Clinical trial NCT04556773: A Phase 1b Study of T-DXd Combinations in HER2-low Advanced or Metastatic Breast Cancer
Official title: A Phase 1b Multicentre, Open-label, Modular, Dose-finding and Dose-expansion Study to Explore the Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Trastuzumab Deruxtecan (T-DXd) in Combination With Other Anti-cancer Agents in Patients With Metastatic HER2-low Breast Cancer (DESTINY-Breast08)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Metastatic Breast Cancer
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)
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Daiichi Sankyo Co., Ltd.
name: Daiichi Sankyo Company, Limited
First posted: 2020-09-21
Enrollment: 138
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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

Eligibility 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.

Primary outcomes:
measure: Occurrence of adverse events (AEs)- Part 1
timeFrame: Up to follow-up period, approximately 24 months
measure: Occurrence of serious adverse events (SAEs)- Part 1
timeFrame: Up to follow-up period, approximately 24 months
measure: Occurrence of adverse events (AEs)- Part 2
timeFrame: Up to follow-up period, approximately 24 months
measure: Occurrence of serious adverse events (SAEs)- Part 2
timeFrame: Up to follow-up period, approximately 24 months
Secondary outcomes:
measure: Objective Response Rate (ORR)- Part 2
timeFrame: Until progression, assessed up to approximately 24 months
measure: Progression Free Survival (PFS)- Part 2
timeFrame: Until progression or death, assessed up to approximately 24 months
measure: Duration of Response (DoR)- Part 2
timeFrame: Until progression or death, assessed up to approximately 24 months
measure: Overall Survival (OS)- Part 2
timeFrame: Until death, assessed up to approximately 24 months
measure: Serum concentration of T-DXd, total anti-HER2 antibody and MAAA-1181a
timeFrame: While on study drug up to study completion, approximately 24 months
measure: Immunogenicity of trastuzumab deruxtecan
timeFrame: Up to follow-up period, approximately 24 months
measure: Serum Concentration of durvalumab
timeFrame: While on study drug up to study completion, approximately 24 months
measure: Immunogenicity of durvalumab
timeFrame: Up to follow-up period, approximately 24 months
Other outcomes:
Locations:
city: Commack
country: United States
facility: Research Site
state: New York
city: Harrison
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Uniondale
country: United States
facility: Research Site
state: New York
city: Chapel Hill
country: United States
facility: Research Site
state: North Carolina
city: Chattanooga
country: United States
facility: Research Site
state: Tennessee
city: Germantown
country: United States
facility: Research Site
state: Tennessee
city: Fort Worth
country: United States
facility: Research Site
state: Texas
city: East Melbourne
country: Australia
facility: Research Site
city: Westmead
country: Australia
facility: Research Site
city: Edegem
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Ottignies
country: Belgium
facility: Research Site
city: Goiania
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Porto Alegre
country: Brazil
facility: Research Site
city: Sao Paulo
country: Brazil
facility: Research Site
city: São Paulo
country: Brazil
facility: Research Site
city: Kelowna
country: Canada
facility: Research Site
state: British Columbia
city: Quebec
country: Canada
facility: Research Site
city: Villejuif Cedex
country: France
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Monterrey
country: Mexico
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Kaohsiung
country: Taiwan
facility: Research Site
city: Taichung
country: Taiwan
facility: Research Site
city: Taipei City
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taipei
country: Taiwan
facility: Research Site
city: Taoyuan
country: Taiwan
facility: Research Site
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Komal Jhaveri, MD, FACP
role: PRINCIPAL_INVESTIGATOR
References: