Ignite Creation Date:
2024-05-06 @ 8:06 PM
Last Modification Date:
2024-10-26 @ 3:20 PM
Study NCT ID:
NCT06250777
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-02-09
First Post:
2024-01-21
Brief Title:
Efficacy and Safety of T-DXd in HER2-mutant Advanced Lung Cancer Patients With Asymptomatic Brain Metastases
Sponsor:
Yonsei University
Organization:
Yonsei University
Study Overview
Official Title:
A Phase 2 Trial to Assess Efficacy and Safety of T-DXd in HER2-mutant Advanced Lung Cancer Patients With Asymptomatic Brain Metastases
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ELPIS
Brief Summary:
1 Objective
Primary objective
- Median Intracranial Progression-free survivalicPFS as defined by RANOResponse Assessment in Neuro-Oncology criteria
Secondary objective
Progression free survivalPFS as defined by RECIST 11
Median Intracranial progression free survivalicPFS as defined by RECIST 11
Intracranial objective response rateicORR as defined by RECIST 11
Overall response rateORR as defined by RECIST 11
Duration of responseDoR as defined by RECIST 11
Disease control rate DCR defined by RECIST 11
Overall survival OS The time from the date of inital IP administration to death due to any cause
Pattern of Progression Site of next progression
Safety objective
To evaluate the safety and tolerability of Trastuzumab deruxtecanAEsSAEs Vital signs Collection of clinical chemistryhaematology parameters ECGs 2 Exploratory Purpose
To identify mechanisms of adaptive resistance using Guardant 360 panel To conduct NGS using Guardant 360 panel in serial plasma collection before treatment and at the time of progression
To identify the profiling of interstitial lung disease ILD after treatment of T-DXd To perform the baseline and follow-up PFT To perform high-resolution chest CT to evaluate for ILD by radiologic expert To evaluate cytokine level in serially collected plasma every 6 weeks for the first 24 weeks and then every 12 weeks The investigators recommend doing one HRCT at baseline and a second one in the event of ILD
3 Background Human epidermal growth factor receptor 2 HER2 ERBB2-activating mutations occur in 2 of lung cancers as a distinct molecular target HER2-targeted therapy is standard of care for HER2-mutation positive non-small cell lung cancer NSCLC
Trastuzumab deruxtecan T-DXd DS-8201 Enhertu is a novel antibody drug conjugate that is comprised of 3 components a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab a topoisomerase I inhibitor payload an exatecan derivative and a tetrapeptide-based cleavable linker
Recently T-DXd induced a confirmed objective response rate ORR of almost 61 and a durable benefit in heavily pre-treated patients with advanced HER2-positive breast cancer according to results from the phase II DESTINY-Breast01 trial In addition the DESTINY-Gastric trial showed the superiority of T-DXd compared with standard chemotherapy in terms of response rate and progression-free and overall survival in this setting Altogether T-DXd received breakthrough therapy designation and orphan drug designation in gastric cancer and approval for the treatment of advanced HER2-positive breast cancer Recently T-DXd showed durable systemic disease control along with CNS response Ongoing trials are assessing the activity of T-DXd in patients with breast cancer and active brain metastases
T-DXd has been approved in the US for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 mutations as detected by a FDA-approved test and who have received a prior systemic therapy The accelerated approval by the FDA was based on the results from the DESTINY-Lung02 Phase II trial An interim efficacy analysis in a pre-specified patient cohort showed T-DXd 54mgkg demonstrated a confirmed ORR of 577 n52 95 CI 432-713 as assessed by blinded independent central review in patients with previously treated unresectable or metastatic non-squamous HER2-mutant NSCLC Complete responses CR were seen in 19 of patients and partial responses PR in 558 of patients with a median DoR of 87 months 95 CI 71-NE
Primary objective
- Median Intracranial Progression-free survivalicPFS as defined by RANOResponse Assessment in Neuro-Oncology criteria
Secondary objective
Progression free survivalPFS as defined by RECIST 11
Median Intracranial progression free survivalicPFS as defined by RECIST 11
Intracranial objective response rateicORR as defined by RECIST 11
Overall response rateORR as defined by RECIST 11
Duration of responseDoR as defined by RECIST 11
Disease control rate DCR defined by RECIST 11
Overall survival OS The time from the date of inital IP administration to death due to any cause
Pattern of Progression Site of next progression
Safety objective
To evaluate the safety and tolerability of Trastuzumab deruxtecanAEsSAEs Vital signs Collection of clinical chemistryhaematology parameters ECGs 2 Exploratory Purpose
To identify mechanisms of adaptive resistance using Guardant 360 panel To conduct NGS using Guardant 360 panel in serial plasma collection before treatment and at the time of progression
To identify the profiling of interstitial lung disease ILD after treatment of T-DXd To perform the baseline and follow-up PFT To perform high-resolution chest CT to evaluate for ILD by radiologic expert To evaluate cytokine level in serially collected plasma every 6 weeks for the first 24 weeks and then every 12 weeks The investigators recommend doing one HRCT at baseline and a second one in the event of ILD
3 Background Human epidermal growth factor receptor 2 HER2 ERBB2-activating mutations occur in 2 of lung cancers as a distinct molecular target HER2-targeted therapy is standard of care for HER2-mutation positive non-small cell lung cancer NSCLC
Trastuzumab deruxtecan T-DXd DS-8201 Enhertu is a novel antibody drug conjugate that is comprised of 3 components a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab a topoisomerase I inhibitor payload an exatecan derivative and a tetrapeptide-based cleavable linker
Recently T-DXd induced a confirmed objective response rate ORR of almost 61 and a durable benefit in heavily pre-treated patients with advanced HER2-positive breast cancer according to results from the phase II DESTINY-Breast01 trial In addition the DESTINY-Gastric trial showed the superiority of T-DXd compared with standard chemotherapy in terms of response rate and progression-free and overall survival in this setting Altogether T-DXd received breakthrough therapy designation and orphan drug designation in gastric cancer and approval for the treatment of advanced HER2-positive breast cancer Recently T-DXd showed durable systemic disease control along with CNS response Ongoing trials are assessing the activity of T-DXd in patients with breast cancer and active brain metastases
T-DXd has been approved in the US for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 mutations as detected by a FDA-approved test and who have received a prior systemic therapy The accelerated approval by the FDA was based on the results from the DESTINY-Lung02 Phase II trial An interim efficacy analysis in a pre-specified patient cohort showed T-DXd 54mgkg demonstrated a confirmed ORR of 577 n52 95 CI 432-713 as assessed by blinded independent central review in patients with previously treated unresectable or metastatic non-squamous HER2-mutant NSCLC Complete responses CR were seen in 19 of patients and partial responses PR in 558 of patients with a median DoR of 87 months 95 CI 71-NE
Detailed Description:
4 Hypothesis T-DXd is actually approved for previously treated HER2m metastatic NSCLC patients but there is a gap of knowledge about intracranial response on T-DXd in NSCLC patients with brain metastasis Therefore in this study the investigators aim to focus on the intracranial treatment outcome in HER2 mut NSCLC patients with brain metastasis
Additionally T-DXd has been shown to harbor more efficacy in HER2-mutated patients rather than HER2-overexpressing NSCLC patients
However severe life-threatening interstitial lung disease ILD including pneumonitis can occur in patients treated with T-DXd A recent findings demonstrated that ILD occurred in less than 16 of patients with HER2-positive metastatic breast cancer following treatment with T-DXd Although the majority of these cases were grade 1 or 2 ILD remains an important risk which highlights the need for close monitoring and early identification of ILD Several cytokines which activate JAKSTAT pathway such as IL-4 IL-13 IL-6 IL-11 and IL-31 are implicated in the pathogenicity of ILD However there is no prospective study which evaluated the association of cytokines with the onset of drug-induced ILD
Given the activity of T-DXd in HER2-mutant lung cancer the investigators hypothesized that HER2-mutated tumors harbor susceptibility to HER2 ADCs and designed this phase 2 clinical trial of T-DXd in NSCLC HER2-mutant patients with brain metastases
5 Study procedure This is Phase 2 Single arm multi-centres Open labelled study to assess efficacy and safety of T-DXd in HER2-mutant advanced lung cancer patients with asymptomatic brain metastases
Advanced or metastatic non-squamous NSCLC with HER2 mutation regardless of HER2 expression with asymptomatic brain metastasis at baseline will be treated with T-DXd every 3weeks
HER2 activating mutation is based on local assessment of archival tissue or plasma ctDNA analysis HER2 activating mutation are included exon 19 or 20
For resistance mechanism analysis the investigators plan to conduct serial plasma collection from patients receiving T-DXd before treatment and at the time of progression to identify mechanisms of adaptive resistance using Guardant 360 panel
To identify the profiling of interstial lung disease ILD after treatment of T-DXd the investigators plan to perform the baseline and follow-up PFT The high-resolution CT will be evaluated for ILD by radiologic expert The investigators serially collected plama for evaluation of cytokine every 6 weeks for the first 24 weeks and then every 12 weeks Pulmonologist expert for ILD will involve the ILD management when the patients show the ILD pattern and the symptoms suspicious for ILD
Detailed Description
1 Objective
Primary objective
- Median Intracranial Progression-free survivalicPFS as defined by RANOResponse Assessment in Neuro-Oncology criteria
Secondary objective
Progression free survivalPFS as defined by RECIST 11
Median Intracranial progression free survivalicPFS as defined by RECIST 11
Intracranial objective response rateicORR as defined by RECIST 11
Overall response rateORR as defined by RECIST 11
Duration of responseDoR as defined by RECIST 11
Disease control rate DCR defined by RECIST 11
Overall survival OS The time from the date of inital IP administration to death due to any cause
Pattern of Progression Site of next progression
Safety objective
- To evaluate the safety and tolerability of Trastuzumab deruxtecanAEsSAEs Vital signs Collection of clinical chemistryhaematology parameters ECGs
Exploratory Purpose
To identify mechanisms of adaptive resistance using Guardant 360 panel To conduct NGS using Guardant 360 panel in serial plasma collection before treatment and at the time of progression
To identify the profiling of interstitial lung disease ILD after treatment of T-DXd To perform the baseline and follow-up PFT To perform high-resolution chest CT to evaluate for ILD by radiologic expert To evaluate cytokine level in serially collected plasma every 6 weeks for the first 24 weeks and then every 12 weeks We recommend doing one HRCT at baseline and a second one in the event of ILD
2 Background Human epidermal growth factor receptor 2 HER2 ERBB2-activating mutations occur in 2 of lung cancers as a distinct molecular target HER2-targeted therapy is standard of care for HER2-mutation positive non-small cell lung cancer NSCLC
Trastuzumab deruxtecan T-DXd DS-8201 Enhertu is a novel antibody drug conjugate that is comprised of 3 components a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab a topoisomerase I inhibitor payload an exatecan derivative and a tetrapeptide-based cleavable linker
Recently T-DXd induced a confirmed objective response rate ORR of almost 61 and a durable benefit in heavily pre-treated patients with advanced HER2-positive breast cancer according to results from the phase II DESTINY-Breast01 trial In addition the DESTINY-Gastric trial showed the superiority of T-DXd compared with standard chemotherapy in terms of response rate and progression-free and overall survival in this setting Altogether T-DXd received breakthrough therapy designation and orphan drug designation in gastric cancer and approval for the treatment of advanced HER2-positive breast cancer Recently T-DXd showed durable systemic disease control along with CNS response Ongoing trials are assessing the activity of T-DXd in patients with breast cancer and active brain metastases
T-DXd has been approved in the US for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 mutations as detected by a FDA-approved test and who have received a prior systemic therapy The accelerated approval by the FDA was based on the results from the DESTINY-Lung02 Phase II trial An interim efficacy analysis in a pre-specified patient cohort showed T-DXd 54mgkg demonstrated a confirmed ORR of 577 n52 95 CI 432-713 as assessed by blinded independent central review in patients with previously treated unresectable or metastatic non-squamous HER2-mutant NSCLC Complete responses CR were seen in 19 of patients and partial responses PR in 558 of patients with a median DoR of 87 months 95 CI 71-NE
3 Hypothesis T-DXd is actually approved for previously treated HER2m metastatic NSCLC patients but there is a gap of knowledge about intracranial response on T-DXd in NSCLC patients with brain metastasis Therefore in this study we aim to focus on the intracranial treatment outcome in HER2 mut NSCLC patients with brain metastasis
Additionally T-DXd has been shown to harbor more efficacy in HER2-mutated patients rather than HER2-overexpressing NSCLC patients
However severe life-threatening interstitial lung disease ILD including pneumonitis can occur in patients treated with T-DXd A recent findings demonstrated that ILD occurred in less than 16 of patients with HER2-positive metastatic breast cancer following treatment with T-DXd Although the majority of these cases were grade 1 or 2 ILD remains an important risk which highlights the need for close monitoring and early identification of ILD Several cytokines which activate JAKSTAT pathway such as IL-4 IL-13 IL-6 IL-11 and IL-31 are implicated in the pathogenicity of ILD However there is no prospective study which evaluated the association of cytokines with the onset of drug-induced ILD
Given the activity of T-DXd in HER2-mutant lung cancer we hypothesized that HER2-mutated tumors harbor susceptibility to HER2 ADCs and designed this phase 2 clinical trial of T-DXd in NSCLC HER2-mutant patients with brain metastases
4 Study procedure This is Phase 2 Single arm multi-centres Open labelled study to assess efficacy and safety of T-DXd in HER2-mutant advanced lung cancer patients with asymptomatic brain metastases
Advanced or metastatic non-squamous NSCLC with HER2 mutation regardless of HER2 expression with asymptomatic brain metastasis at baseline will be treated with T-DXd every 3weeks
HER2 activating mutation is based on local assessment of archival tissue or plasma ctDNA analysis HER2 activating mutation are included exon 19 or 20
For resistance mechanism analysis we plan to conduct serial plasma collection from patients receiving T-DXd before treatment and at the time of progression to identify mechanisms of adaptive resistance using Guardant 360 panel
To identify the profiling of interstial lung disease ILD after treatment of T-DXd we plan to perform the baseline and follow-up PFT The high-resolution CT will be evaluated for ILD by radiologic expert We serially collected plama for evaluation of cytokine every 6 weeks for the first 24 weeks and then every 12 weeks Pulmonologist expert for ILD will involve the ILD management when the patients show the ILD pattern and the symptoms suspicious for ILD
Additionally T-DXd has been shown to harbor more efficacy in HER2-mutated patients rather than HER2-overexpressing NSCLC patients
However severe life-threatening interstitial lung disease ILD including pneumonitis can occur in patients treated with T-DXd A recent findings demonstrated that ILD occurred in less than 16 of patients with HER2-positive metastatic breast cancer following treatment with T-DXd Although the majority of these cases were grade 1 or 2 ILD remains an important risk which highlights the need for close monitoring and early identification of ILD Several cytokines which activate JAKSTAT pathway such as IL-4 IL-13 IL-6 IL-11 and IL-31 are implicated in the pathogenicity of ILD However there is no prospective study which evaluated the association of cytokines with the onset of drug-induced ILD
Given the activity of T-DXd in HER2-mutant lung cancer the investigators hypothesized that HER2-mutated tumors harbor susceptibility to HER2 ADCs and designed this phase 2 clinical trial of T-DXd in NSCLC HER2-mutant patients with brain metastases
5 Study procedure This is Phase 2 Single arm multi-centres Open labelled study to assess efficacy and safety of T-DXd in HER2-mutant advanced lung cancer patients with asymptomatic brain metastases
Advanced or metastatic non-squamous NSCLC with HER2 mutation regardless of HER2 expression with asymptomatic brain metastasis at baseline will be treated with T-DXd every 3weeks
HER2 activating mutation is based on local assessment of archival tissue or plasma ctDNA analysis HER2 activating mutation are included exon 19 or 20
For resistance mechanism analysis the investigators plan to conduct serial plasma collection from patients receiving T-DXd before treatment and at the time of progression to identify mechanisms of adaptive resistance using Guardant 360 panel
To identify the profiling of interstial lung disease ILD after treatment of T-DXd the investigators plan to perform the baseline and follow-up PFT The high-resolution CT will be evaluated for ILD by radiologic expert The investigators serially collected plama for evaluation of cytokine every 6 weeks for the first 24 weeks and then every 12 weeks Pulmonologist expert for ILD will involve the ILD management when the patients show the ILD pattern and the symptoms suspicious for ILD
Detailed Description
1 Objective
Primary objective
- Median Intracranial Progression-free survivalicPFS as defined by RANOResponse Assessment in Neuro-Oncology criteria
Secondary objective
Progression free survivalPFS as defined by RECIST 11
Median Intracranial progression free survivalicPFS as defined by RECIST 11
Intracranial objective response rateicORR as defined by RECIST 11
Overall response rateORR as defined by RECIST 11
Duration of responseDoR as defined by RECIST 11
Disease control rate DCR defined by RECIST 11
Overall survival OS The time from the date of inital IP administration to death due to any cause
Pattern of Progression Site of next progression
Safety objective
- To evaluate the safety and tolerability of Trastuzumab deruxtecanAEsSAEs Vital signs Collection of clinical chemistryhaematology parameters ECGs
Exploratory Purpose
To identify mechanisms of adaptive resistance using Guardant 360 panel To conduct NGS using Guardant 360 panel in serial plasma collection before treatment and at the time of progression
To identify the profiling of interstitial lung disease ILD after treatment of T-DXd To perform the baseline and follow-up PFT To perform high-resolution chest CT to evaluate for ILD by radiologic expert To evaluate cytokine level in serially collected plasma every 6 weeks for the first 24 weeks and then every 12 weeks We recommend doing one HRCT at baseline and a second one in the event of ILD
2 Background Human epidermal growth factor receptor 2 HER2 ERBB2-activating mutations occur in 2 of lung cancers as a distinct molecular target HER2-targeted therapy is standard of care for HER2-mutation positive non-small cell lung cancer NSCLC
Trastuzumab deruxtecan T-DXd DS-8201 Enhertu is a novel antibody drug conjugate that is comprised of 3 components a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab a topoisomerase I inhibitor payload an exatecan derivative and a tetrapeptide-based cleavable linker
Recently T-DXd induced a confirmed objective response rate ORR of almost 61 and a durable benefit in heavily pre-treated patients with advanced HER2-positive breast cancer according to results from the phase II DESTINY-Breast01 trial In addition the DESTINY-Gastric trial showed the superiority of T-DXd compared with standard chemotherapy in terms of response rate and progression-free and overall survival in this setting Altogether T-DXd received breakthrough therapy designation and orphan drug designation in gastric cancer and approval for the treatment of advanced HER2-positive breast cancer Recently T-DXd showed durable systemic disease control along with CNS response Ongoing trials are assessing the activity of T-DXd in patients with breast cancer and active brain metastases
T-DXd has been approved in the US for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 mutations as detected by a FDA-approved test and who have received a prior systemic therapy The accelerated approval by the FDA was based on the results from the DESTINY-Lung02 Phase II trial An interim efficacy analysis in a pre-specified patient cohort showed T-DXd 54mgkg demonstrated a confirmed ORR of 577 n52 95 CI 432-713 as assessed by blinded independent central review in patients with previously treated unresectable or metastatic non-squamous HER2-mutant NSCLC Complete responses CR were seen in 19 of patients and partial responses PR in 558 of patients with a median DoR of 87 months 95 CI 71-NE
3 Hypothesis T-DXd is actually approved for previously treated HER2m metastatic NSCLC patients but there is a gap of knowledge about intracranial response on T-DXd in NSCLC patients with brain metastasis Therefore in this study we aim to focus on the intracranial treatment outcome in HER2 mut NSCLC patients with brain metastasis
Additionally T-DXd has been shown to harbor more efficacy in HER2-mutated patients rather than HER2-overexpressing NSCLC patients
However severe life-threatening interstitial lung disease ILD including pneumonitis can occur in patients treated with T-DXd A recent findings demonstrated that ILD occurred in less than 16 of patients with HER2-positive metastatic breast cancer following treatment with T-DXd Although the majority of these cases were grade 1 or 2 ILD remains an important risk which highlights the need for close monitoring and early identification of ILD Several cytokines which activate JAKSTAT pathway such as IL-4 IL-13 IL-6 IL-11 and IL-31 are implicated in the pathogenicity of ILD However there is no prospective study which evaluated the association of cytokines with the onset of drug-induced ILD
Given the activity of T-DXd in HER2-mutant lung cancer we hypothesized that HER2-mutated tumors harbor susceptibility to HER2 ADCs and designed this phase 2 clinical trial of T-DXd in NSCLC HER2-mutant patients with brain metastases
4 Study procedure This is Phase 2 Single arm multi-centres Open labelled study to assess efficacy and safety of T-DXd in HER2-mutant advanced lung cancer patients with asymptomatic brain metastases
Advanced or metastatic non-squamous NSCLC with HER2 mutation regardless of HER2 expression with asymptomatic brain metastasis at baseline will be treated with T-DXd every 3weeks
HER2 activating mutation is based on local assessment of archival tissue or plasma ctDNA analysis HER2 activating mutation are included exon 19 or 20
For resistance mechanism analysis we plan to conduct serial plasma collection from patients receiving T-DXd before treatment and at the time of progression to identify mechanisms of adaptive resistance using Guardant 360 panel
To identify the profiling of interstial lung disease ILD after treatment of T-DXd we plan to perform the baseline and follow-up PFT The high-resolution CT will be evaluated for ILD by radiologic expert We serially collected plama for evaluation of cytokine every 6 weeks for the first 24 weeks and then every 12 weeks Pulmonologist expert for ILD will involve the ILD management when the patients show the ILD pattern and the symptoms suspicious for ILD
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None