Ignite Creation Date:
2025-12-18 @ 9:53 AM
Ignite Modification Date:
2025-12-23 @ 10:50 PM
Study NCT ID:
NCT05372614
Status:
None
Last Update Posted:
2025-12-09 00:00:00
First Post:
2022-05-12 00:00:00
Is Possible Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
Testing the Safety and Tolerability of the Anti-cancer Drugs Trastuzumab Deruxtecan and Neratinib for Cancers With Changes in the HER2 Gene
Sponsor:
None
Organization:
Study Overview
Official Title:
Phase I Trial of DS-8201a (Trastuzumab Deruxtecan) in Combination With Neratinib in Solid Tumors With HER2 Alterations
Status:
None
Status Verified Date:
2025-08
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:
None
Brief Summary:
PRIMARY OBJECTIVE:
I. To assess dose limiting toxicities and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of neratinib maleate (neratinib) and trastuzumab deruxtecan (DS-8201a) in patients with advanced solid tumors harboring alterations in HER2 (including HER2 overexpression/amplification and selected HER2-activating mutations).
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity of neratinib and DS-8201a, as measured by objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by investigator assessment, and overall survival (OS).
II. To assess the safety and tolerability for the combination neratinib and DS-8201a.
III. To assess the effect of neratinib on DS-8201a payload (DXd/MAAA-1181a) tissue concentration in part 2 at the RP2D chosen in part 1 (and potentially at a lower dose\[s\] of neratinib) before and after addition of neratinib to DS-8201a.
IV. To assess the pharmacokinetics of DS-8201a and neratinib in combination.
EXPLORATORY OBJECTIVES:
I. To assess the pharmacodynamic response to neratinib and DS-8201a as measured by markers of DS-8201a-induced deoxyribonucleic acid (DNA) damage using gammaH2AX, phosphorylated (p) NBS1 and pKAP1 immunofluorescence assay (IFA), multiplex multiple reaction monitoring mass spectrometry (MRM)- based proteomic assay panel of DNA repair response pathway biomarkers, induction of apoptosis, and HER2 signaling along with other pharmacodynamic (PD) biomarkers such as cleaved caspase3 (apoptosis) and TOP1CC (target engagement) pending National Clinical Laboratory Network (NCLN) assay availability.
II. To assess quantifiable HER2 protein expression of pre-treatment or archival tumor biopsies, and at disease progression in correlation with treatment response.
III. To assess tumor tissue mutation profile pre-treatment and at progression in correlation with treatment response.
IV. To assess circulating cell-free DNA (cfDNA) mutation profiles pre-treatment, cycle 2 day 1 (C2D1), and at progression in correlation with treatment response.
OUTLINE: This is a dose-escalation study of neratinib followed by a dose-expansion (PD) study.
Patients receive neratinib orally (PO) once daily (QD) on days 1-21 (days 8-21 of cycle 1, then days 1-21 in cycles thereafter for PD study) of each cycle and trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, computed tomography (CT) scan and echocardiography or multigated acquisition (MUGA) scan throughout study. Additionally, patients may undergo a tissue biopsy at baseline and disease progression.
After completion of study treatment, patients are followed up every 3 months for at least one year or until death.
I. To assess dose limiting toxicities and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of neratinib maleate (neratinib) and trastuzumab deruxtecan (DS-8201a) in patients with advanced solid tumors harboring alterations in HER2 (including HER2 overexpression/amplification and selected HER2-activating mutations).
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity of neratinib and DS-8201a, as measured by objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by investigator assessment, and overall survival (OS).
II. To assess the safety and tolerability for the combination neratinib and DS-8201a.
III. To assess the effect of neratinib on DS-8201a payload (DXd/MAAA-1181a) tissue concentration in part 2 at the RP2D chosen in part 1 (and potentially at a lower dose\[s\] of neratinib) before and after addition of neratinib to DS-8201a.
IV. To assess the pharmacokinetics of DS-8201a and neratinib in combination.
EXPLORATORY OBJECTIVES:
I. To assess the pharmacodynamic response to neratinib and DS-8201a as measured by markers of DS-8201a-induced deoxyribonucleic acid (DNA) damage using gammaH2AX, phosphorylated (p) NBS1 and pKAP1 immunofluorescence assay (IFA), multiplex multiple reaction monitoring mass spectrometry (MRM)- based proteomic assay panel of DNA repair response pathway biomarkers, induction of apoptosis, and HER2 signaling along with other pharmacodynamic (PD) biomarkers such as cleaved caspase3 (apoptosis) and TOP1CC (target engagement) pending National Clinical Laboratory Network (NCLN) assay availability.
II. To assess quantifiable HER2 protein expression of pre-treatment or archival tumor biopsies, and at disease progression in correlation with treatment response.
III. To assess tumor tissue mutation profile pre-treatment and at progression in correlation with treatment response.
IV. To assess circulating cell-free DNA (cfDNA) mutation profiles pre-treatment, cycle 2 day 1 (C2D1), and at progression in correlation with treatment response.
OUTLINE: This is a dose-escalation study of neratinib followed by a dose-expansion (PD) study.
Patients receive neratinib orally (PO) once daily (QD) on days 1-21 (days 8-21 of cycle 1, then days 1-21 in cycles thereafter for PD study) of each cycle and trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, computed tomography (CT) scan and echocardiography or multigated acquisition (MUGA) scan throughout study. Additionally, patients may undergo a tissue biopsy at baseline and disease progression.
After completion of study treatment, patients are followed up every 3 months for at least one year or until death.
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: