ASTX727
Research type
Research Study
Full title
A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727(Cedazuridine and Decitabine Fixed-Dose Combination) versus IV Decitabine in Subjects with Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), and Acute Myeloid Leukemia (AML)
IRAS ID
275819
Contact name
Daniel Wiseman
Contact email
Sponsor organisation
Astex Pharmaceuticals, Inc.
Eudract number
2018-003395-12
Clinicaltrials.gov Identifier
Duration of Study in the UK
2 years, 0 months, 16 days
Research summary
Research Summary
This clinical trial is designed to compare Decitabine blood level after treatment with ASTX727 tablet to IV Decitabine in patients with MDS, CMML and AML.
Adult participants with MDS, CMML, or AML who are candidates to receive IV decitabine will be randomized in a 1:1 ratio to receive the ASTX727 FDC tablet Daily×5 in Cycle 1, followed by IV decitabine 20 mg/m2 Daily×5 in Cycle 2, or the converse order. Adequate PK assessments from Cycles 1 and 2 will be required for participants to be evaluable for analysis of the primary endpoint. After completion of the first 2 treatment cycles, particpants will continue to receive treatment with ASTX727 in 28-day cycles until disease progression, unacceptable toxicity, or the participant decides to discontinue treatment or withdraw from the study.
Approximately 200 participants (at least 118 evaluable for the primary PK endpoint analysis) will be enrolled in this study at approximately 70 study centres in North America and Europe.
The expected study duration is approximately 24 months (18 months of enrollment and at least 6 months of treatment and follow up). The primary analysis will be conducted after at least 118 evaluable particpants complete the first 2 cycles of treatment with sufficient PK data. The final analysis will be conducted after at least 6 months of follow up on all participants.
Summary of Results
In the ASTX727-02 study, patients enrolled (referred to as “subjects”) had a blood cancer called myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia. The overall goals of the study were to collect data on the safety and treatment benefits of ASTX727 in adult subjects with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia using pharmacokinetics (called “drug processing”). The main result of the study was measured by comparing how much drug is in the body after the dose is given between ASTX727 orally and decitabine given intravenously (given through the vein). The ASTX727 02 D clinical study report describes the data on the safety and treatment benefits of ASTX727 in adult subjects with acute myeloid leukemia.
Adult subjects with acute myeloid leukemia in Europe and Canada who received decitabine (given through the vein) were picked randomly (by chance) in a 1:1 ratio to receive the ASTX727 fixed-dose combination tablet daily for 5 days in Cycle 1 followed by decitabine (through the vein) 20 mg/m2 for 5 days (standard dose) in Cycle 2 (Sequence A), or the opposite order (Sequence B). ASTX727 was administered Cycle 3 onward.
On 07 January 2020, the first subject signed an informed consent to be able to participate in the acute myeloid leukemia portion of this study. The last subject randomly assigned for this study was on 22 April 2021.
Eighty-nine subjects were randomly assigned to study treatment and 87 subjects received study treatment. Of the 87 subjects, 80 subjects (90%) received ASTX727, 79 subjects (89%) received decitabine (given through the vein) and 72 subjects (81%) received ASTX727 and decitabine (given through the vein).
Subjects’ average age was 76.7 years, and ages ranged from 61 to 92 years. Fifty-three subjects (61%) were male. Subjects received an average of 9.1 cycles of treatment.
In this study, blood levels of decitabine when given ASTX727 orally were 99.64% similar to that of decitabine given through the vein. Treatment was successful in eliminating the cancer in 19 subjects.
Of the 87 subjects, 67 subjects died as of the study completion. The median time that subjects survived from date of study entry to date of death was 8.9 months. 78 subjects had the cancer becoming more serious, return to a previous/undesirable condition, or died as of the study completion. The median time that subjects survived from date of study entry to date of the cancer becoming more serious or death (from any cause) was 6.1 months. The median time that subjects with the cancer were studied after study treatment was 23.6 months.
Eighty six subjects (99%) had at least 1 adverse event (AE). The AEs were severe in 79 subjects (91%), serious in 70 subjects (81%), life-threatening in 45 subjects (52%), or fatal in 25 subjects (29%). The AEs in at least 20% subjects were low number of blood cells that help blood to clot (thrombocytopenia) (50 subjects, 58%), low number of blood cells that carry oxygen to organs (anemia) (45 subjects, 52%), low number of a type of blood cells for fighting infections (neutropenia) (28 subjects, 32%), fever with a low number of a type of blood cells for fighting infections (febrile neutropenia) (26 subjects, 30%), asthenia (weakness) and lung infection (pneumonia) (each 22 subjects, 25%), fever (19 subjects, 22%), and diarrhea (18 subjects, 21%).
The serious AEs considered in at least 20% subjects were fever with a low number of a type of blood cells for fighting infections (febrile neutropenia) (22 subjects, 25%) and lung infection (pneumonia) (18 subjects, 21%).
Fifty-seven subjects (71%) had at least 1 AE reported by a study doctor as related to ASTX727. These AEs in at least 10% subjects were low number of blood cells that help blood to clot (thrombocytopenia) (26 subjects, 33%), low number of a type of blood cells for fighting infections (neutropenia) (20 subjects, 25%), low number of blood cells that carry oxygen to organs (anemia) (17 subjects, 21%), fever with a low number of a type of blood cells for fighting infections (febrile neutropenia), and nausea (each 9 subjects, 11%).
Forty-five subjects (56%) had at least 1 severe related AE reported by a study doctor as related to ASTX727. These serious AEs reported in more than 10% subjects were low number of blood cells that help blood to clot (thrombocytopenia) (23 subjects, 29%), low number of a type of blood cells for fighting infections (neutropenia) (19 subjects, 24%), low number of blood cells that carry oxygen to organs (anemia) (14 subjects, 18%), and fever with a low number of a type of blood cells for fighting infections (febrile neutropenia) (9 subjects, 11%).
Fifteen subjects (19%) had ASTX727 discontinued because of at least 1 AEs. These AEs reported in at least 2 subjects were lung infection (pneumonia) (4 subjects, 5%) and asthenia (weakness) (2 subjects, 3%).
Forty-three subjects (54%) had ASTX727 dose interrupted or ASTX727 dose reduced because of an AE. These AEs reported in at least 5 subjects were low number of a type of blood cells for fighting infections (neutropenia) (14 subjects, 18%), lung infection (pneumonia) (6 subjects, 8%), and fever with a low number of a type of blood cells for fighting infections (febrile neutropenia) (5 subjects, 6%).
No medically important ASTX727 or decitabine (given through the vein)-related trend on heart rate or general physical health (vital sign) was seen.
No medically important or ASTX727-related trends were seen in laboratory results other than those connected with low numbers of various types of blood cells, often seen in patients with blood cancers.REC name
HSC REC B
REC reference
20/NI/0002
Date of REC Opinion
27 Feb 2020
REC opinion
Further Information Favourable Opinion