A Phase 1b/2 Study of T-DXd Combinations in HER2-positive Metastatic Breast Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1b/2 Multicentre, Open-label, Modular, Dose-finding and Dose-expansion Study to Explore 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 (DESTINY-Breast07)

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab deruxtecan
* Drug: Durvalumab
* Drug: Paclitaxel
* Drug: Pertuzumab
* Drug: Tucatinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patients must be at least 18 years of age Pathologically documented breast cancer that: Is advanced/unresectable (patients that can be treated with curative intent are not eligible) or metastatic 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. 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 Disease progression on or after the last systemic therapy prior to starting study treatment 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

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: Randomized
Intervention Model: Sequential Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Module 1- T-DXd and Durvalumab<br>T-DXd and Durvalumab | 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;|
| Experimental: Module 2- T-DXd and Pertuzumab<br>T-DXd and Pertuzumab | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a, T-DXd;Drug: Pertuzumab<br>* Pertuzumab: administered as an IV infusion<br>|
| Experimental: Module 3- T-DXd and Paclitaxel<br>T-DXd and Paclitaxel | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a, T-DXd;Drug: Paclitaxel<br>* Paclitaxel: administered as an IV infusion<br>|
| Experimental: Module 4- T-DXd and Durvalumab and Paclitaxel<br>T-DXd and Durvalumab and Paclitaxel | 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>|
| Experimental: Module 0- T-DXd<br>T-DXd | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a, T-DXd;|
| Experimental: Module 5 - T-DXd and Tucatanib<br>T-DXd and tucatinib | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a, T-DXd;Drug: Tucatinib<br>* Tucatinib administered orally (tablet) twice daily<br>* Other names: ONT-380;|
| Experimental: Module 6 - T-DXd and Tucatinib<br>T-DXd and tucatinib in patients with active brain metastases (Part 2 Only) | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a, T-DXd;Drug: Tucatinib<br>* Tucatinib administered orally (tablet) twice daily<br>* Other names: ONT-380;|
| Experimental: Module 7 - T-DXd<br>T-DXd monotherapy in patients with active brain metastases (Part 2 Only) | Drug: Trastuzumab deruxtecan<br>* T-DXd: administered as an IV infusion<br>* Other names: DS-8201a, T-DXd;|

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 53 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 53 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 53 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 53 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR)- Part 1 and Part 2 | 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. | Until progression, assessed up to approximately 53 months | 
| Progression Free Survival (PFS)- Part 1 and Part 2 | 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. | Until progression, assessed up to approximately 53 months | 
| Progression Free Survival 2 (PFS2)- Part 2 | 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. | Assessed up to approximately 53 months | 
| Duration of Response (DoR)- Part 2 | 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. | Until progression, assessed up to approximately 53 months | 
| Overall Survival (OS)- Part 2 | OS is defined as time from the date of randomisation until the date of death due to any cause. | Until death, assessed up to approximately 53 months | 
| Serum Concentration of Trastuzumab Deruxtecan (T-DXd) | Determination of trastuzumab deruxtecan concentration in serum at different time points after trastuzumab deruxtecan administration | While on study drug up to study completion, approximately 53 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 53 months | 
| Serum Concentration of Pertuzumab | Determination of pertuzumab concentration in serum at different time points after administration | While on study drug up to study completion, approximately 53 months | 
| Plasma Concentration of Paclitaxel | Determination of paclitaxel concentration in plasma at different time points after administration | While on study drug up to study completion, approximately 53 months | 
| Plasma Concentration of Tucatinib | Determination of tucatinib concentration in plasma at different time points after administration | While on study drug up to study completion, approximately 53 months | 
| Immunogenicity of trastuzumab deruxtecan | Percentage of patients who develop ADA for trastuzumab deruxtecan | Up to follow-up period, approximately 53 months | 
| Immunogenicity of Durvalumab | Percentage of patients who develop ADA for durvalumab | Up to follow-up period, approximately 53 months | 
| Immunogenicity of Pertuzumab | Percentage of patients who develop ADA for pertuzumab | Up to follow-up period, approximately 53 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, HER2-positive, Brain Metastases, Trastuzumab Deruxtecan, T-DXd, DS-8201a, DESTINY-Breast07, Anti-HER2 Antibody Drug Conjugate (ADC)