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
Phase 1/1B Study of DS-8201a in Combination With ATR Inhibition (AZD6738) in Advanced Solid Tumors With HER2 Expression (DASH Trial)
4 other identifiers
interventional
51
1 country
23
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_1
Started Aug 2021
Longer than P75 for phase_1
23 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
January 1, 2021
CompletedFirst Posted
Study publicly available on registry
January 12, 2021
CompletedStudy Start
First participant enrolled
August 9, 2021
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 31, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
March 31, 2027
May 13, 2026
April 1, 2026
5.6 years
January 1, 2021
May 12, 2026
Conditions
Outcome Measures
Primary Outcomes (3)
Incidence of adverse events (Dose escalation phase)
The descriptions and grading scales found in the revised National Cancer institute Common Terminology Criteria for Adverse Events version 5.0 will be utilized for adverse event reporting.
Up to 5 years
Recommended phase 2 dose (Dose escalation phase)
Will be determined based on the totality of safety, clinical activity, and pharmacokinetic data.
Up to completion of dose-escalation phase, assessed on days 1 through 21 of cycle 1 for each dose level
Differential pharmacodynamic (PD) profile of tumor tissue (DNA damage & repair) (Dose expansion phase)
Will assess differential PD profile of tumor tissue between Top1 inhibition and dual inhibition of Top1 and ATR.
Up to 5 years
Secondary Outcomes (10)
Anti-tumor activity of DS-8201a plus (+) AZD6738
Up to 5 years
Objective response rate (ORR)
Up to 5 years
Best overall response
From the time measurement criteria are first met for complete response (CR) until the first date that progressive disease is objectively documented
Duration of response
From the time measurement criteria are met for CR or partial response (any confirmed/unconfirmed) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented
Disease control rate
Up to 5 years
- +5 more secondary outcomes
Other Outcomes (5)
Association of HER2 expression level and HER2 gene copy number and ORR
Up to 5 years
Association of TOP1 expression level and ORR
Up to 5 years
Correlation between next generation immune-MRM HER2 assay and HER2 immunohistochemistry and association with ORR
Up to 5 years
- +2 more other outcomes
Study Arms (1)
Treatment (trastuzumab deruxtecan, ceralasertib)
EXPERIMENTALPatients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle and ceralasertib PO 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, CT or PET/CT and ECHO or MUGA throughout the study.
Interventions
Undergo blood sample collection
Undergo CT or PET/CT
Undergo ECHO
Undergo MUGA
Undergo PET/CT
Undergo tissue biopsy
Given IV
Eligibility Criteria
You may qualify if:
- DOSE-ESCALATION PHASE: Must have histologically confirmed advanced solid tumor including but not restricted to breast cancer, gastric or gastroesophageal cancer, colon cancer, endometrial cancer, salivary gland tumors, and hepatobiliary tumors
- DOSE-EXPANSION PHASE: Must have histologically confirmed advanced/metastatic gastroesophageal cancer (cohort A) or colorectal cancer (cohort B)
- DOSE-EXPANSION PHASE: Patients must have a biopsiable lesion and provide consent for on treatment biopsy
- Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of AZD6738 in combination with DS-8201a in patients \< 18 years of age, children are excluded from this study
- Patients must have HER2-positive or HER2-expressing tumors determined by a Clinical Laboratory Improvement Act (CLIA)-certified laboratory. As a rule, for HER2 immunohistochemistry (IHC) scoring system trastuzumab for gastric cancer (TOGA) criteria used for gastric/gastroesophageal junction (GEJ) cancers will be employed (Note: in escalation phase, for breast cancer patients that are included, breast cancer criteria can be used). Specific requirement of HER2 status is outlined below:
- HER2 expression (1-3+) by IHC locally and confirmed centrally OR
- HER2 expression (1-3+) by IHC tested centrally OR
- HER2 amplification based on fluorescence in situ hybridization (FISH) or next generation sequencing
- Must have received at least one line of systemic chemotherapy for either locally advanced or metastatic disease and should have either progressed on this therapy or been intolerant to this therapy
- For tumors where anti-HER2 therapy is standard of care, patients must have progressed on at least 1 line of anti-HER2 therapy if eligible. For patients where DS8201a is approved as standard of care, prior treatment with DS8201a is not allowed
- Must have unresectable, advanced/metastatic disease
- Must have at least 1 measurable lesion on CT scan per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Patient without measurable but evaluable disease are allowed for dose-escalation phase
- Must be willing and able to provide an adequate archival tumor sample available to confirm HER2 status by Central Laboratory (if local testing is used for enrollment), else must be willing and able to provide an adequate archival tumor sample for HER2 testing centrally
- Must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
- Must have life expectancy of at least 3 months
- +30 more criteria
You may not qualify if:
- Patients with a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Patient using e-cigarettes/vaping are also excluded
- Patients with a medical history of myocardial infarction within 6 months before enrollment (study treatment), symptomatic congestive heart failure (New York Heart Association Class II to IV, corrected QT interval (Fridericia's formula-corrected QT interval \[QTcF\]) prolongation to \> 470 ms (females) or \> 450 ms (males) as corrected by Framingham's formula
- Patients with spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
- Patients with multiple primary malignancies within 2 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other curatively treated solid tumors
- Patients with a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product
- Patients with an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
- Patients with substance abuse or any other medical conditions that would increase the safety risk to the subject or interfere with participation of the subject or evaluation of the clinical study in the opinion of the investigator
- Patients with a concomitant medical condition that would increase the risk of toxicity in the opinion of the investigator
- Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities grade \>1) with the exception of alopecia. Subjects with chronic grade 2 toxicities may be eligible per discretion of the investigator after discussion with study principal investigator (PI) (e.g., grade 2 chemo-induced neuropathy).
- Any previous treatment with an ATR inhibitor
- Patients with any clinically apparent pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\], restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e., Rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy
- Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
- Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
- Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir). The required washout period prior to starting study treatment is 2 weeks. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
- Patients with a pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to screening assessment)
- +10 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (23)
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612, United States
Los Angeles General Medical Center
Los Angeles, California, 90033, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, 90033, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817, United States
UF Health Cancer Institute - Gainesville
Gainesville, Florida, 32610, United States
Memorial Hospital East
Shiloh, Illinois, 62269, United States
National Cancer Institute Developmental Therapeutics Clinic
Bethesda, Maryland, 20892, United States
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892, United States
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376, United States
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141, United States
Washington University School of Medicine
St Louis, Missouri, 63110, United States
Siteman Cancer Center-South County
St Louis, Missouri, 63129, United States
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136, United States
NYP/Weill Cornell Medical Center
New York, New York, 10065, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104, United States
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania, 19107, United States
University of Texas at Austin
Austin, Texas, 78712, United States
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390, United States
University of Texas Medical Branch
Galveston, Texas, 77555-0565, United States
M D Anderson Cancer Center
Houston, Texas, 77030, United States
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Kanwal P Raghav
University of Texas MD Anderson Cancer Center LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
January 1, 2021
First Posted
January 12, 2021
Study Start
August 9, 2021
Primary Completion (Estimated)
March 31, 2027
Study Completion (Estimated)
March 31, 2027
Last Updated
May 13, 2026
Record last verified: 2026-04
Data Sharing
- IPD Sharing
- Will share
NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.