Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Recurrence

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasms by Histologic Type

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Antineoplastic Agents

All Drugs and Chemicals

Venetoclax

Decitabine

Antimetabolites

Enzyme Inhibitors

Patients receive venetoclax PO daily for 28 days in a 28-day cycle. Patients receive DEC-C PO daily on days 1-5 of a 28-day cycle. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.

Cedazuridine

Bone Marrow Aspiration and Biopsy

Biospecimen Collection

Vanderbilt-Ingram Services for Timely Access

Vanderbilt-Ingram Service for Timely Access

Sanjay Mohan, MD

This phase II trial tests how well decitabine and cedazuridine (DEC-C) works in combination with venetoclax in treating acute myeloid leukemia (AML) in patients whose AML has come back after a period of improvement (relapse) after a donor stem cell transplant. 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. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving DEC-C in combination with venetoclax may kill more cancer cells in patients with relapsed AML.

PRIMARY OBJECTIVE:

I. To assess the effect of DEC-C/venetoclax on the investigator-assessed composite complete remission (CR) rate (CR/complete remission with partial hematologic recovery \[CRh\]/complete remission with incomplete hematologic recovery \[CRi\]).

SECONDARY OBJECTIVES:

I. To assess the rate of partial response (PR) and morphologic leukemia free state (MLFS) following treatment with DEC-C/venetoclax. II. To assess the relapse free survival of patients treated with DEC-C/venetoclax.

III. To assess overall survival of patients treated with DEC-C/venetoclax. IV. To assess the safety and tolerability of DEC-C/venetoclax in the post-hematopoietic cell transplant (HCT) setting.

V. To assess the rates of measurable residual disease negativity in patients achieving a CR.

OUTLINE:

Patients receive venetoclax orally (PO) daily for 28 days in a 28-day cycle. Patients receive DEC-C PO daily on days 1-5 of a 28-day cycle. Patients undergo bone marrow biopsy and aspiration and blood sample collection throughout the study.

Decitabine and Cedazuridine in Combination With Venetoclax for the Treatment of Patients Who Have Relapsed Acute Myeloid Leukemia After Donor Stem Cell Transplant

Phase 2 Study of Decitabine and Cedazuridine in Combination With Venetoclax for AML Relapse After Allogeneic Hematopoietic Cell Transplantation

Categorical variables (e.g., objective response) will be summarized in frequency tables and compared among patient subgroups using the chi-square test. Linear regression and logistic (or ordinal logistic) regression will be used to construct multivariable models for continuous, binary, and ordinal variables, as appropriate. In addition to ORR, the distributions of progression-free and overall survival will be estimated using the Kaplan-Meier method. We will consider statistical comparisons statistically, but not necessarily clinically, significant for p\<0.05.

The distributions of progression-free and overall survival will be estimated using the Kaplan-Meier method.

National Comprehensive Cancer Network

Taiho Oncology, Inc.

Sanjay Mohan

Assistant Professor of Medicine

Syndrome

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Precancerous Conditions

Pevonedistat

Pevonedistat 20 mg/m\^2, 60-minute intravenous (IV) infusion, once daily, on Days 1, 3, and 5 in each 28-day cycle in combination with decitabine 35 mg and cedazuridine 100 mg tablets, orally, once daily on Days 1 through 5 in each 28-day cycle up to 30 months.

Study Director

The main aim of the study is to see if signs and symptoms of myelodysplastic syndromes disappear when treated with pevonedistat combined with decitabine and cedazuridine.

Participants will receive an infusion of pevonedistat 3 times during a 28-day cycle. They will also take decitabine and cedazuridine tablets once a day for the first 5 days of the same cycle. A minimum of 6 28-day cycles is recommended, but participants can stop treatment at any time.

A bone marrow biopsy, bone marrow aspirates, and blood samples will be collected during the study.

Participants will attend a follow-up visit 30 days after their last dose of pevonedistat. Once treatment has ended, participants will be followed up with either monthly clinic visits or will be contacted every 3 months.

The drug being tested in this study is called Pevonedistat (TAK-924/MLN4924). Pevonedistat is being tested to treat people who have higher-risk myelodysplastic syndromes (HR MDS). This study will look at the overall survival, event free survival and response in people who take pevonedistat in combination with oral decitabine and cedazuridine in addition to standard care.

The study will enroll approximately 94 patients. Participants will be assigned to following treatment group:

• Pevonedistat 20 mg/m\^2 + Decitabine 35 mg + Cedazuridine 100 mg

All participants will receive pevonedistat in combination with decitabine and cedazuridine as specified in the protocol.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is approximately 30 months. Participants will make multiple visits to the clinic and will be contacted by telephone OR plus a final visit after receiving their last dose of drug/compound 30 days after last dose of study drug for event free survival (EFS) follow-up followed by overall survival (OS) follow-up.

A Study of Pevonedistat Combined With Decitabine and Cedazuridine in Adults With Higher-risk Myelodysplastic Syndromes

A Phase 2, Open-Label Study of Intravenous Pevonedistat in Combination With Oral Decitabine and Cedazuridine in Adult Patients With Higher-Risk Myelodysplastic Syndromes

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

CR Rate is defined as percentage of participants with HR MDS who achieve CR. CR for HR MDS as per the Modified IWG Response Criteria is defined as ≤5% myeloblasts with normal maturation of all cell lines in the bone marrow, and ≥11 grams per deciliter (g/dL) Hemoglobin (Hb), ≥100\*10\^9 per liter (/L) platelets (pl), ≥1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood.

DOR is defined as the time that criteria are met for CR to the date of first documented disease progression or relapse after CR for responders of CR. CR for HR MDS as per modified IWG response criteria is defined as ≤5% myeloblasts with normal maturation of all cell lines in the bone marrow, and greater than or equal to (≥)11 g/dL hemoglobin (Hgb), ≥100\*10\^9/liter (/L) platelets (pl), ≥1.0\*10\^9/L neutrophils and 0% blasts in peripheral blood.

ORR as per the modified IWG criteria for MDS is defined as percentage of participants with CR or partial remission (PR), CR: ≤5% myeloblasts with normal maturation of bone marrow (BM) cell lines, ≥11g/dL Hb, ≥100\*10\^9/L platelets, ≥1.0\*10\^9/L absolute neutrophil count (ANC), 0% blasts in peripheral blood. PR: all CR criteria met except bone marrow blasts ≥50% decrease over pretreatment but still \>5%.

It is defined as the time from the date of first dose of combination treatment to the first documented CR or PR or HI. CR: ≤5% myeloblasts with normal maturation of all bone marrow cell lines, ≥11 g/dL Hb, ≥100\*10\^9/L platelet, ≥1.0\*10\^9/L ANC, 0% blasts in peripheral blood; PR: all CR criteria met except bone marrow blasts ≥50% decrease over pretreatment but still \>5%. HI: Hb increase ≥1.5 g/dL if pretreatment \<11 g/dL; platelets absolute increase ≥30\*10\^9/L if baseline\>20\*10\^9/L or increase from \<20\*10\^9/L to \>20\*10\^9/L and by at least 100%; neutrophil increase by 100% and absolute increase of \>0.5\*10\^9/L if baseline \<1.0\*10\^9/L.

HI for HR MDS is defined as per Modified IWG Response Criteria for MDS. HI: Hb increase ≥1.5 g/dL if pretreatment \<11 g/dL; platelets absolute increase ≥30\*10\^9/L if baseline\>20\*10\^9/L or increase from \<20\*10\^9/L to \>20\*10\^9/L and by at least 100%; neutrophil increase by 100% and absolute increase of \>0.5\*10\^9/L if baseline \<1.0\*10\^9/L.

A participant is defined as RBC and/or platelet transfusion-independent if they receive no RBC and/or platelet transfusions for a period of at least 8 weeks during the time-period from the first dose of study drug administration through 30 days after the last dose of any study drug. Rate of RBC and/or platelet transfusion independence is defined as the percentage of participants who become RBC and/or platelet transfusion-independent divided by the number of participants who are RBC and/or platelet transfusion-dependent at Baseline.

The duration of transfusion independence is defined as the longest time between the last RBC and/or platelet transfusion before the start of the RBC and/or platelet transfusion-independent period and the first RBC and/or platelet transfusion after the start of the transfusion-independent period, which occurs at least 8 weeks later.

OS is defined as the time from the date of first dose of combination treatment to the date of death due to any cause.

EFS is defined as the time from the date of first dose of combination treatment to the date of the occurrence of an EFS event. An EFS event is defined as death or transformation to acute myelogenous leukemia (AML), whichever occurs first.

Takeda

Leukemia, Myelomonocytic, Chronic

Leukemia, Myelomonocytic, Juvenile

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Chronic Graft Versus Host Disease

Decitabine and cedazuridine drug combination

ASTX660 once daily (Days 1-7 and 15-21 per 28-day cycle) + ASTX727 FDC once daily (Days 1-5 per 28-day cycle)

ASTX660 once daily (Days 1-7 and 15-21 per 28-day cycle) as a single agent or in combination with ASTX727 FDC once daily (Days 1-5 per 28-day cycle)

ASTX660 at the recommended dose for expansion identified in Part 2 + ASTX727 FDC once daily (Days 1-5 per 28-day cycle)

ASTX660

ASTX727

To evaluate the safety, pharmacokinetics (PK), and efficacy of ASTX660 when given alone and in combination with ASTX727 in participants with relapsed/refractory (R/R) acute myeloid leukemia (AML). The duration of the study is expected to be approximately 30 months.

This is a three-part dose escalation and dose expansion Phase 1 study of ASTX660 alone and in combination with ASTX727 in adults with R/R AML.

Part 1 is an open-label, single arm, dose escalation with ASTX660 in combination with ASTX727 at the standard fixed dose combination (FDC).

Part 2 is an open-label, randomized, dose escalation intended to evaluate ASTX660 as a monotherapy and ASTX660 in combination with ASTX727 FDC.

Part 3 is an exploratory single arm dose expansion to further expand the number of participants treated with ASTX660 in combination with ASTX727 FDC.

A Study of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)

A Phase 1, Parallel, Open-Label Study of the Safety and Tolerability, Pharmacokinetics, and Antileukemic Activity of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Astex Pharmaceuticals, Inc.

Nervous System Diseases

Skin and Connective Tissue Diseases

Diseases and Abnormalities at or Before Birth

Nerve Sheath Neoplasms

Neurofibrosarcoma

Neoplasms, Nerve Tissue

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Peripheral Nervous System Diseases

Neuromuscular Diseases

Fibrosarcoma

Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Sarcoma

Neurofibromatoses

Neurofibroma

Malignant Peripheral Nerve Sheath Tumor

Soft Tissue Sarcoma

Neurofibromatosis

Patients who meet the eligibility criteria will be treated with oral ASTX727 (INQOVI) on days 1-5 of each 21-day cycle with Pegfilgrastim support on day 7. A delay in the start of subsequent cycles due to holidays, weather, or other circumstances will be permitted up to 7 days and not considered a protocol deviation. Drug dosing will be interrupted for any Grade 4 adverse events or clinically significant laboratory abnormalities. For Grade 3 or 4 AE, if the AE returns to Grade 1 or baseline, the patient may be re-escalated.

ASTX727 will be self-administered orally by the patient on a once daily basis, days 1 through 5 of each 21-day cycle. Cycle 1 day 1 (C1D1) is defined as the first day that ASTX727 is administered.

Ping Chi, MD, PhD

Ciara Kelly, MBBCH BAO

The purpose of this study is to see whether the study drug ASTX727 is an effective treatment for people who have MPNST with a PCR2 mutation.

ASTX727 is a combination of two drugs (cedazuridine and decitabine) that have been designed to target cancer cells with a PCR2 mutation and to disrupt the cells' ability to survive and grow. The study researchers think that the study drug allows decitabine to work better than decitabine given alone.

This is a phase II trial to evaluate the efficacy of ASTX727 in patients with PRC2-loss MPNST.

A Study of ASTX727 in People With Malignant Peripheral Nerve Sheath Tumors (MPNST)

A Phase II Study of ASTX727 in Patients With PRC2 Loss Malignant Peripheral Nerve Sheath Tumor (MPNST)

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

(complete response \[CR\] + partial response \[PR\] + stable disease \[SD\]) by RECIST1.1

Memorial Sloan Kettering Cancer Center

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Chronic Disease

Disease Attributes

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

The recommended starting dose is the fixed-dose combination (FDC) tablet, containing 100 mg cedazuridine and 35 mg decitabine, once daily, Days 1 through 5 in 28-day cycles. Participants should receive ASTX727 at the same dose they received in the last cycle of their parent study; if an adjustment from that dose is required, a different total cycle dose may be employed, as guided by the dose adjustment guidelines in the parent study protocol.

Participants will receive ASTX727 once daily on Days 1 through 5 in a 28-day cycle (Cycle 1). Participants will fast for at least 2 hours before and 2 hours after dosing on Days 1, 3, 5 and for at least 10 hours before and 4 hours after dosing on Day 2. Participants will receive a high-calorie/high-fat breakfast meal after an overnight fast of at least 10 hours before dosing on Day 4 and will continue to fast for at least 4 hours post-dose.

Participants will continue treatment with ASTX727 in Cycle 2 onwards in the ASTX727-06 study at the Investigator's discretion, where they will continue to receive ASTX727 unless there is occurrence of disease progression requiring alternative therapy, unacceptable toxicity, noncompliance, a decision to discontinue treatment, or if the participant withdraws from the study.

Participants will receive ASTX727 once daily on Days 1 through 5 in a 28-day cycle (Cycle 1). Participants will fast for at least 2 hours before and 2 hours after dosing on Days 1, 3, 5 and for at least 10 hours before and 4 hours after dosing on Day 2. Participants will receive low-calorie/low-fat breakfast meal after an overnight fast of at least 10 hours before dosing on Day 4 and will continue to fast for at least 4 hours post-dose.

Participants will continue treatment with ASTX727 in Cycle 2 onwards in the ASTX727-06 study at the Investigator's discretion, where they will continue to receive ASTX727 unless there is occurrence of disease progression requiring alternative therapy, unacceptable toxicity, noncompliance, a decision to discontinue treatment, or if the participant withdraws from the study.

ASTX727 film-coated, immediate-release FDC tablets

Extension study to provide ongoing long-term treatment with ASTX727 for participants who were benefitting from ASTX727 treatment in a previous Astex-sponsored clinical study of ASTX727 (including, but not limited to ASTX727-01 \[NCT02103478\], ASTX727-02 \[NCT03306264\], ASTX727-04 \[NCT03813186\]), and Food Effect Substudy to obtain survival information and long-term safety information.

The purpose of the Food Effect Substudy is to evaluate the pharmacokinetics (PK) and safety of decitabine and cedazuridine when ASTX727 is given under fed (high-calorie/high-fat meal or low-calorie/low-fat meal) versus fasted conditions.

Main Extension Study: Participants will attend clinic visits on Day 1 of each 28-day cycle to undergo study procedures and to be given ASTX727 tablets for Days 1-5 of that dose cycle. Participants should continue to receive the same ASTX727 dose and regimen they were receiving in the last cycle of the parent study in which they were originally enrolled. Subsequent treatment delays and/or dose reductions are at the discretion of the investigator as guided by the dose adjustment guidelines of the parent study protocol.

Food Effect Substudy: Participants will receive ASTX727 once daily on Days 1 through 5 followed by a 23-day treatment-free period in a 28-day cycle (Cycle 1). Participants will receive either a high-calorie, high-fat breakfast meal (Arm A) or a low-calorie/low-fat breakfast meal (Arm B) predose on Day 4. Participants in Arms A and B will receive ASTX727 on Days 1, 2, 3, and 5 in the fasted condition. Participants may continue treatment with ASTX727 in Cycle 2 onwards in the ASTX727-06 study at the Investigator's discretion, where they will continue to receive ASTX727. This substudy consists of a 21-day Screening Period, a 1-cycle (28 days) Treatment Period, and a 30-day (+7 days) Safety Follow-up Period (only if the participant discontinues from the ASTX727-06 food effect substudy and does not continue to receive ASTX727 in the ASTX727-06 study).

A Study for Participants Who Participated in Prior Clinical Studies of ASTX727 (Standard Dose), With a Food Effect Substudy at Select Study Centers

An Open-Label, Multicenter, Extension Study for Participants Who Participated in Prior Clinical Studies of ASTX727 (Standard Dose), With a Food Effect Substudy at Select Study Centers

An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal finding in laboratory tests or other diagnostic procedures), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. TEAEs are defined as events that first occur or worsen on or after the date of the first study treatment until 30 days after the last dose of study treatment, or the start of an alternative anticancer treatment, whichever first.

Assessments of conversion to AML in participants with hematological malignancies will be performed following local standards at the discretion of the Investigator.

An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal finding in laboratory tests or other diagnostic procedures), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. TEAEs are defined as events that first occur or worsen on or after the date of the first study treatment (Cycle 1 Day 1) until 30 days after the last dose of study treatment, or the start of an alternative anticancer treatment, whichever first. Severity of TEAEs will be graded using Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE v4.03).

The laboratory parameters of hematology, serum chemistry, and urinalysis will be assessed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Decitabine and Cedazuridine in Combination With Venetoclax for the Treatment of Patients Who Have Relapsed Acute Myeloid Leukemia After Donor Stem Cell Transplant	NCT05799079	Recurrent Acute...	Venetoclax Decitabine Cedazuridine Bone Marrow Asp... Biospecimen Col...	18 Years -	Vanderbilt-Ingram Cancer Center
A Study of Pevonedistat Combined With Decitabine and Cedazuridine in Adults With Higher-risk Myelodysplastic Syndromes	NCT04985656	Myelodysplastic...	Pevonedistat Decitabine Cedazuridine	18 Years -	Takeda
A Study of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)	NCT04155580	Acute Myeloid L...	ASTX660 ASTX727	18 Years -	Astex Pharmaceuticals, Inc.
A Study of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)	NCT04155580	Acute Myeloid L...	ASTX660 ASTX727	18 Years -	Astex Pharmaceuticals, Inc.
A Study of ASTX727 in People With Malignant Peripheral Nerve Sheath Tumors (MPNST)	NCT04872543	Malignant Perip...	ASTX727	18 Years -	Memorial Sloan Kettering Cancer Center
A Study of ASTX660 as a Single Agent and in Combination With ASTX727 in Subjects With Relapsed/Refractory Acute Myeloid Leukemia (AML)	NCT04155580	Acute Myeloid L...	ASTX660 ASTX727	18 Years -	Astex Pharmaceuticals, Inc.
A Study of ASTX727 in People With Malignant Peripheral Nerve Sheath Tumors (MPNST)	NCT04872543	Malignant Perip...	ASTX727	18 Years -	Memorial Sloan Kettering Cancer Center
A Study for Participants Who Participated in Prior Clinical Studies of ASTX727 (Standard Dose), With a Food Effect Substudy at Select Study Centers	NCT04093570	Acute Myeloid L... Chronic Myelomo... Myelodysplastic...	ASTX727	18 Years -	Astex Pharmaceuticals, Inc.

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