Metastatic Breast Cancer
Conditions
Keywords
Breast Cancer, HER2-positive, Brain Metastases, Trastuzumab Deruxtecan, T-DXd, DS-8201a, DESTINY-Breast07, Anti-HER2 Antibody Drug Conjugate (ADC)
Brief summary
DESTINY-Breast07 will investigate the safety, tolerability, and anti-tumour activity of trastuzumab deruxtecan (T-DXd) in combination with other anti-cancer agents in patients with HER2-positive Metastatic Breast Cancer
Detailed description
This study is modular in design allowing assessment of safety, tolerability and anti-tumour activity of T-DXd in combination with other anti-cancer agents. Combination-treatment modules will have 2 parts: a dose-finding phase (Part 1), and a dose expansion phase (Part 2); the recommended Phase 2 dose (RP2D) determined in Part 1 will be used for the dose-expansion in Part 2. The target population of interest in this study is patients with HER2-positive (as per ASCO/CAP 2018 guidelines) advanced/MBC inclusive of patients with active and stable brain metastases. Part 1 of each module will enroll patients with locally assessed HER2-positive advanced/MBC in second-line or later patients. Part 2 of each module will enroll patients with locally assessed HER2-positive breast cancer who have not received prior treatment for advanced/metastatic disease.
Interventions
DRUGTrastuzumab deruxtecan
T-DXd: administered as an IV infusion
DRUGDurvalumab
Durvalumab: administered as an IV infusion
DRUGPaclitaxel
Paclitaxel: administered as an IV infusion
DRUGPertuzumab
Pertuzumab: administered as an IV infusion
DRUGTucatinib
Tucatinib administered orally (tablet) twice daily
Sponsors
Daiichi Sankyo Company, Limited
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study will consist of 2 phases: a dose escalation phase (Part 1) and a dose expansion phase (Part 2). Part 1 of each module will enroll patients with locally assessed HER2-positive advanced/MBC in second-line or later.Part 2 of each module will enroll patients with locally assessed HER2-positive breast cancer who have not received prior treatment for advanced/metastatic disease.
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 * Pathologically documented breast cancer that: 1. Is advanced/unresectable (patients that can be treated with curative intent are not eligible) or metastatic 2. HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local assessment. The local HER2 result must be from a tumour sample obtained in the metastatic setting. 3. Is documented as hormone receptor-positive (estrogen or progesterone receptor) or negative in the metastatic setting * Patient must have adequate tumor sample from the metastatic setting for biomarker assessment * ECOG Performance Status of 0 or 1 * Part 1 1. Disease progression on or after the last systemic therapy prior to starting study treatment 2. At least 1 prior treatment line in metastatic setting required. * Part 2 (Modules 0 - 5) a) No prior lines of therapy for advanced/MBC allowed * Part 2 (Module 6 and 7) a) Zero or one prior lines of therapy for advanced/MBC allowed CNS Inclusion * Modules 0 - 5 Patients must have no brain metastases or stable brain metastases. * Module 6 and 7 Patients must have untreated brain metastases not needing local therapy or previously treated brain metastases that have progressed since prior local therapy Key
Exclusion criteria
* Uncontrolled or significant cardiovascular disease * Active or prior documented (non-infectious) ILD/pneumonitis that required steroids, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening * Lung-specific intercurrent clinically significant illnesses * Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals * Spinal cord compression or a history of leptomeningeal carcinomatosis * Prior treatment with immune checkpoint inhibitors * Prior treatment with an ADC containing a topoisomerase I inhibitor * Prior treatment with tucatinib CNS Exclusion * Modules 0 - 5: Has untreated brain metastasis * Module 6 and 7: Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of \> 2 mg dexamethasone or any brain lesion thought to require immediate local therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of serious adverse events (SAEs)- Part 2 | Up to follow-up period, approximately 53 months | Occurrence of SAEs in Part 2 graded according to NCI CTCAE v5.0 |
| Occurrence of adverse events (AEs)- Part 1 | Up to follow-up period, approximately 53 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 53 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 53 months | Occurrence of AEs in Part 2 graded according to NCI CTCAE v5.0 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS)- Part 2 | Until death, assessed up to approximately 53 months | OS is defined as time from the date of randomisation until the date of death due to any cause. |
| Serum Concentration of Trastuzumab Deruxtecan (T-DXd) | While on study drug up to study completion, approximately 53 months | Determination of trastuzumab deruxtecan concentration in serum at different time points after trastuzumab deruxtecan administration |
| Serum Concentration of Durvalumab | While on study drug up to study completion, approximately 53 months | Determination of durvalumab concentration in serum at different time points after administration |
| Serum Concentration of Pertuzumab | While on study drug up to study completion, approximately 53 months | Determination of pertuzumab concentration in serum at different time points after administration |
| Duration of Response (DoR)- Part 2 | Until progression, assessed up to approximately 53 months | DoR is defined as time from the date of first documented response until the date of documented progression or death in the absence of disease progression. |
| Plasma Concentration of Tucatinib | While on study drug up to study completion, approximately 53 months | Determination of tucatinib concentration in plasma at different time points after administration |
| Immunogenicity of trastuzumab deruxtecan | Up to follow-up period, approximately 53 months | Percentage of patients who develop ADA for trastuzumab deruxtecan |
| Immunogenicity of Durvalumab | Up to follow-up period, approximately 53 months | Percentage of patients who develop ADA for durvalumab |
| Immunogenicity of Pertuzumab | Up to follow-up period, approximately 53 months | Percentage of patients who develop ADA for pertuzumab |
| Plasma Concentration of Paclitaxel | While on study drug up to study completion, approximately 53 months | Determination of paclitaxel concentration in plasma at different time points after administration |
| Objective Response Rate (ORR)- Part 1 and Part 2 | Until progression, assessed up to approximately 53 months | ORR is defined as the proportion of patients who have a CR or PR, as determined by the Investigator at local site per RECIST 1.1. |
| Progression Free Survival (PFS)- Part 1 and Part 2 | Until progression, assessed up to approximately 53 months | PFS is defined as time from the date of randomization until the date of progression as assessed by the Investigator at local site per RECIST 1.1, or death due to any cause. |
| Progression Free Survival 2 (PFS2)- Part 2 | Assessed up to approximately 53 months | PFS2 is defined as time from the date of randomisation until the date of progression on next line treatment (the earliest of the progression event subsequent to first subsequent anticancer therapy) or death; second progression will be defined according to local standard clinical practice. |
Countries
Australia, Brazil, Canada, France, Germany, India, Italy, Poland, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Outcome results
None listed