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

Running, not enrolling · Phase 1

Conditions studied: Advanced Breast Carcinoma, Advanced Colon Carcinoma, Advanced Colorectal Carcinoma, Advanced Endometrial Carcinoma, Advanced Gastric Carcinoma, Advanced Gastroesophageal Junction Adenocarcinoma, Advanced Malignant Solid Neoplasm, Advanced Salivary Gland Carcinoma, Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Clinical Stage III Gastric Cancer AJCC v8, Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8, Clinical Stage IV Gastric Cancer AJCC v8, Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8, HER2-Positive Breast Carcinoma, Malignant Hepatobiliary Neoplasm, Metastatic Breast Carcinoma, Metastatic Colon Carcinoma, Metastatic Colorectal Carcinoma, Metastatic Endometrial Carcinoma, Metastatic Gastric Carcinoma, Metastatic Gastroesophageal Junction Adenocarcinoma, Metastatic Malignant Solid Neoplasm, Metastatic Salivary Gland Carcinoma, Stage III Colon Cancer AJCC v8, Stage III Colorectal Cancer AJCC v8, Stage III Major Salivary Gland Cancer AJCC v8, Stage III Uterine Corpus Carcinoma or Carcinosarcoma AJCC v8, Stage IV Colon Cancer AJCC v8, Stage IV Colorectal Cancer AJCC v8, Stage IV Major Salivary Gland Cancer AJCC v8, Stage IV Uterine Corpus Carcinoma or Carcinosarcoma AJCC v8, Unresectable Breast Carcinoma, Unresectable Colon Carcinoma, Unresectable Colorectal Carcinoma, Unresectable Endometrial Carcinoma, Unresectable Gastric Carcinoma, Unresectable Gastroesophageal Junction Adenocarcinoma, Unresectable Malignant Solid Neoplasm, Unresectable Salivary Gland Carcinoma

In brief

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.

Key facts

Study ID: NCT04704661
Run by: National Cancer Institute (NCI)
People needed: 51
Starts: 2021-08-09
Expected to finish: 2027-03-31
Last updated by the study team: 2026-06-17

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

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
Must have left ventricular ejection fraction (LVEF) >= 50% within 28 days before enrollment (study drug treatment) by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan
Must have a negative pregnancy test (if female)
Platelets >= 100,000/mcL (within 14 days before enrollment)
No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
Hemoglobin >= 9.0 g/dL (within 14 days before enrollment)
Absolute neutrophil count >= 1,500/mcL (within 14 days before enrollment)
No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment
Creatinine clearance > 45/mL/min (using the Cockcroft-Gault equation) (within 14 days before enrollment)
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional upper limit of normal (ULN) (within 14 days before enrollment)
Total bilirubin =< 1.5 x ULN if no liver metastases or < 3 x ULN with Gilbert's Syndrome or liver metastases at baseline (within 14 days before enrollment)

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)
Patients with previous allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable within the last 28 days as long as they are not within 1 week prior to screening assessment)
Patients at risk of brain perfusion problems, e.g., medical history of carotid stenosis or pre-syncopal or syncopal episodes, history of transient ischemic attacks (TIAs)
Uncontrolled hypertension (grade 2 or above) requiring clinical intervention
Patients with relative hypotension (< 90/60 mm Hg) or clinically relevant orthostatic hypotension, including a fall in blood pressure of > 20 mm Hg
Patients who have received corticosteroids (at a dose > 10 mg prednisone/day or equivalent) for any reason within 2 weeks prior to first dose
Patients with uncontrolled intercurrent illness
Patients with psychiatric illness/social situations that would limit compliance with study requirements
Pregnant women are excluded from this study because DS-8201a is a HER2 antibody conjugated to a topoisomerase 1 inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DS-8201a, breastfeeding should be discontinued if the mother is treated with DS-8201a. These potential risks may also apply to AZD6738
Patients cannot be receiving chloroquine or hydroxychloroquine. Patients receiving these drugs must have a washout period of > 14 days before enrollment/randomization

Where it is running

UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care — Irvine, California, United States
Los Angeles General Medical Center — Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center — Los Angeles, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center — Orange, California, United States
University of California Davis Comprehensive Cancer Center — Sacramento, California, United States
UF Health Cancer Institute - Gainesville — Gainesville, Florida, United States
Memorial Hospital East — Shiloh, Illinois, United States
National Cancer Institute Developmental Therapeutics Clinic — Bethesda, Maryland, United States
National Institutes of Health Clinical Center — Bethesda, Maryland, United States
Siteman Cancer Center at Saint Peters Hospital — City of Saint Peters, Missouri, United States
Siteman Cancer Center at West County Hospital — Creve Coeur, Missouri, United States
Washington University School of Medicine — St Louis, Missouri, United States
Siteman Cancer Center-South County — St Louis, Missouri, United States
Siteman Cancer Center at Christian Hospital — St Louis, Missouri, United States
NYP/Weill Cornell Medical Center — New York, New York, United States
Ohio State University Comprehensive Cancer Center — Columbus, Ohio, United States
University of Oklahoma Health Sciences Center — Oklahoma City, Oklahoma, United States
Thomas Jefferson University Hospital — Philadelphia, Pennsylvania, United States
University of Texas at Austin — Austin, Texas, United States
UT Southwestern/Simmons Cancer Center-Dallas — Dallas, Texas, United States
University of Texas Medical Branch — Galveston, Texas, United States
UT MD Anderson Cancer Center — Houston, Texas, United States
Huntsman Cancer Institute/University of Utah — Salt Lake City, Utah, United States

Full record on ClinicalTrials.gov

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