Trial Title:
Testing the Addition of an Anti-cancer Drug, ASTX727 (Cedazuridine, Decitabine), to Chemotherapy (Paclitaxel) and Immunotherapy (Pembrolizumab) for Metastatic Triple-Negative Breast Cancer
NCT ID:
NCT05673200
Condition:
Anatomic Stage III Breast Cancer AJCC v8
Anatomic Stage IV Breast Cancer AJCC v8
Metastatic Triple-Negative Breast Carcinoma
Unresectable Triple-Negative Breast Carcinoma
Conditions: Official terms:
Carcinoma
Breast Neoplasms
Triple Negative Breast Neoplasms
Paclitaxel
Pembrolizumab
Albumin-Bound Paclitaxel
Decitabine
Decitabine and cedazuridine drug combination
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Suspended
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo biopsy
Arm group label:
Treatment (ASTX727, paclitaxel, pembrolizumab)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo collection of blood
Arm group label:
Treatment (ASTX727, paclitaxel, pembrolizumab)
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:
Treatment (ASTX727, paclitaxel, pembrolizumab)
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:
Drug
Intervention name:
Decitabine and Cedazuridine
Description:
Given PO
Arm group label:
Treatment (ASTX727, paclitaxel, pembrolizumab)
Other name:
ASTX 727
Other name:
ASTX-727
Other name:
ASTX727
Other name:
C-DEC
Other name:
CDA Inhibitor E7727/Decitabine Combination Agent ASTX727
Other name:
Cedazuridine/Decitabine Combination Agent ASTX727
Other name:
Cedazuridine/Decitabine Tablet
Other name:
DEC-C
Other name:
Inaqovi
Other name:
Inqovi
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Treatment (ASTX727, paclitaxel, pembrolizumab)
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:
Drug
Intervention name:
Paclitaxel
Description:
Given IV
Arm group label:
Treatment (ASTX727, paclitaxel, pembrolizumab)
Other name:
Anzatax
Other name:
Asotax
Other name:
Bristaxol
Other name:
Praxel
Other name:
Taxol
Other name:
Taxol Konzentrat
Intervention type:
Biological
Intervention name:
Pembrolizumab
Description:
Given IV
Arm group label:
Treatment (ASTX727, paclitaxel, pembrolizumab)
Other name:
BCD-201
Other name:
GME 751
Other name:
GME751
Other name:
Keytruda
Other name:
Lambrolizumab
Other name:
MK 3475
Other name:
MK-3475
Other name:
MK3475
Other name:
Pembrolizumab Biosimilar BCD-201
Other name:
Pembrolizumab Biosimilar GME751
Other name:
Pembrolizumab Biosimilar QL2107
Other name:
QL2107
Other name:
SCH 900475
Other name:
SCH-900475
Other name:
SCH900475
Summary:
This phase I trial tests the safety, side effects, and best dose of ASTX727 when given in
combination with a usual approach of treatment with paclitaxel and pembrolizumab in
patients with triple-negative breast cancer that has spread from where it first started
(primary site) to other places in the body (metastatic). The usual approach is defined as
care most people get for this type of cancer. The usual approach for patients with
metastatic triple negative breast cancer who are not in a study is chemotherapy with
drugs like paclitaxel, carboplatin, cisplatin, eribulin, vinorelbine, capecitabine,
gemcitabine, doxorubicin or cyclophosphamide. There is a protein called PD-L1 that helps
regulate the body's immune system. For patients who have PD-L1+ tumors, immunotherapy
(pembrolizumab) is usually added to paclitaxel or carboplatin/gemcitabine as initial
treatment. For patients who have PD-L1-negative tumors, chemotherapy alone is used,
without immunotherapy. ASTX727 is a combination of two drugs, decitabine and
cedazuridine. Cedazuridine is in a class of medications called cytidine deaminase
inhibitors. It prevents the breakdown of decitabine, making it more available in the body
so that decitabine will have a greater effect. Decitabine is in a class of medications
called hypomethylation agents. It works by helping the bone marrow produce normal blood
cells and by killing abnormal cells in the bone marrow. Paclitaxel is in a class of
medications called antimicrotubule agents. It stops tumor cells from growing and dividing
and may kill them. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may
help the body's immune system attack the cancer, and may interfere with the ability of
tumor cells to grow and spread. Giving ASTX727 with usual treatment approach with
paclitaxel and pembrolizumab may be able to shrink or stabilize the tumor for longer than
the usual approach alone in patients with metastatic triple negative breast cancer.
Detailed description:
PRIMARY OBJECTIVES:
I. To determine the recommended phase 2 dose (RP2D) of oral decitabine and cedazuridine
(ASTX727) administered concurrently with paclitaxel and pembrolizumab (MK-3475). (Part 1
[Dose finding cohort]).
II. To further describe the adverse event profile of the combination of oral ASTX727 at
the RP2D when administered concurrently with paclitaxel and pembrolizumab (MK-3475).
(Part 2 [Expansion cohort]).
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity of this combination. II. To describe the
adverse event profile of the combination of oral ASTX727 administered concurrently with
paclitaxel and pembrolizumab (MK-3475). (Part 1 [Dose finding cohort]).
III. To explore the association of baseline gene expression profiles ribonucleic
acid-sequencing (RNA-Seq), with focus on DNMT isoforms and TRAF-6 signaling, with
clinical benefit from study treatment, as well as changes in expression after 1 cycle of
treatment. (Part 2 [Expansion cohort]).
IV. To evaluate the impact of study treatment on methylation (in tumor tissue and
circulating tumor deoxyribonucleic acid [ctDNA]). (Part 2 [Expansion Cohort]).
EXPLORATORY OBJECTIVES:
I. To preliminarily evaluate the association of baseline DNMT3A protein expression by
immunohistochemistry (IHC) and antitumor activity, as well as whether study treatment
results in reduction of DNMT3A protein expression. (Part 1 [Dose finding cohort]).
II. To preliminarily evaluate the association of baseline tumor-infiltrating lymphocytes
(TILs) and PD-L1 expression with antitumor activity. (Part 1 [Dose finding cohort]).
III. To evaluate the impact of study treatment on ctDNA methylation, peripheral blood
immune phenotype and function, and serum thymidine kinase (TK1). (Part 1 [Dose finding
cohort]).
IV. To evaluate the impact of study treatment on immune phenotype (in tumor and
peripheral blood) and function. (Part 2 [Expansion cohort]).
V. To explore the impact of study treatment on immune-related genomic signaling by
RNA-Seq. (Part 2 [Expansion cohort]).
VI. To evaluate the association between baseline TILs and PD-L1 expression with treatment
response, as well as changes in expression after 1 cycle of treatment. (Part 2 [Expansion
cohort]).
VII. To evaluate the association between mutations in driver genes, epigenetic genes and
homologous recombination deficiency status (assessed by whole exome sequencing) with
clinical outcome. (Part 2 [Expansion cohort]).
OUTLINE: This is a dose-escalation study of ASTX727 in combination with fixed-dose
pembrolizumab and fixed or reduced-dose paclitaxel, followed by a dose-expansion study.
Patients receive ASTX727 orally (PO) on days 1-4, paclitaxel intravenously (IV) over 1
hour on days 1, 8, and 15, and pembrolizumab IV over 30 minutes on day 1 of each cycle.
Cycles repeat every 28 days in the absence of disease progression or unacceptable
toxicity. Patients undergo collection of blood samples and computed tomography (CT)
and/or magnetic resonance imaging (MRI) throughout the trial. Patients in the
dose-expansion phase also undergo a tumor biopsy during screening and day 1 of the
treatment cycle 2 of the study.
Patients will be followed every 6 months for 3 years post registration or until death,
whichever occurs first.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients must have histologically confirmed triple-negative breast cancer (TNBC)
(estrogen receptor [ER] and progesterone receptor [PR] =< 10%, human epidermal
growth factor receptor-2 [HER2]-negative per American Society of Clinical Oncology
[ASCO]/College of American Pathologists [CAP] guidelines) that is metastatic or
unresectable.
- Age >= 18 years. Because no dosing or adverse event data are currently available on
the use of ASTX727 in combination with pembrolizumab (MK-3475) and paclitaxel in
patients <18 years of age, children are excluded from this study.
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >=
60%)
- Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days prior to registration)
- Platelets >= 100,000/mm^3 (within 14 days prior to registration)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L(within 14 days prior to registration)
- Criteria must be met without packed red blood cell (pRBC) transfusion within
the prior 14 days of registration. Participants can be on stable dose of
erythropoietin (90 days or more prior to registration).
- Creatinine clearance (CrCl) >= 30 mL/min (within 14 days prior to registration)
- Glomerular filtration rate (GFR) can also be used in place of CrCl
- Total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for
patients with total bilirubin levels > 1.5 × ULN (within 14 days prior to
registration)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])
and alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) =< 3
x institutional ULN (within 14 days prior to registration)
- 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 there is evidence of
measurable extracranial disease, and if follow-up brain imaging 4 weeks after
central nervous system (CNS)-direct therapy shows no evidence of progression.
Patients with carcinomatous meningitis are not eligible.
- Patients with a prior malignancy whose natural history does not have the potential
to interfere with the safety or efficacy assessment of the investigational regimen
are eligible for this trial. Concurrent use of other antineoplastic treatments is
not allowed.
- Patients should be New York Heart Association Functional Classification of class II
or better.
- Patients who have received live attenuated vaccines within the 30 days prior to
registration are not eligible. Seasonal flu vaccines that do not contain live virus,
and coronavirus disease 2019 (COVID-19) vaccinations and boosters are permitted.
- Patients with prior history of peripheral neuropathy are allowed if it has recovered
to grade 1 or less.
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months of registration are eligible
for this trial.
- Any number of prior lines in the metastatic setting. Patients who have received
prior PD-1/PD-L1 monoclonal antibodies in any disease setting are eligible.
- For enrollment to Dose Finding Cohort: Availability and willingness to provide
archival tumor tissue as required per protocol.
- For enrollment to Dose Expansion Cohort: (i) Willingness to provide baseline and
3-week tumor tissue biopsy specimens. (ii) Patients must have a measurable disease
per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
- The effects of ASTX727 and pembrolizumab (MK-3475) on the developing human fetus are
unknown. For this reason and because these agents as well as other therapeutic
agents used in this trial are known to be teratogenic, 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 180 days after the last dose of study treatment. 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. Pregnant women
are excluded from this study because pembrolizumab (MK-3475) is an anti PD-1
monoclonal antibody agent, ASTX727 is a hypomethylating agent, and paclitaxel is a
class D 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 pembrolizumab (MK-3475), breastfeeding
should be discontinued if the mother is treated with pembrolizumab (MK-3475). These
potential risks may also apply to other agents used in this study. 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 180 days after completion of
study treatment.
- Ability to understand and the willingness to sign a written informed consent
document (or have legally acceptable representative sign, if applicable).
- Patients who have recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia.
- Note: If patients received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy.
- Has not received transfusion of blood products (including platelets or red blood
cells) or administration of colony stimulating factors (including granulocyte
colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor
[GM-CSF], or recombinant erythropoietin) within 4 weeks prior to registration.
Exclusion Criteria:
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within the 7 days prior to registration.
- Has a known additional malignancy that is progressing or requires active treatment.
- Has an active autoimmune disease that has required systemic treatment within 2 years
prior to registration (i.e., with use of disease modifying agents, corticosteroids,
or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment. Current
treatment with systemic steroids up to 10 mg of prednisone daily or equivalent is
allowed.
- Patients with uncontrolled intercurrent illness (including but not limited to
interstitial lung disease or active, non-infectious pneumonitis) or a history of
(non-infectious) pneumonitis that required steroids.
- History of grade 3-4 immediate hypersensitivity reaction to paclitaxel or other
drugs formulated in polyoxyl 35 castor oil.
- Patients who are receiving any other investigational agents.
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to ASTX727, pembrolizumab (MK-3475), and/or paclitaxel.
- Has a known history of active tuberculosis (TB).
- Gastrointestinal disorder that may impact absorption of oral medications.
- History of solid organ or bone marrow transplantation.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Mayo Clinic Hospital in Arizona
Address:
City:
Phoenix
Zip:
85054
Country:
United States
Facility:
Name:
UC Irvine Health Cancer Center-Newport
Address:
City:
Costa Mesa
Zip:
92627
Country:
United States
Facility:
Name:
UC Irvine Health/Chao Family Comprehensive Cancer Center
Address:
City:
Orange
Zip:
92868
Country:
United States
Facility:
Name:
University of California Davis Comprehensive Cancer Center
Address:
City:
Sacramento
Zip:
95817
Country:
United States
Facility:
Name:
Mayo Clinic in Florida
Address:
City:
Jacksonville
Zip:
32224-9980
Country:
United States
Facility:
Name:
Mayo Clinic in Rochester
Address:
City:
Rochester
Zip:
55905
Country:
United States
Facility:
Name:
Ohio State University Comprehensive Cancer Center
Address:
City:
Columbus
Zip:
43210
Country:
United States
Facility:
Name:
University of Oklahoma Health Sciences Center
Address:
City:
Oklahoma City
Zip:
73104
Country:
United States
Facility:
Name:
University of Pittsburgh Cancer Institute (UPCI)
Address:
City:
Pittsburgh
Zip:
15232
Country:
United States
Start date:
September 25, 2023
Completion date:
February 23, 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/NCT05673200
