Ignite Creation Date:
2025-12-24 @ 12:08 PM
Ignite Modification Date:
2026-04-15 @ 7:34 PM
Study NCT ID:
NCT04704661
Status:
RECRUITING
Last Update Posted:
2025-11-26
First Post:
2021-01-01
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Testing the Combination of Two Anti-cancer Drugs, DS-8201a and AZD6738, for The Treatment of Advanced Solid Tumors Expressing the HER2 Protein or Gene, The DASH Trial
Sponsor:
National Cancer Institute (NCI)
Organization:
Study Overview
Official Title:
Phase 1/1B Study of DS-8201a in Combination With ATR Inhibition (AZD6738) in Advanced Solid Tumors With HER2 Expression (DASH Trial)
Status:
RECRUITING
Status Verified Date:
2025-11
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:
The dose escalation phase of this trial identifies the safety, side effects and best dose of ceralasertib (AZD6738) when given in combination with trastuzumab deruxtecan (DS-8201a) in treating patients with solid tumors that have a change (mutation) in the HER2 gene or protein and have spread to other places in the body (advanced). The dose expansion phase (phase Ib) of this trial compares how colorectal and gastroesophageal cancers with HER2 mutation respond to treatment with a combination of ceralasertib and trastuzumab deruxtecan versus trastuzumab deruxtecan alone. Ceralasertib may stop the growth of tumor cells and may kill them by blocking some of the enzymes needed for cell growth. Trastuzumab deruxtecan is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Ceralasertib and trastuzumab deruxtecan may be safe, tolerable and effective in treating patients with advanced solid tumors expressing the HER2 protein or gene.
Detailed Description:
PRIMARY OBJECTIVES:
I. Evaluate safety, tolerability, and recommended phase 2 dose (RP2D) of trastuzumab deruxtecan (DS-8201a) in combination with ceralasertib (AZD6738) in advanced solid tumors with HER2 expression. (Escalation Phase) II. Assess differential pharmacodynamic (PD) profile of tumor tissue (deoxyribonucleic acid \[DNA\] damage \& repair) between Top1 inhibition and dual inhibition of Top1 and ATR in patients with colorectal cancer and gastroesophageal cancer with HER2 expression. (Expansion Phase)
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To evaluate pharmacokinetics (PK) of DS-8201a and AZD6738 and immunogenicity of DS8201a.
EXPLORATORY OBJECTIVES:
I. Evaluate association between HER2 heterogeneity and response to DS-8201a plus (+) AZD6738 therapy using central protein expression assessment.
II. Determine predictive biomarkers (including but not restricted to: HER2 protein levels, HER2 gene copy number, alterations of TP53, ATM and RAS) of DS-8201a + AZD6738 efficacy in advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer) with HER2 expression.
III. To characterize PD biomarkers for efficacy of DS-8201a + AZD6738 efficacy in advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer) with HER2 expression (such as phosphorylated \[p\]RAD50 and SLFN11).
IV. To establish a biorepository of tissue, blood and pre-clinical models (PDXs) for HER2 expressing advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer).
OUTLINE: This is a dose-escalation study of ceralasertib with fixed dose trastuzumab deruxtecan followed by a dose-expansion study.
Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 of each cycle and ceralasertib orally (PO) twice daily (BID) on days 1-7 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: During the dose-expansion phase, the first 6 patients in each disease cohort (gastroesophageal cancer \[cohort A\] and colorectal cancer \[cohort B\]) receive only trastuzumab deruxtecan for the first cycle, followed by trastuzumab deruxtecan and ceralasertib together in subsequent cycles. Additionally, patients undergo tissue biopsy on study and blood sample collection, computed tomography (CT) or positron emission tomography (PET)/CT and echocardiography (ECHO) or multigated acquisition scan (MUGA) throughout the study.
After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.
I. Evaluate safety, tolerability, and recommended phase 2 dose (RP2D) of trastuzumab deruxtecan (DS-8201a) in combination with ceralasertib (AZD6738) in advanced solid tumors with HER2 expression. (Escalation Phase) II. Assess differential pharmacodynamic (PD) profile of tumor tissue (deoxyribonucleic acid \[DNA\] damage \& repair) between Top1 inhibition and dual inhibition of Top1 and ATR in patients with colorectal cancer and gastroesophageal cancer with HER2 expression. (Expansion Phase)
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To evaluate pharmacokinetics (PK) of DS-8201a and AZD6738 and immunogenicity of DS8201a.
EXPLORATORY OBJECTIVES:
I. Evaluate association between HER2 heterogeneity and response to DS-8201a plus (+) AZD6738 therapy using central protein expression assessment.
II. Determine predictive biomarkers (including but not restricted to: HER2 protein levels, HER2 gene copy number, alterations of TP53, ATM and RAS) of DS-8201a + AZD6738 efficacy in advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer) with HER2 expression.
III. To characterize PD biomarkers for efficacy of DS-8201a + AZD6738 efficacy in advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer) with HER2 expression (such as phosphorylated \[p\]RAD50 and SLFN11).
IV. To establish a biorepository of tissue, blood and pre-clinical models (PDXs) for HER2 expressing advanced solid tumors (specifically colorectal cancer and gastroesophageal cancer).
OUTLINE: This is a dose-escalation study of ceralasertib with fixed dose trastuzumab deruxtecan followed by a dose-expansion study.
Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 of each cycle and ceralasertib orally (PO) twice daily (BID) on days 1-7 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. NOTE: During the dose-expansion phase, the first 6 patients in each disease cohort (gastroesophageal cancer \[cohort A\] and colorectal cancer \[cohort B\]) receive only trastuzumab deruxtecan for the first cycle, followed by trastuzumab deruxtecan and ceralasertib together in subsequent cycles. Additionally, patients undergo tissue biopsy on study and blood sample collection, computed tomography (CT) or positron emission tomography (PET)/CT and echocardiography (ECHO) or multigated acquisition scan (MUGA) throughout the study.
After completion of study treatment, patients are followed up every 3 months for 2 years, then every 6 months for 3 years.
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
True
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?: