DESTINY-Breast08 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

Phase 1

Active, not recruiting

Conditions: Metastatic Breast Cancer

Registration Number: 2023-505690-33-00

Lead Sponsor: Astrazeneca AB

Brief Summary: 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 for advanced/metastatic disease.

Part 1: To assess the safety and tolerability, and determine RP2D for the T-DXd combinations Part 2: To assess the safety and tolerability of T-DXd combinations

Part 2: To assess the safety and tolerability of T-DXd combinations

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

Recruitment & Eligibility

Status: Ongoing, recruitment ended

Sex: Not specified

Target Recruitment: 12

Inclusion Criteria

Patients must be at least 18 years of age

Male or female patients who have pathologically documented breast cancer that: a)Has a history of HER2-low expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) with a validated assay b)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.

Exclusion Criteria

Uncontrolled intercurrent illness

Uncontrolled or significant 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

Combination partner as the most recent anti-cancer therapy for MBC prior to commencing study treatment

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Part 1: AEs, SAEs, DLTs, laboratory findings		Part 1: AEs, SAEs, DLTs, laboratory findings
Part 2: AEs, SAEs, laboratory findings		Part 2: AEs, SAEs, laboratory findings

Secondary Outcome Measures

Name	Time	Method
Part 2: 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		Part 2: 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
Part 2: 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		Part 2: 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
Part 2: 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		Part 2: 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
Part 2: OS defined as time from the date of first dose until the date of death by any cause		Part 2: 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		Serum concentration of T-DXd, total anti-HER2 antibody and MAAA- 1181a
Serum concentration of durvalumab		Serum concentration of durvalumab
Immunogenicity of T-DXd and durvalumab		Immunogenicity of T-DXd and durvalumab

Trial Locations

Locations (1): Clinique Saint-Pierre
🇧🇪
Ottignies-Louvain-La-Neuve, Belgium
Clinique Saint-Pierre
🇧🇪Ottignies-Louvain-La-Neuve, Belgium
Lionel Duck
Site contact
+3210437241
lionel.duck@cspo.be