A Randomized, Open-Label, Phase 1-2 Study of ASTX727 Low Dose (ASTX727 LD) Extended Schedule in Subjects with Lower Risk (IPSS Low or Intermediate-1) Myelodysplastic Syndromes (MDS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Taiho Oncology Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

11 Nov 2021 → 13 Jan 2026

Decision date (initial)

2024-09-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-516296-32-00

EudraCT number

2019-003281-40

ClinicalTrials.gov

NCT03502668

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Dose response, Safety, Pharmacodynamic, Therapy, Efficacy, Pharmacokinetic

Phase 1:
- to assess the safety profile of doses and schedules of ASTX727.
- to select the ASTX727 dose(s) and schedule(s) to study in Phase 2.
Phase 2:
- to assess the clinical efficacy of ASTX727 dose(s) and schedule(s) studied.

Secondary objectives 2

1. Phase 1: - to assess the pharmacodynamic (PD) activity of doses and schedules of ASTX727. - to characterize the pharmacokinetics (PK) of decitabine, cedazuridine, and its metabolite cedazuridine-epimer. - to assess hematologic response.
2. Phase 2: - to assess the safety of the ASTX727 dose(s) and schedule(s) studied. - to assess PD activity and PK of decitabine at the ASTX727 dose(s) and schedule(s) studied.

Conditions and MedDRA coding

Myelodysplastic Syndromes (MDS)

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Able to understand and comply with the study procedures, understand the risks involved in the study, and provide legally effective informed consent before the first study-specific procedure.
2. Men or women ≥18 years with IPSS low risk or Int-1 MDS (all subjects). Subjects must have had at least 1 of the following disease-related criteria during the 8 weeks before randomization: a) RBC transfusion dependence, defined as 2 or more units of RBC transfusions.* b) Hb of ≤9.0 g/dL in at least 2 blood counts prior to randomization or in 1 blood count if RBC transfusion was received. c) ANC of <0.5×10e9/L in at least 2 blood counts prior to randomization. d) Platelet counts of <50×10^9/L in at least 2 blood counts prior to randomization. *RBC transfusions administered for Hb levels ≤9.0 g/dL are counted
3. ECOG performance status of 0 to 2.
4. Adequate organ function defined as follows: a) Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤5 × ULN. b) Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance or glomerular filtration rate ≥50 mL/min.
5. Women of childbearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential and their partners must use at least 1 highly effective birth control method (with a failure rate of <1% per year; preferably with low user dependency), from the start of participation in the study and for 6 months after the last dose of study treatment. Contraceptive measures that are considered highly effective with low user dependency include implantable progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, or azoospermic partner (vasectomized or due to a medical cause).
6. Male subjects with female partners of childbearing potential must agree to use a male condom and advise their partners to practice 1 highly effective contraceptive measure of birth control (user dependent or with low user dependency) and must agree not to father a child while receiving study treatment for at least 3 months after completing treatment.

Exclusion criteria 9

1. Known active infection with human immunodeficiency virus or hepatitis viruses.
2. Treatment with any investigational drug or therapy within 2 weeks before study treatment, or 5 half-lives, whichever is longer, before the first dose of study treatment, or ongoing clinically significant AEs from previous treatment.
3. Prior treatment with azacitidine, decitabine or gaudecitabine.
4. Treatments for MDS, including erythropoietins, colony-stimulating factors (CSFs), thrombopoietins, chemotherapy, and immunosuppression including calcineurin inhibitors, glucocorticoids, etc., must be concluded 1 month prior to study treatment.
5. Diagnosis of chronic myelomonocytic leukemia (CMML).
6. Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
7. Known significant mental illness or other condition, such as active alcohol or other substance abuse or addiction, that in the opinion of the investigator predisposes the subject to high risk of noncompliance with the protocol.
8. Life-threatening illness, medical condition or organ system dysfunction, or other reasons including laboratory abnormalities, which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ASTX727 LD, or compromise the integrity of the study outcomes.
9. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, prostate cancer or breast cancer under control with hormone therapy, or other cancer from which the subject has been disease free for at least 1 year.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase 1 - Safety as determined by incidence of drug-related Grade ≥3 AEs or dose-limiting toxicities (DLTs) (if any) for each cohort dose/schedule.
2. Phase 2 - Hematologic response as defined in the Efficacy Analysis section (Section 11.6.1 of study protocol).

Secondary endpoints 11

1. %LINE-1 methylation change from baseline
2. PK parameters, including area under the curve (AUC), maximum concentration (Cmax), Tmax, and t1/2 of decitabine, cedazuridine, and cedazuridine-epimer in the first cycle of treatment
3. Safety as determined by incidence of AEs, AEs of Grade ≥3, and serious adverse events (SAEs) (Primary endpoint for Phase 1)
4. Hematologic response (Secondary endpoint for Phase 1 only)
5. HbF induction compared with baseline to >1% from ≤1%, or increase of 50% in subjects with ≥1% at baseline in at least 2 successive measurements
6. RBC transfusion independence, as defined in Section 11.6.2 of study protocol.
7. Platelet transfusion independence, as defined in Section 11.6.3 of study protocol.
8. Overall response rate (ORR): complete response (CR), marrow complete response (mCR), and hematologic improvement (HI) based on International Working Group IIWG) 2006 MDS response criteria, as defined in Section 11.6.4 of study protocol.
9. Time to bone marrow blasts >5%, defined as the number of days from the date of randomization to the date when bone marrow blasts are >5% and increased by ≥50%
10. Leukemia-free survival, defined as the number of days from the date of randomization to the date when bone marrow or peripheral blood blasts reach ≥20%, or death from any cause
11. Overall survival (OS), defined as the number of days from the date of randomization to the date of death from any cause

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Taiho Oncology Inc.

Sponsor organisation

Taiho Oncology Inc.

Address

101 Carnegie Center Suite 101

City

Princeton

Postcode

08540-6231

Country

United States

Scientific contact point

Organisation

Taiho Oncology Inc.

Contact name

Medical Monitor

Public contact point

Organisation

Taiho Oncology Inc.

Contact name

Medical Monitor

Third parties 11

Locations

3 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications