Study Stopped
Other - Correlative sample analysis.
Testing the Safety and Tolerability of the Anti-cancer Drugs Trastuzumab Deruxtecan and Neratinib for Cancers With Changes in the HER2 Gene
Phase I Trial of DS-8201a (Trastuzumab Deruxtecan) in Combination With Neratinib in Solid Tumors With HER2 Alterations
4 other identifiers
interventional
33
1 country
18
Brief Summary
This phase I trial tests the safety, side effects, and best dose of neratinib in combination with trastuzumab deruxtecan in treating patients with solid tumors that have spread from where it first started (primary site) to other places in the body (metastatic) or that cannot be removed by surgery (unresectable), and have changes in a gene called human epidermal growth factor receptor 2 (HER2). Neratinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps slow or stop the spread of tumor cells. Trastuzumab deruxtecan is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive tumor cells in a targeted way and delivers deruxtecan to kill them. Adding neratinib to trastuzumab deruxtecan may be able to shrink cancer with a change in the HER2 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 Oct 2022
Longer than P75 for phase_1
18 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
May 12, 2022
CompletedFirst Posted
Study publicly available on registry
May 13, 2022
CompletedStudy Start
First participant enrolled
October 5, 2022
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 17, 2025
CompletedStudy Completion
Last participant's last visit for all outcomes
January 23, 2027
ExpectedApril 14, 2026
January 1, 2026
3 years
May 12, 2022
April 11, 2026
Conditions
Outcome Measures
Primary Outcomes (2)
Incidence of dose limiting toxicities
Safety endpoints will be listed for each dose level.
In the first 2 cycles in dose escalation of combination of neratinib and trastuzumab deruxtecan (DS-8201a) (cycle length = 21 days)
Incidence of treatment-emergent adverse events
Safety endpoints will be listed for each dose level and the tabulations of adverse events will also be produced by severity and by relationship to study drug.
In the first 2 cycles of combination of neratinib and DS-8201a (cycle length = 21 days)
Secondary Outcomes (8)
Incidence of adverse events
Up to 1 year
Objective response rate
Up to 1 year
Duration of response
Time from first documentation of response (CR or PR) until the time of first documentation of disease progression, assessed up to 1 year
Progression free survival
Time from first dose to the earlier date of assessment of progression or death by any cause in the absence of progression, assessed up to 1 year
Overall survival
From date of first dose to the date of death by any cause, assessed up to 1 year
- +3 more secondary outcomes
Other Outcomes (4)
Deoxyribonucleic acid (DNA) damage
Up to 1 year
Quantitative HER2 protein
At cycle 1 days 3-5 and cycle 2 days 3-5, and at progression, assessed up to 1 year (cycle length = 21 days)
Tumor mutation profile
Before treatment and at progression, assessed up to 1 year
- +1 more other outcomes
Study Arms (1)
Treatment (neratinib, trastuzumab deruxtecan)
EXPERIMENTALPatients receive neratinib PO 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 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, CT scan and echocardiography or MUGA scan throughout study. Additionally, patients may undergo a tissue biopsy at baseline and disease progression.
Interventions
Undergo biopsy
Undergo blood sample collection
Undergo CT scan
Undergo echocardiography
Undergo MUGA scan
Given PO
Given IV
Eligibility Criteria
You may qualify if:
- Patients must have histologically confirmed malignancy that is metastatic or unresectable with participation in this clinical trial determined to be the best option for next treatment in the opinion of the investigator
- Patients must have a solid tumor with HER2-positivity as determined by any one or more of the following:
- HER2 overexpression defined by immunohistochemistry (IHC) 3+
- ERBB2 amplification by in situ hybridization (ISH) or next-generation sequencing as determined by any Clinical Laboratory Improvement Act (CLIA) certified lab
- A known HER2 activating mutation
- HER2 overexpression by IHC/ISH will follow histology specific American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guidelines for breast and gastric cancers. For tumor histologies without specific guidelines the following criteria will apply:
- HER2 IHC should be performed first, followed by ISH methods in cases showing 2+ (equivocal) expression by IHC. Positive (IHC 3+) or negative (IHC 0 or 1+) do not require further ISH testing. Cases with HER2:CEP17 ratio ≥ 2 or an average HER2 copy number ≥ 6.0 signals per cell are considered positive by ISH
- Known HER2 activating mutations:
- G309A/E
- S310F/Y
- S653C
- V659E
- G660D
- R678Q
- E693K
- +59 more criteria
You may not qualify if:
- With the exception of medications that are under investigation in the study (e.g., standard of care, comparators, or combination therapies), the following medications, treatment, and procedures will be prohibited during the treatment period:
- Other anticancer therapy, including small-molecule targeted agents within 2 weeks or five half-lives, whichever is longer; chemotherapy otherwise not specified (including, but not limited to cytotoxic chemotherapy, antibody drug conjugates, retinoid therapy, hormonal therapy) within 3 weeks; immunotherapy or monoclonal antibody within 4 weeks; and nitrosureas or mitomycin C within 6 weeks (concurrent use of hormones for noncancer-related conditions \[e.g., insulin for diabetes and hormone replacement therapy\] is acceptable)
- Other investigational therapeutic agents
- Patients who have had major surgery or radiation within 4 weeks; palliative stereotactic radiation within 2 weeks (except for palliative radiation to known metastatic sites as long as it does not affect assessment of response or interrupt treatment for more than the maximum time specified in dose modification section)
- Radiotherapy to the thorax (palliative radiation to known metastatic sites in the thoracic spine is permitted in this study)
- Concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications except for managing adverse events (inhaled steroids or intra-articular steroid injections are permitted in this study); chronic replacement dose steroids (e.g., for those with adrenal insufficiency) are permitted in this study
- Subjects with bronchopulmonary disorders who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study
- Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during the study treatment due to concern for overlapping toxicities. If treatment with chloroquine and hydroxychloroquine treatment is absolutely required, study treatment must be interrupted. If chloroquine or hydroxychloroquine is administered, then a wash-out period of more than 14 days is required before restarting study treatment
- Receipt of live, attenuated vaccine (messenger ribonucleic acid \[mRNA\] and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of study drug
- Patients with a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
- Patients with clinically severe 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 history of allergic reactions attributed to compounds of similar chemical or biologic composition to DS-8201a, the inactive ingredients in the drug product, or neratinib
- Patients who have a history of severe hypersensitivity reactions to other monoclonal antibodies
- Patients receiving any medications or substances that are moderate or strong inhibitors or inducers of CYP3A4 and P-glycoprotein are ineligible. Avoid concomitant use with proton pump inhibitors and P-glycoprotein substrates. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- Patients with a medical history of myocardial infarction within 6 months before enrollment, or symptomatic congestive heart failure (CHF) (New York Heart Association class II to IV)
- +13 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (18)
City of Hope Comprehensive Cancer Center
Duarte, California, 91010, United States
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, 92612, United States
City of Hope at Irvine Lennar
Irvine, California, 92618, United States
City of Hope Antelope Valley
Lancaster, California, 93534, 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
City of Hope South Pasadena
South Pasadena, California, 91030, United States
City of Hope Upland
Upland, California, 91786, United States
UF Health Cancer Institute - Gainesville
Gainesville, Florida, 32610, United States
Northwestern University
Chicago, Illinois, 60611, United States
University of Kentucky/Markey Cancer Center
Lexington, Kentucky, 40536, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215, United States
Washington University School of Medicine
St Louis, Missouri, 63110, United States
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232, United States
M D Anderson Cancer Center
Houston, Texas, 77030, United States
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
Madison, Wisconsin, 53718, United States
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792, United States
Related Publications (1)
Jhaveri K, Eli LD, Wildiers H, Hurvitz SA, Guerrero-Zotano A, Unni N, Brufsky A, Park H, Waisman J, Yang ES, Spanggaard I, Reid S, Burkard ME, Vinayak S, Prat A, Arnedos M, Bidard FC, Loi S, Crown J, Bhave M, Piha-Paul SA, Suga JM, Chia S, Saura C, Garcia-Saenz JA, Gambardella V, de Miguel MJ, Gal-Yam EN, Rapael A, Stemmer SM, Ma C, Hanker AB, Ye D, Goldman JW, Bose R, Peterson L, Bell JSK, Frazier A, DiPrimeo D, Wong A, Arteaga CL, Solit DB. Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: outcomes and biomarker analysis from the SUMMIT trial. Ann Oncol. 2023 Oct;34(10):885-898. doi: 10.1016/j.annonc.2023.08.003. Epub 2023 Aug 18.
PMID: 37597578DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Andrew A Davis
Yale University 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
May 12, 2022
First Posted
May 13, 2022
Study Start
October 5, 2022
Primary Completion
September 17, 2025
Study Completion (Estimated)
January 23, 2027
Last Updated
April 14, 2026
Record last verified: 2026-01
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."