Anatomic Stage III Breast Cancer AJCC v8Phase 1NCT05673200
Testing the Addition of an Anti-cancer Drug, ASTX727 (Cedazuridine, Decitabine), to Chemotherapy (Paclitaxel) and Immunotherapy (Pembrolizumab) for Metastatic Triple-Negative Breast Cancer
A Phase 1 study testing Biopsy Procedure, Biospecimen Collection and Computed Tomography in people with Anatomic Stage III Breast Cancer AJCC v8 and Anatomic Stage IV Breast Cancer AJCC v8, run by National Cancer Institute (NCI) at 10 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Triple-Negative Breast Carcinoma
- What is being tested?
- Biopsy Procedure, Biospecimen Collection and Computed Tomography
- Type of treatment
- Pill or oral medicine, Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 32 participants
- Where
- 10 sitesUnited States
- Study dates
- 25 Sep 2023to 23 Feb 2027
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
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- 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.
- Patients who have received 0-3 prior lines of chemotherapy 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
United States10 sites
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
UC Irvine Health Cancer Center-Newport
Costa Mesa, California, 92627
Mayo Clinic in Florida
Jacksonville, Florida, 32224-9980
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, 92868
Mayo Clinic Hospital in Arizona
Phoenix, Arizona, 85054
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298
Mayo Clinic in Rochester
Rochester, Minnesota, 55905
University of California Davis Comprehensive Cancer Center
Sacramento, California, 95817
About this study
Official title: Phase I Study Targeting DNA Methyltransferases in Metastatic Triple-Negative Breast Cancer
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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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:
- 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 1-5, 1-4, 1-3, or days 1, 3, and 5 of each cycle, and paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15 of each 28-day cycle or days 1 and 8 of each 21-day cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes every 6 weeks (treatment day varies in 28-day cycles; day 1 of every odd 21-day cycle) 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.
- Conditions
- Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Triple-Negative Breast Carcinoma, Unresectable Triple-Negative Breast Carcinoma
- Being tested
- Biopsy Procedure, Biospecimen Collection, Computed Tomography, Decitabine and Cedazuridine, Magnetic Resonance Imaging
- Medical subject headings
- Triple Negative Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Biopsy ProcedureProcedure or surgery
Also called Biopsy, BIOPSY_TYPE, Bx
Undergo biopsy
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection
Undergo collection of blood
Computed TomographyProcedure or surgery
Also called CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography
Undergo CT
Decitabine and CedazuridineDrug
Also called ASTX 727, ASTX-727, ASTX727, C-DEC
Given PO
Magnetic Resonance ImagingProcedure or surgery
Also called Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan
Undergo MRI
PaclitaxelDrug
Also called Anzatax, Asotax, Bristaxol, Praxel
Given IV
PembrolizumabBiological
Also called BCD-201, GME 751, GME751, Keytruda
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Treatment (ASTX727, paclitaxel, pembrolizumab) | Experimental | Patients receive ASTX727 PO on days 1-5, 1-4, 1-3, or days 1, 3, and 5 of each cycle, and paclitaxel IV over 1 hour on days 1, 8, and 15 of each 28-day cycle or days 1 and 8 of each 21-day cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes every 6 weeks (treatment day varies in 28-day cycles; day 1 of every odd 21-day cycle) in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood samples and CT and/or 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. Receives: Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Drug: Decitabine and Cedazuridine; Procedure: Magnetic Resonance Imaging; Drug: Paclitaxel; Biological: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximally tolerated dose (MTD) of ASTX727 in combination with paclitaxel and pembrolizumab (MK-3475) (Dose Finding Phase)
Defined as the highest dose level among those under consideration where at most 1 of 6 patients develops a dose limiting toxicity and 2 or more of the 3-6 patients treated at the next higher dose level develop a dose limiting toxicity.
Measured: Within the first cycle of treatment (28 days)
Safety profile of ASTX727 in combination with paclitaxel and pembrolizumab (MK-3475) (Dose Finding Phase)
The maximum grade of each type of toxicity will be recorded for each patient. For each toxicity reported by dose level, the percentage of patients developing any degree of that toxicity as well as the percentage of patients developing a severe degree (grade 3 or higher) will be determined.
Measured: Up to 4 years
Secondary outcomes (5)
Tolerability (Dose Expansion Phase)
The maximum grade of each type of adverse event will be recorded for each patient and the percentage of patients developing any degree of that adverse event as well as the percentage of patients developing a severe degree (grade 3 or higher) will be determined.
Measured: Upon completion of the dose expansion phase
Tumor response rate (Dose Expansion Phase)
Defined as the number of patients whose tumor has met the immune-modified Response Evaluation Criteria in Solid Tumors criteria for complete response (CR) or partial response (PR) on two consecutive evaluations at least 8 weeks apart among all the eligible patients who have begun treatment. A 90% binomial confidence interval for the tumor response rate will be determined.
Measured: Up to 4 years
Duration of response (Dose Expansion Phase)
Will be estimated using the Kaplan-Meier method.
Measured: From the time measurement criteria are met for CR or PR until the first date that recurrent or progressive disease is objectively documented, assessed up to 4 years
Overall survival (Dose Expansion Phase)
Will be estimated using the Kaplan-Meier method.
Measured: From study entry to death due to any cause, assessed up to 4 years
Progression-free survival (Dose Expansion Phase)
Will be estimated using the Kaplan-Meier method.
Measured: From study entry to the documentation of disease progression, assessed up to 4 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jan 2023
- Study start25 Sep 2023
- Primary completion23 Feb 2027 (estimated)
- Study completion23 Feb 2027 (estimated)
Why it stopped: Other - DLT assessment and phase 2 dose determination
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Anatomic Stage III Breast Cancer AJCC v8Studies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 32 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Roberto A Leon-Ferre, Principal investigator, Dana-Farber - Harvard Cancer Center LAO
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05673200
- Sponsor's protocol ID
- NCI-2022-10810
- Other IDs
- NCI-2022-10810, 10546, 10546, UM1CA186709
- Status last verified
- Jun 2026
- First submitted
- 4 Jan 2023
- Last updated
- 31 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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
Study at a glance
From the registry record, last updated by the sponsor on 31 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study Targeting DNA Methyltransferases in Metastatic Triple-Negative Breast Cancer
- ClinicalTrials.gov ID
- NCT05673200
- Acronym / sponsor ID
- NCI-2022-10810
- Conditions
- Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Metastatic Triple-Negative Breast Carcinoma, Unresectable Triple-Negative Breast Carcinoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- SuspendedReason stopped: Other - DLT assessment and phase 2 dose determination
- Enrolment
- 32 participants (estimated)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 25 Sep 2023 (actual)
- Primary completion
- 23 Feb 2027 (estimated)
- Study completion
- 23 Feb 2027 (estimated)
- First posted
- 6 Jan 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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:
- 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:
- 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 1-5, 1-4, 1-3, or days 1, 3, and 5 of each cycle, and paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15 of each 28-day cycle or days 1 and 8 of each 21-day cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes every 6 weeks (treatment day varies in 28-day cycles; day 1 of every odd 21-day cycle) 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment (ASTX727, paclitaxel, pembrolizumab) | Experimental | Procedure: Biopsy Procedure, Procedure: Biospecimen Collection, Procedure: Computed Tomography, Drug: Decitabine and Cedazuridine, Procedure: Magnetic Resonance Imaging, Drug: Paclitaxel, Biological: PembrolizumabPatients receive ASTX727 PO on days 1-5, 1-4, 1-3, or days 1, 3, and 5 of each cycle, and paclitaxel IV over 1 hour on days 1, 8, and 15 of each 28-day cycle or days 1 and 8 of each 21-day cycle. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes every 6 weeks (treatment day varies in 28-day cycles; day 1 of every odd 21-day cycle) in the absence of disease progression or unacceptable toxicity. Patients undergo collection of blood samples and CT and/or 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (27 listed)
- 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)
Key exclusion criteria (10 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Biopsy ProcedureAlso: Biopsy, BIOPSY_TYPE, BxUndergo biopsy | Procedure or surgery | Treatment (ASTX727, paclitaxel, pembrolizumab) |
| Biospecimen CollectionAlso: Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen CollectionUndergo collection of blood | Procedure or surgery | Treatment (ASTX727, paclitaxel, pembrolizumab) |
| Computed TomographyAlso: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial TomographyUndergo CT | Procedure or surgery | Treatment (ASTX727, paclitaxel, pembrolizumab) |
| Decitabine and CedazuridineAlso: ASTX 727, ASTX-727, ASTX727, C-DECGiven PO | Drug | Treatment (ASTX727, paclitaxel, pembrolizumab) |
| Magnetic Resonance ImagingAlso: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging ScanUndergo MRI | Procedure or surgery | Treatment (ASTX727, paclitaxel, pembrolizumab) |
| PaclitaxelAlso: Anzatax, Asotax, Bristaxol, PraxelGiven IV | Drug | Treatment (ASTX727, paclitaxel, pembrolizumab) |
| PembrolizumabAlso: BCD-201, GME 751, GME751, KeytrudaGiven IV | Biological | Treatment (ASTX727, paclitaxel, pembrolizumab) |
Primary outcome
Maximally tolerated dose (MTD) of ASTX727 in combination with paclitaxel and pembrolizumab (MK-3475) (Dose Finding Phase)
Time frame: Within the first cycle of treatment (28 days)
Defined as the highest dose level among those under consideration where at most 1 of 6 patients develops a dose limiting toxicity and 2 or more of the 3-6 patients treated at the next higher dose level develop a dose limiting toxicity.
Safety profile of ASTX727 in combination with paclitaxel and pembrolizumab (MK-3475) (Dose Finding Phase)
Time frame: Up to 4 years
The maximum grade of each type of toxicity will be recorded for each patient. For each toxicity reported by dose level, the percentage of patients developing any degree of that toxicity as well as the percentage of patients developing a severe degree (grade 3 or higher) will be determined.
5 secondary outcomes
Tolerability (Dose Expansion Phase)
Time frame: Upon completion of the dose expansion phase
Tumor response rate (Dose Expansion Phase)
Time frame: Up to 4 years
Duration of response (Dose Expansion Phase)
Time frame: From the time measurement criteria are met for CR or PR until the first date that recurrent or progressive disease is objectively documented, assessed up to 4 years
Overall survival (Dose Expansion Phase)
Time frame: From study entry to death due to any cause, assessed up to 4 years
Progression-free survival (Dose Expansion Phase)
Time frame: From study entry to the documentation of disease progression, assessed up to 4 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jul 2026.
- Individual participant dataSharing planned: Yes. 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Roberto A Leon-Ferre principal investigator
Dana-Farber - Harvard Cancer Center LAO
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Biopsy Procedure, Biospecimen Collection and Computed Tomography in people with Anatomic Stage III Breast Cancer AJCC v8 and Anatomic Stage IV Breast Cancer AJCC v8, run by National Cancer Institute (NCI) at 10 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 27 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: paused, as of the sponsor's last update on 31 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximally tolerated dose (MTD) of ASTX727 in combination with paclitaxel and pembrolizumab (MK-3475) (Dose Finding Phase) (time frame: Within the first cycle of treatment (28 days)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jul 2026.