Metastatic Breast Cancer
Conditions
Keywords
Breast Cancer, HER2-negative, HER2-low, Trastuzumab Deruxtecan, T-DXd, DS-8201a, DESTINY-Breast08, Anti-HER2 Antibody Drug Conjugate (ADC), Triple-negative breast cancer (TNBC)
Brief summary
DESTINY-Breast 08 will investigate the safety, tolerability, PK and preliminary anti-tumour activity of T-DXd in combination with other therapies in patients with Metastatic HER2-low Advanced or Metastatic Breast Cancer
Detailed description
This study is modular in design allowing assessment of the safety, tolerability, PK and preliminary anti-tumour activity of T-DXd in combination with other therapies. Combination-treatment modules will have 2 parts: a dose-finding phase (Part 1), and a dose expansion phase (Part 2); the Part 2 dose-expansion phase will use the RP2D determined in Part 1. The target population of interest in this study is patients with HER2-low (IHC 1+ or IHC 2+/ISH -) (as per ASCO/CAP 2018 guidelines) advanced/MBC. Part 1 of each module will enroll patients with locally confirmed HER2-low advanced/MBC in second-line or later (≥ 2L) settings Part 2 of each module will enroll patients with HER2-low MBC who have either not received prior treatment, or received only 1 prior treatment (depending on the module-specific exclusion criteria) for advanced/metastatic disease
Interventions
DRUGDurvalumab
Durvalumab: administered as an IV infusion
DRUGPaclitaxel
Paclitaxel: administered as an IV infusion
DRUGCapivasertib
Capivasertib: administered orally
DRUGAnastrozole
Anastrozole: administered orally
DRUGFulvestrant
Fulvestrant: administered as an IM injection
DRUGCapecitabine
Capecitabine: administered orally
DRUGTrastuzumab deruxtecan
T-DXd: administered as an IV infusion
Sponsors
AstraZeneca
Daiichi Sankyo Co., Ltd.
Daiichi Sankyo Company, Limited
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study will initially consist of 5 treatment modules, each of which includes T-DXd in combination with other anti-cancer agents. Each module will have 2 parts: a dose-finding phase (Part 1) and a dose-expansion phase (Part 2). The Part 2 dose-expansion phase will use the recommended Phase 2 dose (RP2D) for the combination, either as determined in Part 1 or from another clinical study if appropriate. For each module, patients will be centrally assigned to one of the open modules, as per the module specific criteria. In addition to safety and tolerability, this study will also assess ORR, PFS, DoR, and OS for each treatment combination.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Patients must be at least 18 years of age * Male or female patients who have pathologically documented breast cancer that: 1. Has a history of HER2-low expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) with a validated assay 2. Is documented as HR+ (either ER and/or PgR positive \[ER or PgR ≥1%\]) or ER and PgR negative (ER and PgR \<1%) per ASCO/CAP guidelines in the metastatic setting * Patient must have adequate tumor sample for biomarker assessment * ECOG Performance Status of 0 or 1 For patients with HR+ disease: Part 1: At least 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors), and at least 1 prior line of chemotherapy for MBC are required. Part 2: Only 1 prior treatment line of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors) for MBC is allowed. No prior chemotherapy in the metastatic setting is allowed. Note there are no patients with HR+ disease in Part 2 of Modules 2 and 3. For patients with HR- disease: Part 1: At least 1 prior line of chemotherapy for MBC is required. Note there are no patients with HR- disease in Part 1 of Modules 4 and 5. Part 2: For Module 2, no prior lines of therapy for MBC are allowed, and for Modules 1 and 3, only 1 prior line of chemotherapy for MBC is allowed. Note there are no patients with HR- disease in Part 2 of Modules 4 and 5. Key
Exclusion criteria
* Uncontrolled intercurrent illness * Uncontrolled or siginificant cardiovascular disease * 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 * Has spinal cord compression or clinically active central nervous system metastases * Active primary immunodeficiency * Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals * Prior treatment with ADC that comprises of an exatecan derivative that is a topoisomerase I inhibitor.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of adverse events (AEs)- Part 1 | Up to follow-up period, approximately 24 months | Occurrence of AEs in Part 1 graded according to NCI CTCAE v5.0 |
| Occurrence of serious adverse events (SAEs)- Part 1 | Up to follow-up period, approximately 24 months | Occurrence of SAEs in Part 1 graded according to NCI CTCAE v5.0 |
| Occurrence of adverse events (AEs)- Part 2 | Up to follow-up period, approximately 24 months | Occurrence of AEs in Part 2 graded according to NCI CTCAE v5.0 |
| Occurrence of serious adverse events (SAEs)- Part 2 | Up to follow-up period, approximately 24 months | Occurrence of SAEs in Part 2 graded according to NCI CTCAE v5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR)- Part 2 | Until progression, assessed up to approximately 24 months | ORR defined as the proportion of patients who have a confirmed CR or PR, as determined by the investigator at local site per RECIST 1.1 |
| Progression Free Survival (PFS)- Part 2 | Until progression or death, assessed up to approximately 24 months | PFS defined as time from the date of first dose until the date of progression as determined by the investigator at local site per RECIST 1.1, or death due to any cause |
| Duration of Response (DoR)- Part 2 | Until progression or death, assessed up to approximately 24 months | DoR defined as time from the date of first documented response (which is subsequently confirmed) until the date of documented progression or death in the absence of disease progression |
| Overall Survival (OS)- Part 2 | Until death, assessed up to approximately 24 months | OS defined as time from the date of first dose until the date of death by any cause |
| Serum concentration of T-DXd, total anti-HER2 antibody and MAAA-1181a | While on study drug up to study completion, approximately 24 months | Determination of trastuzumab deruxtecan concentration in serum at different time points after trastuzumab deruxtecan administration |
| Immunogenicity of trastuzumab deruxtecan | Up to follow-up period, approximately 24 months | Percentage of patients who develop ADA for trastuzumab deruxtecan |
| Serum Concentration of durvalumab | While on study drug up to study completion, approximately 24 months | Determination of durvalumab concentration in serum at different time points after administration |
| Immunogenicity of durvalumab | Up to follow-up period, approximately 24 months | Percentage of patients who develop ADAs for durvalumab |
Countries
Australia, Belgium, Brazil, Canada, France, Mexico, Russia, South Korea, Taiwan, United States
Contacts
PRINCIPAL_INVESTIGATORKomal Jhaveri, MD, FACP
Memorial Sloan Kettering Cancer Center
Outcome results
None listed