Trial Title:
Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors
NCT ID:
NCT06364410
Condition:
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
Locally Advanced Gastric Carcinoma
Locally Advanced Gastroesophageal Junction Adenocarcinoma
Locally Advanced Malignant Solid Neoplasm
Metastatic Gastric Carcinoma
Metastatic Gastroesophageal Junction Adenocarcinoma
Metastatic Malignant Solid Neoplasm
Unresectable Gastric Carcinoma
Unresectable Gastroesophageal Junction Adenocarcinoma
Unresectable Malignant Solid Neoplasm
Conditions: Official terms:
Carcinoma
Neoplasms
Adenocarcinoma
Stomach Neoplasms
Esophageal Neoplasms
Trastuzumab
Camptothecin
Trastuzumab deruxtecan
Immunoconjugates
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Azenosertib
Description:
Given PO
Arm group label:
Dose escalation (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 1 (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 2 (T-DXd, azenosertib)
Other name:
Wee1 Inhibitor ZN-c3
Other name:
ZN c3
Other name:
ZN-c3
Other name:
ZNc3
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo biopsy
Arm group label:
Dose expansion, Cohort 1 (T-DXd, azenosertib)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo collection of blood samples
Arm group label:
Dose escalation (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 1 (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 2 (T-DXd, azenosertib)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Dose escalation (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 1 (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 2 (T-DXd, azenosertib)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Procedure
Intervention name:
Echocardiography
Description:
Undergo ECHO
Arm group label:
Dose escalation (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 1 (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 2 (T-DXd, azenosertib)
Other name:
EC
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Dose escalation (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 1 (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 2 (T-DXd, azenosertib)
Other name:
Magnetic Resonance
Other name:
Magnetic Resonance Imaging (MRI)
Other name:
Magnetic resonance imaging (procedure)
Other name:
Magnetic Resonance Imaging Scan
Other name:
Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
Other name:
MR
Other name:
MR Imaging
Other name:
MRI
Other name:
MRI Scan
Other name:
MRIs
Other name:
NMR Imaging
Other name:
NMRI
Other name:
Nuclear Magnetic Resonance Imaging
Other name:
sMRI
Other name:
Structural MRI
Intervention type:
Procedure
Intervention name:
Multigated Acquisition Scan
Description:
Undergo MUGA
Arm group label:
Dose escalation (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 1 (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 2 (T-DXd, azenosertib)
Other name:
Blood Pool Scan
Other name:
Equilibrium Radionuclide Angiography
Other name:
Gated Blood Pool Imaging
Other name:
Gated Heart Pool Scan
Other name:
MUGA
Other name:
MUGA Scan
Other name:
Multi-Gated Acquisition Scan
Other name:
Radionuclide Ventriculogram Scan
Other name:
Radionuclide Ventriculography
Other name:
RNV Scan
Other name:
RNVG
Other name:
SYMA Scanning
Other name:
Synchronized Multigated Acquisition Scanning
Intervention type:
Biological
Intervention name:
Trastuzumab Deruxtecan
Description:
Given IV
Arm group label:
Dose escalation (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 1 (T-DXd, azenosertib)
Arm group label:
Dose expansion, Cohort 2 (T-DXd, azenosertib)
Other name:
DS-8201
Other name:
DS-8201a
Other name:
Enhertu
Other name:
Fam-trastuzumab Deruxtecan-nxki
Other name:
T-DXd
Other name:
WHO 10516
Summary:
This phase I trial tests the safety, side effects, and best dose of azenosertib in
combination with trastuzumab deruxtecan in treating patients with HER2-positive and
cyclin E amplified gastric or gastroesophageal junction cancer and other HER2-positive
solid tumors that have spread to nearby tissue or lymph nodes (locally advanced), 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). Azenosertib is in a
class of medications called kinase inhibitors. It inhibits a protein called Wee1.
Inhibition of the Wee1 protein can make tumor cells more vulnerable to chemotherapy
drugs, leading to tumor cell death. 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 cancer cells in a targeted way and delivers deruxtecan to kill them. Giving
azenosertib in combination with trastuzumab deruxtecan may be safe, tolerable, and/or
more effective in treating patients with locally advanced, metastatic, or unresectable
HER2-positive gastric, gastroesophageal junction, or other solid tumors, compared to just
trastuzumab deruxtecan alone.
Detailed description:
PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of trastuzumab deruxtecan (T-DXd; DS-8201a) in
combination with azenosertib (ZN-c3) in human epidermal growth factor receptor 2
(HER2)-expressing/amplified solid tumors.
SECONDARY OBJECTIVES:
I. To observe and record the antitumor activity of the T-DXd (DS-8201a) and azenosertib
(ZN-c3) combination.
II. To assess the pharmacodynamic effects of T-DXd (DS-8201a) in combination with
azenosertib (ZN-c3).
III. To assess predictors of response and acquired resistance to the T-DXd (DS-8201a) and
azenosertib (ZN-c3) combination.
OUTLINE: This is a dose-escalation study of azenosertib followed by a dose-expansion
study.
DOSE ESCALATION: Patients receive T-DXd intravenously (IV) over 30-90 minutes on day 1 of
each cycle and azenosertib orally (PO) once daily (QD) on days 1-5, 8-12, and 15-19 of
each cycle. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity. Patients also undergo echocardiography (ECHO) or multigated
acquisition scan (MUGA) and collection of blood samples at screening and on study and
undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the
trial.
DOSE EXPANSION: Patients are assigned to 1 of 2 cohorts.
COHORT 1: Patients receive T-DXd IV over 30-90 minutes on day 1 of each cycle and
azenosertib PO QD on days 8-12 and 15-19 of cycle 1 and days 1-5, 8-12, and 15-19 in
subsequent cycles. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity. Patients also undergo ECHO or MUGA and collection of blood samples
at screening and on study and undergo CT or MRI throughout the trial. Patients also
undergo biopsy at screening and on study.
COHORT 2: Patients receive treatment as in the dose escalation arm. Patients also undergo
ECHO or MUGA and collection of blood samples at screening and on study and undergo CT or
MRI throughout the trial. Patients also undergo biopsy at screening and on study.
After completion of study treatment, patients are followed up at 30 days and then every 3
months in years 1 and 2 and every 6 months in year 3.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- In the dose escalation, patients must have a histologically documented locally
advanced, unresectable, or metastatic solid tumor that has progressed following at
least one prior line of treatment in the metastatic setting or has no satisfactory
alternative treatment option and all of the following:
- HER2 expression by immunohistochemistry (IHC) (1+, 2+, or 3+) or HER2
amplification by in situ hybridization (ISH) or next generation sequencing
(NGS) (on any Clinical Laboratory Improvements Amendments [CLIA] platform), AND
- T-DXd (DS-8201a)-naive disease
- In the dose expansion, patients must have histologically documented locally
advanced, unresectable or metastatic gastric or gastroesophageal junction (GEJ)
cancer that has progressed following at least one prior line of treatment in the
metastatic setting and have all of the following:
- CCNE1 amplification, AND
- HER2 expression by IHC (1+, 2+, or 3+) or HER2 amplification by ISH or NGS (on
any CLIA platform), AND
- T-DXd (DS-8201a)-naive disease
- Received prior trastuzumab-based treatment, if eligible for such treatment
- For the dose escalation and dose expansion, patients can have evaluable or
measurable disease
- Potential trial participants should have recovered from clinically significant
adverse events (AEs) of their most recent therapy/intervention prior to enrollment
- Age ≥ 18 years. Because no dosing or AE data are currently available on the use of
T-DXd (DS-8201a) in combination with azenosertib (ZN-c3) in patients < 18 years of
age, children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (Karnofsky ≥
70%). Both T-DXd (DS-8201a) and azenosertib (ZN-c3) have fatigue as an adverse
effect. Due to the overlapping adverse effect, the performance status cannot be less
restrictive
- Absolute neutrophil count ≥ 1.5 × 10^9/L (within 7 days of study treatment
initiation)
- No transfusions with red blood cells or platelets are allowed within 1 week
prior to screening assessment
- No administration of granulocyte colony-stimulating factor is allowed within 1
week prior to screening assessment
- Hemoglobin > 9.0 g/dL (within 7 days of study treatment initiation)
- No transfusions with red blood cells or platelets are allowed within 1 week
prior to screening assessment
- No administration of granulocyte colony-stimulating factor is allowed within 1
week prior to screening assessment
- Platelets ≥ 100 × 10^9/L (within 7 days of study treatment initiation)
- No transfusions with red blood cells or platelets are allowed within 1 week
prior to screening assessment
- No administration of granulocyte colony-stimulating factor is allowed within 1
week prior to screening assessment
- Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN). Documented Gilbert
syndrome is allowed if total bilirubin is ≤ 3 × institutional ULN (within 7 days of
study treatment initiation)
- No transfusions with red blood cells or platelets are allowed within 1 week
prior to screening assessment
- No administration of granulocyte colony-stimulating factor is allowed within 1
week prior to screening assessment
- Aspartate aminotransferase (AST [serum glutamic-oxaloacetic transaminase
(SGOT)])/alanine aminotransferase (ALT [serum glutamate pyruvate transaminase
(SGPT)]) ≤ 3 × institutional ULN. In the presence of liver metastases, AST or ALT up
to 5 × institutional ULN is permitted (within 7 days of study treatment initiation)
- No transfusions with red blood cells or platelets are allowed within 1 week
prior to screening assessment
- No administration of granulocyte colony-stimulating factor is allowed within 1
week prior to screening assessment
- Measured of calculated creatinine clearance (CrCl) ≥ 60 mL/min (CrCl should be
calculated per institutional standard; glomerular filtration rate can also be used
in place of CrCl) ≥ 60 mL/min for patients with creatinine levels > 1.5 x
institutional ULN (within 7 days of study treatment initiation)
- No transfusions with red blood cells or platelets are allowed within 1 week
prior to screening assessment
- No administration of granulocyte colony-stimulating factor is allowed within 1
week prior to screening assessment
- International normalized ratio/prothrombin time and activated partial thromboplastin
time ≤ 1.5 × institutional ULN (within 7 days of study treatment initiation)
- No transfusions with red blood cells or platelets are allowed within 1 week
prior to screening assessment
- No administration of granulocyte colony-stimulating factor is allowed within 1
week prior to screening assessment
- Patients must have left ventricular ejection fraction (LVEF) ≥ 50% by either an
echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before
enrollment
- Human immunodeficiency virus-infected patients on effective anti-retroviral therapy
with undetectable viral load within 6 months are eligible for this trial
- 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 follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression
- Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate CNS-specific treatment is not required and is unlikely to be required
during the first cycle of study treatment
- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial
- Life expectancy ≥ 3 months
- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
result within 3 days of study treatment initiation
- Agents composed of HER2 antibody conjugated to a topoisomerase 1 inhibitor and
azenosertib (ZN-c3) are known to be teratogenic; thus, WOCBP must agree to use
highly effective contraception from time of screening and throughout the study
treatment period and for at least 7 months after final study treatment
administration. 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. Female patients 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 treatment administration
- Women of non-childbearing potential defined as premenopausal females with 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 > 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 WOCBP if they wish to continue their HRT during the study.
Otherwise, they must discontinue HRT to allow confirmation of postmenopausal 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 postmenopausal status, they
can resume use of HRT during the study without use of a contraception method
- Male patients involved with WOCBP must agree to use a highly effective form of
contraception or avoid intercourse from time of screening and throughout the study
treatment period and for at least 4 months after the last dose of study treatment.
Male patients must not freeze or donate sperm starting at screening and throughout
the study period and at least 4 months after the final study treatment
administration. Preservation of sperm should be considered prior to enrollment in
this study
- Ability to understand and the willingness to sign a written informed consent
document. Legally authorized representatives may sign and give informed consent on
behalf of study participants
- Willing to undergo biopsy as required by the study (dose expansion only)
Exclusion Criteria:
- As azenosertib (ZN-c3) is a substrate of CYP3A4, use of prescription or
non-prescription drugs known to be moderate or strong inhibitors or inducers of
CYP3A4 are prohibited with the exception of moderate or strong inhibitors or
inducers of CYP3A4 that are part of the prophylactic antiemetic regimen.
Chloroquine/hydroxychloroquine are metabolized by CYP3A4 and therefore, should be
prohibited. For patients who have received prior moderate or strong inhibitors or
inducers of CYP3A4, the required washout period is approximately 5 half-lives prior
to study treatment initiation
- Patients who are receiving any other investigational agents
- Patients who have a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to the study drugs
- Patients who have a history of severe hypersensitivity reactions to other monoclonal
antibodies (mAbs)
- 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 3 months of the study enrollment, severe asthma,
severe chronic obstructive pulmonary disease, 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
- Pregnant women are excluded from this study because T-DXd (DS-8201a) and azenosertib
(ZN-c3) have the potential risk for teratogenic or abortifacient effects. Because
there is an unknown but potential risk for AEs in nursing infants secondary to
treatment of the mother with T-DXd (DS-8201a) and azenosertib (ZN-c3), breastfeeding
should be discontinued if the mother is treated with T-DXd (DS-8201a) or azenosertib
(ZN-c3)
- Patients with history of non-infectious pneumonitis/interstitial lung disease (ILD),
current ILD, or where suspected ILD cannot be ruled out by imaging at screening
- Patients with active infections requiring antibiotics at the time of study treatment
initiation are not eligible
- Patients with history of malabsorption syndrome or other condition that would
interfere with enteral absorption or results in the inability or unwillingness to
swallow pills
- Patients with current signs or symptoms of bowel obstruction including sub-occlusive
disease related to underlying disease
- Patients with a medical history of myocardial infarction within 6 months before
enrollment, symptomatic congestive heart failure (New York Heart Association class
IIb to IV), and/or troponin levels consistent with myocardial infarction as defined
according to the manufacturer 28 days prior to enrollment
- Patients with clinically significant corneal disease
- 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 history of Torsades de Pointes unless all risk factors that
contributed to Torsades de Pointes have been corrected
- Based on an average of triplicate 12-lead electrocardiogram (ECG), patients with a
mean resting corrected QT (QTc) interval using Fridericia formula of > 470 msec for
both males and females at screening or a history of congenital long QT syndrome will
be excluded
- Patients with prior treatment with a WEE1 inhibitor (dose escalation and dose
expansion)
- Patients with prior treatment with T-DXd (DS-8201a) or other topoisomerase
inhibitors (dose escalation and dose expansion)
- Patients with uncontrolled intercurrent illness
- Patients with prior allogeneic organ transplantation including allogeneic stem cell
transplantation
- Patients with clinically significant chronic gastrointestinal disorder with diarrhea
as a major symptom; ≥ grade 2 diarrhea at baseline. Please contact the protocol
principal investigator (PI) for any patient with more than two episodes of diarrhea
per day averaged over at least a 7-day period at time of screening to determine
whether the diarrhea would be considered clinically significant
- Patients with spinal cord compression
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of Texas MD Anderson Cancer Center LAO
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
Funda Meric-Bernstam
Phone:
713-792-3245
Email:
fmeric@mdanderson.org
Investigator:
Last name:
Funda Meric-Bernstam
Email:
Principal Investigator
Start date:
July 7, 2025
Completion date:
July 8, 2027
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06364410
