A Phase 1b Study of T-DXd Combinations in HER2-low Advanced or Metastatic Breast Cancer

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)

Sponsors

Lead Sponsor: AstraZeneca

Collaborator: Daiichi Sankyo Company, Limited

Source AstraZeneca
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

Overall Status Not yet recruiting
Start Date November 27, 2020
Completion Date December 23, 2022
Primary Completion Date December 23, 2022
Phase Phase 1
Study Type Interventional
Primary Outcome
Measure Time Frame
Occurrence of adverse events (AEs)- Part 1 Up to follow-up period, approximately 24 months
Occurrence of serious adverse events (SAEs)- Part 1 Up to follow-up period, approximately 24 months
Occurrence of adverse events (AEs)- Part 2 Up to follow-up period, approximately 24 months
Occurrence of serious adverse events (SAEs)- Part 2 Up to follow-up period, approximately 24 months
Secondary Outcome
Measure Time Frame
Objective Response Rate (ORR)- Part 2 Until progression, assessed up to approximately 24 months
Progression Free Survival (PFS)- Part 2 Until progression or death, assessed up to approximately 24 months
Duration of Response (DoR)- Part 2 Until progression or death, assessed up to approximately 24 months
Overall Survival (OS)- Part 2 Until death, assessed up to approximately 24 months
Serum concentration of T-DXd, total anti-HER2 antibody and MAAA-1181a While on study drug up to study completion, approximately 24 months
Immunogenicity of trastuzumab deruxtecan Up to follow-up period, approximately 24 months
Serum Concentration of durvalumab While on study drug up to study completion, approximately 24 months
Immunogenicity of durvalumab Up to follow-up period, approximately 24 months
Enrollment 185
Condition
Intervention

Intervention Type: Drug

Intervention Name: Trastuzumab deruxtecan

Description: T-DXd: administered as an IV infusion

Other Name: DS-8201a, T-DXd

Intervention Type: Drug

Intervention Name: Durvalumab

Description: Durvalumab: administered as an IV infusion

Arm Group Label: Module 2: T-DXd + durvalumab + paclitaxel

Other Name: MEDI4736

Intervention Type: Drug

Intervention Name: Paclitaxel

Description: Paclitaxel: administered as an IV infusion

Arm Group Label: Module 2: T-DXd + durvalumab + paclitaxel

Intervention Type: Drug

Intervention Name: Capivasertib

Description: Capivasertib: administered orally

Arm Group Label: Module 3: T-DXd + capivasertib

Other Name: AZD5363

Intervention Type: Drug

Intervention Name: Anastrozole

Description: Anastrozole: administered orally

Arm Group Label: Module 4: T-DXd + anastrozole

Intervention Type: Drug

Intervention Name: Fulvestrant

Description: Fulvestrant: administered as an IM injection

Arm Group Label: Module 5: T-DXd + fulvestrant

Intervention Type: Drug

Intervention Name: Capecitabine

Description: Capecitabine: administered orally

Arm Group Label: Module 1: T-DXd + capecitabine

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.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Contact

Last Name: AstraZeneca Clinical Study Information Center

Phone: 1-877-240-9479

Email: [email protected]

Verification Date

September 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 5
Arm Group

Label: Module 1: T-DXd + capecitabine

Type: Experimental

Description: T-DXd: 5.4 mg/kg Q3W, intravenous use Capecitabine: 1000mg/m2 BID, days 1-14 Q3W, oral use

Label: Module 2: T-DXd + durvalumab + paclitaxel

Type: Experimental

Description: T-DXd: 5.4 mg/kg Q3W, intravenous use Durvalumab: 1120 mg Q3W, intravenous use Paclitaxel: 80 mg/m2 QW in 3-week cycles, intravenous use

Label: Module 3: T-DXd + capivasertib

Type: Experimental

Description: T-DXd: 5.4 mg/kg Q3W, intravenous use Capivasertib: 400 mg BID, oral use

Label: Module 4: T-DXd + anastrozole

Type: Experimental

Description: T-DXd: 5.4 mg/kg Q3W, intravenous use Anastrozole: 1 mg daily, oral

Label: Module 5: T-DXd + fulvestrant

Type: Experimental

Description: T-DXd: 5.4 mg/kg Q3W, intravenous use Fulvestrant: 500 mg Q4W, intramuscular use

Acronym DB-08
Patient Data Yes
Study Design Info

Allocation: Non-Randomized

Intervention Model: Parallel Assignment

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

Masking: None (Open Label)

Source: ClinicalTrials.gov