Phase I Trial of DS-8201a (Trastuzumab Deruxtecan) in Combination With Neratinib in Solid Tumors With HER2 Alterations

  • End date
    Jun 17, 2024
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 13 October 2022


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 to other parts of 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.



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).


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.


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 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, 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.

After completion of study treatment, patients are followed up every 3 months for at least one year or until death.

Condition Metastatic Malignant Solid Neoplasm, Unresectable Malignant Solid Neoplasm
Treatment biopsy, Trastuzumab deruxtecan, Neratinib Maleate
Clinical Study IdentifierNCT05372614
SponsorNational Cancer Institute (NCI)
Last Modified on13 October 2022


Yes No Not Sure

Inclusion Criteria

Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
Patients must have HER2-positive or HER2-overexpressing tumors as defined by Clinical Laboratory Improvement Act (CLIA)-certified laboratories (labs). Specific requirement of HER2 status is outlined below
Solid tumor with HER2 overexpression by immunohistochemistry (IHC) or amplification by in situ hybridization (ISH)/sequencing or activating mutation (see below) by sequencing from a CLIA certified lab (both local HER2 IHC and sequencing data required even if enrollment is based on one of the criteria)
HER2 overexpression by IHC/ISH will follow histology specific American Society of Clinical Oncology-College of American Pathologists (ASCO-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
L755P; T862A
Del. 755-759; D769Y/H; V842I
All exon 20 insertions, including
G660D, R678Q, E693K, and Q709L
If a different mutation is identified, contact the study chair for conferral
No limitation on number of prior therapies; however, may not have received
neratinib or DS-8201a previously. Prior HER2-targeted therapy other than
neratinib or DS-8201a is allowed (e.g., trastuzumab, pertuzumab, TDM-1
lapatinib, etc.)
Age >= 18 years. Because no dosing or adverse event data are currently available
on the use of neratinib in combination with DS-8201a in patients < 18 years of
age, children are excluded from this study
Patients must have Eastern Cooperative Oncology Group (ECOG) performance status
=< 1 (Karnofsky >= 70%)
Hemoglobin >= 9.0 g/dL (>= 8.0 g/dL for gastric cancer [GC] only) (within 14 days
of enrollment)
No transfusions with red blood cells or platelets are allowed within 1 week prior to
screening assessment
Leukocytes >= 3,000/mcL (within 14 days of enrollment)
Absolute neutrophil count >= 1,500/mcL (within 14 days of enrollment)
No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1
week prior to screening assessment
Platelets >= 100,000/mcL (within 14 days of enrollment)
No transfusions with red blood cells or platelets are allowed within 1 week prior to
screening assessment
Serum albumin >= 2.5 g/dL (within 14 days of enrollment)
Total bilirubin =< 1.5 × institutional upper limit of normal (ULN), (< 3 × ULN in
the presence of documented Gilbert's syndrome or liver metastases at baseline)
(within 14 days of enrollment)
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase
[SGPT]) =< 3 x ULN (if liver metastases are present =< 5 x ULN) (within 14 days
of enrollment)
International normalized ratio (INR)/prothrombin time (PT) and activated partial
thromboplastin time (aPTT) =< 1.5 x institutional ULN (within 14 days of
This applies only to patients who are not receiving therapeutic anticoagulation that
may affect INR. Those who are on therapeutic anticoagulation, should be on a stable
dose for 4 weeks and should be considered within therapeutic range
Creatinine =< 1.5 x institutional ULN OR Glomerular filtration rate (GFR) >= 30
mL/min/1.73 m^2 (using the Cockcroft-Gault equation) (within 14 days of
Patients who are human immunodeficiency virus (HIV)-positive may participate IF
they meet the following eligibility requirements
They must be stable on their anti-retroviral regimen, and they must be healthy from an
HIV perspective
They must have a CD4 count of greater than 250 cells/mcL over the past 6 months on
this same anti-retroviral regimen and must not have had a CD4 count < 200 cells/ul
over the past 2 years, unless it was deemed related to THE CANCER AND/OR
CHEMOTHERAPY-induced bone marrow suppression
For patients who have received chemotherapy in the past 6 months, a CD4 count <
cells/ul during chemotherapy is permitted as long as viral loads were
undetectable during this same chemotherapy
They must have an undetectable viral load and a CD4 count >= 250 cells/uL within 7
days of enrollment
They must not be currently receiving prophylactic therapy for an opportunistic
infection and must not have had an opportunistic infection within the past 6 months
HIV-infected patients should be monitored every 12 weeks for viral load and CD4 counts
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated
Patients with a history of hepatitis C virus (HCV) infection must have been
treated and cured. For patients with HCV infection who are currently on
treatment, they are eligible if they have an undetectable HCV viral load
Patients with treated brain metastases are eligible if the following criteria are
met: 1) follow-up brain imaging done at least in 4 weeks after central nervous
system (CNS)-directed therapy shows no evidence of progression and 2) the patient
no longer requires steroids, or is on a stable steroid dose > 4 weeks
Patients with radiographically new or progressive brain metastases (active brain
metastases) or leptomeningeal disease are eligible only if has no progressive
clinical symptoms and if the treating physician determines that immediate CNS
specific treatment is not required and is unlikely to be required during the
first cycle of therapy
Patients should be New York Heart Association functional classification of class
B or better
Patients must have left ventricular ejection fraction (LVEF) >= 50% by either an
echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before
Dose expansion phase (PD cohort): Patients must have disease that is evaluable or
measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Dose expansion phase (PD cohort): Patients must have at least one lesion suitable
for biopsy without significant risk to the patient. The biopsiable lesion can be
the same as the evaluable lesion for response by RECIST 1.1
Patients who had clinically significant side effects from prior cancer therapy
must have recovered to grade 1 or below
HER2 antibody conjugated to a topoisomerase 1 inhibitor agents as well as other
therapeutic agents used in this trial are known to be teratogenic; thus, women of
child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry
for the duration of study participation, and for at least 1 month after the last
dose of neratinib, or at least 7 months after the last dose of DS-8201a
whichever is longer (women of childbearing potential [WOCBP] only). Should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician
immediately. Men treated or enrolled on this protocol must also agree to use
adequate contraception prior to the study, for the duration of study
participation, and 3 months after the last dose of neratinib, or 4 months after
completion of DS-8021a administration, whichever is longer
Women of non-child-bearing potential defined as pre-menopausal females with a
documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months
of spontaneous amenorrhea (in questionable cases, a blood sample with
simultaneous follicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol < 40
pg/mL [< 147 pmol/L] is confirmatory) are eligible. Females on hormone
replacement therapy (HRT) and whose menopausal status is in doubt will be
required to use one of the contraception methods outlined for women of
child-bearing potential if they wish to continue their HRT during the study
Otherwise, they must discontinue HRT to allow confirmation of post-menopausal
status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will
elapse between the cessation of therapy and the blood draw; this interval depends
on the type and dosage of HRT. Following confirmation of their post-menopausal
status, they can resume use of HRT during the study without use of a
contraceptive method
Male subjects must not freeze or donate sperm starting at screening and
throughout the study period, and at least 4 months after the final study drug
administration. Preservation of sperm should be considered prior to enrollment in
this study
Female subjects must not donate, or retrieve for their own use, ova from the time
of screening and throughout the study treatment period, and for at least 7 months
after the final study drug administration
Ability to understand and the willingness to sign a written informed consent
document. Participants with impaired decision-making capacity who have a
legally-authorized representative (LAR) and/or family member available will also
be eligible

Exclusion Criteria

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. The sponsor
must be notified if a subject receives any of these during the study
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
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
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
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)
Patients with a corrected QT interval (QTc) prolongation to > 470 ms (females) or >
ms (males) based on average of the screening triplicate 12-lead electrocardiogram
Patients with clinically significant corneal disease in the opinion of the