RecruitingPhase 2ACTRN12621001713886

A dose determining trial to assess the recommended dose of ES-3000 and ASTX727 for patients with Myelodysplasia

MDS05/D1: (MYDAS-T) Assessing the safety of ES-3000 and ASTX727 in patients with myelodysplasia

Sponsor

Australasian Leukaemia and Lymphoma Group

Enrollment

32 participants

Start Date

Jun 30, 2023

Study Type

Interventional

Conditions

Myelodysplasia

Summary

High risk MDS is a challenging condition with limited treatment options. Patients often depend on blood transfusions and unfortunately chemotherapy is rarely successful as a treatment option. The main type of therapy used in MDS are hypomethylating agents (HMAs) such as Azacitidine (AZA) and Decitabine (DEC). Traditionally, combination therapy has not proven to be effective in MDS given the increased toxicity of drugs used in combination with AZA, even where the overall responses may have been promising. Therefore, this trial aims to test a relatively non-cytotoxic drug called ES-3000, in combination with a HMA named ASTX727. Who is it for? You may be eligible to join this study if you are aged 16 years or above, and have a diagnosis of MDS or acute myeloid leukaemia (AML) with <30% blasts. Trial details: All participants will receive treatment in 28-day cycles. At first, each participant will receive a single cycle of ES-3000 alone, in order to take blood samples at various timepoints throughout the day to establish how the drug is metabolised by the body. ES-3000 is an oral tablet administered three times per day on days 1-14 of the cycle. Each subsequent participant recruited to the trial will receive a higher dose of ES-3000, until the dose is no longer tolerated. From the second cycle onwards, participants will receive the same dose of ES-3000 in combination with a previously established safe dose of ASTX727 once per day on days 1-5 of each cycle. This will continue until the participant experiences either unacceptable toxicity, or disease progression. Participants will be monitored for adverse effects for the duration of treatment, as well as every 3 months for assessment of their response to treatment through blood samples and bone marrow biopsies, and assessment of quality of life through completion of a questionnaire. It is hoped that this study may show that ES-3000 administered in combination with Inqovi is safe and effective for the treatment of MDS and AML. This study may help to inform the dosing of ES-3000 required for patients with these conditions in future.

Eligibility

Sex: Both males and femalesMin Age: 16 Yearss

Inclusion Criteria7

Eligibility criteria are noted in the MDS05 Master Protocol as below:
Provision of written informed consent
Provision of written informed consent to the ALLG NBCR
Age 18+ (Age 16-17 permitted if consent for minor PICF approved by the authorising HREC)
A diagnosis of MDS or AML with < 30% blasts
The following point must also be met to be eligible for participation in this domain:
All previously treatment naïve myelodysplasia patients with IPSS score >= 1.5 and be eligible for standard AZA treatment in Australia. AML with blasts <30% (in peripheral blood and bone marrow) will also be eligible for this study.

Exclusion Criteria19

History of other malignancy requiring active systemic treatment, or which is likely to result in an expected survival time of < 12 months.
Viral infection with known HIV or viral hepatitis type B or C not adequately controlled by antiviral medication.
Prior bone marrow or stem cell transplantation for a diagnosis of Myelodysplasia or acute myeloid leukaemia. If stem cell transplantation has been undertaken for other reasons- refer to individual domain and discuss with study team.
In addition, the following patients will be excluded:
Patients with QTcF> 480msecs (females) and QTcF> 450msecs (males) will be excluded from this study
Subjects who has received allogeneic HSCT or solid organ transplantation.
Subject has a history of an active malignancy within the past 2 years prior to study entry, with the exception of:
a. Adequately treated in situ carcinoma of the cervix uteri
b. Adequately treated basal cell carcinoma or localized squamous cell carcinoma
of the skin
c. Asymptomatic prostate cancer without known metastatic disease and with no
requirement for therapy
Subject has a known positive test for human immunodeficiency virus (HIV). Note: HIV testing is not required at Screening.
Subject has chronic active hepatitis B (HBV) or hepatitis C (HCV) requiring treatment.
Subject exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to ongoing systemic infection (viral, bacterial, or fungal).
Subject has a malabsorption syndrome or other condition that precludes an enteral route of administration.
Subject has history of a significant cardiovascular, endocrine, hepatic, immunologic metabolic, neurologic, psychiatric, pulmonary, renal disease, or any other condition that in the opinion of the investigator would adversely affect his/her participation in this study or interpretation of study results. Note: For subjects who have required an intervention for any above diseases within the past 6 months requires a discussion between the investigator and study team.
Subject is concurrently participating in another therapeutic clinical trial.
Subject is pregnant or breastfeeding.

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Interventions

There are 2 drugs used in this treatment domain of the platform trial; ES-3000 and ASTX727. This domain is separated into 2 parts; Part 1 is dose finding and part 2 is expanding recruitment using the

There are 2 drugs used in this treatment domain of the platform trial; ES-3000 and ASTX727. This domain is separated into 2 parts; Part 1 is dose finding and part 2 is expanding recruitment using the recommended phase 2 dose (RP2D). The first cycle of the protocol treatment will include only ES-3000 (without ASTX727) to establish safety and and recommended part 2 dose of the combination. Cycle 2 onwards will be a combination of ES-3000 and standard dose of ASTX727, to identify the maximum tolerated dose (MTD) and recommended phase 2 dose of ES-3000 in combination with ASTX727. The standard dose of AST727 is 1 tablet (35 mg decitabine and 100 mg cedazuridine). In the part 1 dose finding run in study, ES-3000 (tablet) will be administered orally 3 times per day approximately every 8 hours on Days 1 to 14 of each 28-day cycle with the starting dose of 60mg TiD. Doses will increase or decrease by 20mg each dose level, depending on the findings of the safety review. Safety review by assessing adverse events will be assessed at the end of the treatment cycle. Depending on the results of the safety review, the dose may increase or decrease. From cycle 2 and onwards, subjects will receive oral ASTX727 (tablet) on days 1 to 5 of each cycle. Patients will continue treatment until reaching a defined event; unacceptable toxicity, disease progression. Drug accountability will be performed by the administering institutions to assess compliance.