review (ICR) per RECIST 1.1. |
| Measure: | Overall Survival (OS) in Months |
| Time Frame: | At safety F/U (40+7 days after last dose) visit, thereafter survival F/U q3months ± 14 days (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the treatment effect on the development and progression of BM in participants with or without baseline BM using additional efficacy measurements. An OS is defined as the time from the date of the first dose of study intervention until death due to any cause. |
| Measure: | Duration of Response (DoR) |
| Time Frame: | Screening Day (-28 days) until end-of-treatment (EOT) (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the treatment effect on the development and progression of BM in participants with or without baseline BM using additional efficacy measurements. The DoR will be 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. |
| Measure: | Time to Progression |
| Time Frame: | Screening Day (-28 days) until PD (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the treatment effect on the development and progression of BM in participants with or without baseline BM using additional efficacy measurements. 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. |
| Measure: | Duration of Treatment on Subsequent Lines of Therapy |
| Time Frame: | At safety follow-up (40+7 days after last dose) then survival F/U q3months ± 14 days (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the treatment effect on the development and progression of BM in participants with or without baseline BM using additional efficacy measurements. Duration of treatment on subsequent therapy will be defined as the time from the date of first dose of a subsequent therapy until date of the last dose of that therapy. |
| Measure: | Time to Second Progression or Death (PFS2) |
| Time Frame: | At safety F/U (40+7 days after last dose) visit, thereafter survival F/U q3months ± 14 days (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the treatment effect on the development and progression of BM in participants with or without baseline BM using additional efficacy measurements. The PFS2 is defined as time from the first dose of study intervention to second progression (the earliest of the progression event subsequent to first subsequent therapy) or death. |
| Measure: | Incidence of new Symptomatic Central Nervous System (CNS) Metastasis During Treatment in Participants without BM at Baseline (Cohort 1) |
| Time Frame: | At Screening day (-28 days), Cycle 1 (15 days ± 2 days) Day 1 and Cycle 3 (15 days ± 2 days) Day 1 and thereafter every 3 subsequent cycles (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the treatment effect on the development and progression of BM in participants without baseline BM using additional efficacy measurements. |
| Measure: | Time to Next Progression (CNS or extracranial) or Death |
| Time Frame: | Screening Day (-28 days) until next PD (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the treatment effect on the development and progression (central nervous system [CNS] progression) of BM in participants without baseline BM using additional efficacy measurements. 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 will be summarized descriptively in participants who develop isolated CNS progression, receive local therapy, and continue on protocol therapy. |
| Measure: | Site (CNS vs extracranial vs both) of Next Progression |
| Time Frame: | Screening Day (-28 days) until next PD (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the treatment effect on the development and progression (CNS progression) of BM in participants without baseline BM using additional efficacy measurements. Site of next progression will be summarized descriptively in participants who develop isolated CNS progression, receive local therapy, continue on protocol therapy, and have a subsequent documented disease progression (CNS or extracranial) per RECIST 1.1. |
| Measure: | Objective Response Rate in Participants with BM at Baseline (Cohort 2) |
| Time Frame: | From screening until PD (Up to 2.5 Years) |
| Safety Issue: | |
| Description: | To describe efficacy in participants with stable or untreated BM. An ORR will be evaluated by RECIST 1.1 per ICR. |
| Measure: | Central Nervous System Progression-free Survival in Participants with BM at Baseline (Cohort 2) |
| Time Frame: | At safety follow-up (40+7 days after last dose) then survival F/U q3months ± 14 days (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe efficacy in participants with stable or untreated BM. The CNS PFS is defined as time from the first dose of study intervention to CNS progression per CNS RECIST 1.1 or death resulting from any cause, whichever occurs first. |
| Measure: | Time to new CNS Lesions in Participants with BM at Baseline (Cohort 2) |
| Time Frame: | Screening Day (-28 days) until EOT (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe efficacy in participants with stable or untreated BM. 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. |
| Measure: | Central Nervous System Objective Response Rate in Participants with BM at Baseline by ICR (Cohort 2) |
| Time Frame: | Screening Day (-28 days) until EOT (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe efficacy in participants with stable or untreated BM. The CNS ORR is defined as the proportion of participants with measurable BM at baseline who have a confirmed CR or confirmed PR of brain lesions, as determined by ICR per CNS RECIST 1.1. |
| Measure: | Central Nervous System Duration of Response in Participants with BM at Baseline (Cohort 2) |
| Time Frame: | Screening Day (-28 days) until EOT (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe efficacy in participants with stable or untreated BM. The CNS DoR will be 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. |
| Measure: | European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) |
| Time Frame: | Cycle 1 (15 days ± 2 days) Day 1, thereafter every 3 weeks (q3w) until 24 weeks post EOT visit and prior to second progression, and at the EOT visit (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the effect of T-DXd on symptoms, functioning, and health-related quality of life (HRQoL) in HER2+ MBC participants with or without baseline BM. |
| Measure: | Neurologic Assessment in Neuro-Oncology Scale |
| Time Frame: | Cycle 1 (15 days ± 2 days [Day 1]), Cycle 2 (15 days ± 2 days) Day 1, Cycle 3 (15 days ± 2 days) Day 1, Cycle 4 (15 days ± 2 days) Day 1 thereafter subsequent Cycles until PD and at EOT visit (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM. |
| Measure: | Cognitive Functions Tests |
| Time Frame: | Cycle 1 (15 days ± 2 days) Day 1, thereafter q12w and at EOT visit (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM. |
| Measure: | MD Anderson Symptom Inventory Brain Tumor-specific Items |
| Time Frame: | Cycle 1 (15 days ± 2 days) Day 1, thereafter q3w until 24 weeks post EOT visit and prior to second progression, and at the EOT visit (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM. |
| Measure: | St. George's Respiratory Questionnaire - idiopathic pulmonary fibrosis version in Participants with Interstitial Lung Disease (ILD)/Pneumonitis |
| Time Frame: | After diagnosis of ILD/pneumonitis and thereafter once weekly until EOT and safety F/U (40+7 days after last dose) (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM. |
| Measure: | Number of Participants with Adverse Events |
| Time Frame: | Cycle 1 (15 days ± 2 days) Day 1 until safety F/U (40+7 days after last dose) (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the safety profile of T-DXd. |
| Measure: | Number of Participants with Investigator-assessed ILD/Pneumonitis or Rate of Investigator-assessed ILD/Pneumonitis |
| Time Frame: | Cycle 1 (15 days ± 2 days) Day 1 until C4 (15 days ± 2 days) Day 1 and thereafter subsequent cycles until PD (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the safety profile of T-DXd. |
| Measure: | Number of Participants with Adverse Events with BM at Baseline |
| Time Frame: | Cycle 1 (15 days ± 2 days) Day 1 until safety F/U (40+7 days after last dose) (Approximately 2.5 Years) |
| Safety Issue: | |
| Description: | To describe the safety profile of T-DXd. |
| Phase: | Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | AstraZeneca |
July 29, 2021
