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

Study Overview
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Brief Summary
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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
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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

Official Title
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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)

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab deruxtecan
* Drug: Durvalumab
* Drug: Paclitaxel
* Drug: Capivasertib
* Drug: Anastrozole
* Drug: Fulvestrant
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patients must be at least 18 years of age Male or female patients who have pathologically documented breast cancer that: Has a history of HER2-low expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) with a validated assay 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module 1: T-DXd + capecitabine<br>T-DXd: 5.4 mg/kg Q3W, intravenous use Capecitabine: 1000mg/m2 BID, days 1-14 Q3W, oral use | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a, T-DXd;Drug: Capecitabine<br>* Capecitabine: administered orally<br>|
| Experimental: Module 2: T-DXd + durvalumab + paclitaxel<br>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 | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a, T-DXd;Drug: Durvalumab<br>* Durvalumab: administered as an IV infusion<br>* Other names: MEDI4736;Drug: Paclitaxel<br>* Paclitaxel: administered as an IV infusion<br>* Other names: Taxol A;|
| Experimental: Module 3: T-DXd + capivasertib<br>T-DXd: 5.4 mg/kg Q3W, intravenous use Capivasertib: 400 mg BID, oral use | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a, T-DXd;Drug: Capivasertib<br>* Capivasertib: administered orally<br>* Other names: AZD5363;|
| Experimental: Module 4: T-DXd + anastrozole<br>T-DXd: 5.4 mg/kg Q3W, intravenous use Anastrozole: 1 mg daily, oral | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a, T-DXd;Drug: Anastrozole<br>* Anastrozole: administered orally<br>* Other names: Anastrozol;|
| Experimental: Module 5: T-DXd + fulvestrant<br>T-DXd: 5.4 mg/kg Q3W, intravenous use Fulvestrant: 500 mg Q4W, intramuscular use | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a, T-DXd;Drug: Fulvestrant<br>* Fulvestrant: administered as an IM injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of adverse events (AEs)- Part 1 | Occurrence of AEs in Part 1 graded according to NCI CTCAE v5.0 | Up to follow-up period, approximately 24 months | 
| Occurrence of serious adverse events (SAEs)- Part 1 | Occurrence of SAEs in Part 1 graded according to NCI CTCAE v5.0 | Up to follow-up period, approximately 24 months | 
| Occurrence of adverse events (AEs)- Part 2 | Occurrence of AEs in Part 2 graded according to NCI CTCAE v5.0 | Up to follow-up period, approximately 24 months | 
| Occurrence of serious adverse events (SAEs)- Part 2 | Occurrence of SAEs in Part 2 graded according to NCI CTCAE v5.0 | Up to follow-up period, approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR)- 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 | Until progression, assessed up to approximately 24 months | 
| Progression Free Survival (PFS)- 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 | Until progression or death, assessed up to approximately 24 months | 
| Duration of Response (DoR)- 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 | Until progression or death, assessed up to approximately 24 months | 
| Overall Survival (OS)- Part 2 | OS defined as time from the date of first dose until the date of death by any cause | Until death, assessed up to approximately 24 months | 
| Serum concentration of T-DXd, total anti-HER2 antibody and MAAA-1181a | Determination of trastuzumab deruxtecan concentration in serum at different time points after trastuzumab deruxtecan administration | While on study drug up to study completion, approximately 24 months | 
| Immunogenicity of trastuzumab deruxtecan | Percentage of patients who develop ADA for trastuzumab deruxtecan | Up to follow-up period, approximately 24 months | 
| Serum Concentration of durvalumab | Determination of durvalumab concentration in serum at different time points after administration | While on study drug up to study completion, approximately 24 months | 
| Immunogenicity of durvalumab | Percentage of patients who develop ADAs for durvalumab | Up to follow-up period, approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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)