Clinical trial NCT04093570: A Study for Participants Who Participated in Prior Clinical Studies of ASTX727 (Standard Dose)
Official title: An Open-Label, Multicenter, Extension Study for Subjects Who Participated in Prior Clinical Studies of ASTX727 (Standard Dose)
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndromes
Keywords: cedazuridine
decitabine
MDS
CMML
AML
myelodysplastic syndromes
chronic myelomonocytic leukemia
acute myeloid leukemia
ASTX727
INQOVI
Lead sponsor: Taiho Oncology, Inc.
Sponsor class: INDUSTRY
First posted: 2019-09-18
Enrollment: 332
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Extension study to provide ongoing long-term treatment with ASTX727 for participants who were benefitting from ASTX727 treatment in a previous Taiho (formerly Astex)-sponsored clinical study of ASTX727 (including, but not limited to ASTX727-01 \[NCT02103478\], ASTX727-02 \[NCT03306264\], ASTX727-04 \[NCT03813186\]), ASTX727-06 \[NCT04093570\] food effect substudy, ASTX727-17 \[NCT04953897\], and ASTX727-18 \[NCT04953910\] to obtain long-term safety information.

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

Detailed description: 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 received ASTX727 once daily on Days 1 through 5 followed by a 23-day treatment-free period in a 28-day cycle (Cycle 1). Participants received 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 received 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 continued 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).

Eligibility criteria: Inclusion Criteria for the Main Extension Study:

Participants must fulfill all of the following inclusion criteria:

1. Previous participation in a Taiho (formerly Astex)-sponsored ASTX727 clinical trial (including, but not limited to studies ASTX727-01, ASTX727-02, and ASTX727-04, , ASTX727-17, and ASTX727-18, and the food effect substudy of ASTX727-06) in which the participant was treated with ASTX727 and was still on active treatment with ASTX727 at the time of study completion as determined by Taiho.
2. Participant is considered to be benefitting from ASTX727 treatment in the opinion of the treating investigator at the time of parent study completion (Participants must not be withdrawn from the parent study until eligibility for this study is confirmed).
3. Participant is able to understand and comply with the study procedures and understands the risks involved in the study.
4. Participant provides legally effective informed consent before undergoing any study-specific procedure.
5. Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential must agree to practice 1 highly effective contraceptive methods of birth control during the study and for 6 months after the last dose of study treatment, agree not to donate eggs for the purpose of reproduction during this period and must agree not to become pregnant for 6 months after completing treatment; men with female partners of childbearing potential must agree to practice 2 highly effective contraceptive measures and must agree not to father a child while receiving ASTX727 and for at least 3 months after completing ASTX727 treatment.

Inclusion Criteria for the Food Effect Substudy:

1. Participants must have a confirmed diagnosis of-

   i. Myelodysplastic syndromes (MDS) including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia \[CMML\])), and participants with MDS International Prognostic Scoring System (IPSS) int-1, int-2, or high-risk MD.

   ii. Acute myeloid leukemia (AML), as diagnosed according to the 2016 World Health Organization (WHO) guidelines on acute leukemia, of any subtype except M3 (acute promyelocytic leukemia), who are not candidates for intensive chemotherapy, including participants receiving hypomethylating agent (HMA) treatment, who have a confirmed diagnosis and a prior confirmatory bone marrow report. Participants who are currently receiving HMA treatment must complete the ongoing (at the time of Screening) treatment cycle before enrolling in this study; timing of start of treatment cycle with ASTX727 is at the principal investigator's discretion.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
3. Adequate organ function defined as follows:

   1. Hepatic: Total bilirubin ≤1.5 × upper limit of normal (ULN); aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) ≤5 × ULN.
   2. Renal: Calculated creatinine clearance ≥60 mL/min.

Exclusion Criterion for the Main Extension Study:

1. Any participant who, in the opinion of the investigator, may have other conditions, organ dysfunction, or for whom safety data from parent study participation suggests the risks of continuing treatment with ASTX727 may outweigh the benefits.

Exclusion Criteria for the Food Effect Substudy:

1. Participants with known or suspected hypersensitivity to decitabine, cedazuridine, or any of the excipients in the ASTX727 tablets.
2. Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
3. Life-threatening illness, medical condition or organ system dysfunction, or other reasons including laboratory abnormalities, which, in the Investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of decitabine + cedazuridine or compromise the integrity of the study outcomes.
4. Prior gastric surgery for ulcer disease, weight loss, etc, that would impair normal motility or absorption.
5. Second malignancy currently requiring active chemotherapy. To clarify, participants with breast or prostate cancer stable on or responding to endocrine therapy, are eligible.
6. Known history of human immunodeficiency virus or known seropositive for hepatitis C virus or hepatitis B virus.
7. Active uncontrolled gastric or duodenal ulcer.
8. Participants with acute promyelocytic leukemia.
9. Prior cytotoxic chemotherapy for AML except for hydroxyurea to control high white blood cell (WBC) counts.
10. Treated with any investigational drug or therapy within 2 weeks of study treatment, or 5 half-lives, whichever is longer, before the protocol-defined first dose of study treatment, or ongoing clinically significant AEs from previous treatment with investigational drug or therapy.

Primary outcomes:
measure: Main Extension Study: Safety: Number of Participants with Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From date of transition into this extension study until 30 days following the last dose, up to approximately 2 years
measure: Food Effect Substudy: AUC0-last: Area Under the Plasma Concentration-time Curve From Time Zero to Last Concentration Measured of Decitabine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 ( up to 28 days)
measure: Food Effect Substudy: AUC0-last: Area Under the Plasma Concentration-time Curve From Time Zero to Last Concentration Measured of Cedazuridine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: AUC0-last: Area Under the Plasma Concentration-time Curve From Time Zero to Last Concentration Measured of Cedazuridine-epimer in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: AUC0-8h: Area Under the Concentration-time Curve From Time Zero to 8 Hours of Decitabine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: AUC0-8h: Area Under the Concentration-time Curve From Time Zero to 8 Hours of Cedazuridine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: AUC0-8h: Area Under the Concentration-time Curve From Time Zero to 8 Hours of Cedazuridine-epimer in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: AUC0-24h: Area Under the Concentration-time Curve From Time Zero to 24 Hours of Decitabine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: AUC0-24h: Area Under the Concentration-time Curve From Time Zero to 24 Hours of Cedazuridine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: AUC0-24h: Area Under the Concentration-time Curve From Time Zero to 24 Hours of Cedazuridine-epimer in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: AUC 0-inf: Area Under the Concentration-time Curve From Time Zero to Infinity of Decitabine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: AUC 0-inf: Area Under the Concentration-time Curve From Time Zero to Infinity of Cedazuridine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: AUC 0-inf: Area Under the Concentration-time Curve From Time Zero to Infinity of Cedazuridine-epimer in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: Cmax: Maximum Observed Plasma Concentration of Decitabine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: Cmax: Maximum Observed Plasma Concentration of Cedazuridine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: Cmax: Maximum Observed Plasma Concentration of Cedazuridine-epimer in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: Tmax: Time of First Occurrence of Cmax of Decitabine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: Tmax: Time of First Occurrence of Cmax of Cedazuridine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: Tmax: Time of First Occurrence of Cmax of Cedazuridine-epimer in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: T1/2: Terminal Half Life of Decitabine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: T1/2: Terminal Half Life of Cedazuridine in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
measure: Food Effect Substudy: T1/2: Terminal Half Life of Cedazuridine-epimer in the Fasted and Fed State
timeFrame: Pre-dose and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post dose on Days 2 (fasted state) and 4 (fed state) in Cycle 1 (up to 28 days)
Secondary outcomes:
measure: Food Effect Substudy: Percentage of Participants with Treatment Emergent Adverse Events (TEAEs), by Severity
timeFrame: From first dose of study drug up to 30 days after the last dose (Up to approximately 65 days)
measure: Food Effect Substudy: Percentage of Participants with Clinically Significant Abnormal Laboratory Values
timeFrame: From Day 1 up to Day 28 in Cycle 1 (Up to 28 days)
Other outcomes:
Locations:
city: Fountain Valley
country: United States
facility: Compassionate Care Research Group
state: California
city: Plantation
country: United States
facility: Boca Raton Clinical Research
state: Florida
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Baltimore
country: United States
facility: The Sidney Kimmel Comprehensive Cancer Center at John Hopkins
state: Maryland
city: Grand Rapids
country: United States
facility: Cancer and Hematology Centers for Western Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo - Rochester
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack Medical Center - 06 FE Study
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Rosewell Park Cancer Institute
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute - 06 FE Study
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center Research - 06 FE Study
state: Ohio
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Charleston
country: United States
facility: Charleston Hematology Oncology Associates
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt - Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor Scott White University Medical Center
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: May Cancer Center
state: Texas
city: Kennewick
country: United States
facility: Kadlec Clinic Hematology and Oncology
state: Washington
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center
state: Washington
city: Yerevan
country: Armenia
facility: Erebuni Medical Center
city: Yerevan
country: Armenia
facility: Hematology Center After Prof. R. Yeolyan (Adult Blood Disorders)
city: Yerevan
country: Armenia
facility: Hematology Center After Prof. R. Yeolyan (Clinic of Adults Oncology)
city: Yerevan
country: Armenia
facility: National Center of Oncology Named After V.A. Fanarjyan
city: Vienna
country: Austria
facility: Wiener Gesundheitsverbund - Klinik Hietzing 06 FE Study
city: Vienna
country: Austria
facility: Wiener Gesundheitsverbund - Klinik Hietzing 06 Study
city: Plovdiv
country: Bulgaria
facility: Complex Oncology Center - Plovdiv - Base II
city: Sofia
country: Bulgaria
facility: Specialized Hospital for Active Treatment of Hematological Disease EAD
city: Edmonton
country: Canada
facility: University of Alberta Hospital
city: Nova Scotia
country: Canada
facility: QEII Health Sciences Centre
city: Ottawa
country: Canada
facility: The Ottawa Hosptial
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
city: Mulhouse
country: France
facility: Hôpital Emile Muller
state: Grand Est
city: Braunschweig
country: Germany
facility: Städtisches Klinikum Braunschweig
state: Niedersachsen
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein - Campus Lübeck
state: Schleswig-Holstein
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont, Belgyogyszati Klinika, B epulet, Hematologia
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
city: Wroclaw
country: Poland
facility: Centrum Badań Klinicznych Piotr Napora Lekarze Sp. p.
state: Dolnoslaskie
city: Bucharest
country: Romania
facility: Institutul Oncologic Bucuresti - Prof. Dr. Alexandru Trestioreanu
city: Cluj-Napoca
country: Romania
facility: Institutul Oncologic Prof. Dr. Ion Chiricuta
city: Bratislava
country: Slovakia
facility: Summit Clinical Research s.r.o
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova
city: Madrid
country: Spain
facility: Clínica Universidad de Navarra - Madrid
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Murcia
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
Study officials:
References: