A Phase 1 Trial of ASTX030 in Patients With Myelodysplastic Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to identify the doses of the oral azacitidine formulations and cedazuridine (CED) tablets which achieve a total AUC for AZA comparable to that for AZA injection at 75 mg/m2

Official Title
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A Phase 1, Multi-center, Open-label, Uncontrolled, Dose-escalation Study to Evaluate the Pharmacokinetics of ASTX030 in Patients With Myelodysplastic Syndrome (MDS)

Conditions
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Myelodysplastic Syndrome (MDS)

Intervention / Treatment
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* Drug: ASTX030


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 20 years or older Patients with a diagnosis of MDS (refractory anemia [RA], refractory anemia with ringed sideroblasts [RARS], refractory anemia with excess blasts [RAEB], refractory anemia with excess blasts in transformation [RAEB-T], or chronic myelomonocytic leukemia [CMML]) according to the French-American-British (FAB) classification Low-risk patients who fall under the risk category of low or intermediate-1 (Int-1) based on the International Prognostic Scoring System (IPSS) can be enrolled only if they are unlikely to respond to any other treatment or if they are currently being treated with azacytidine (AZA) injection Patients with an ECOG PS score of 0 or 1 or with an ECOG PS score of 2 due to primary disease-associated conditions Patients with adequate organ function as indicated below Hepatic function: All of the following criteria must be satisfied. Total bilirubin ≤ 2.0 × upper limit of normal (ULN) Aspartate aminotransferase (AST) ≤ 2.5 × ULN Alanine aminotransferase (ALT) ≤ 2.5 × ULN Renal function: Either of the following criteria must be satisfied. Serum creatinine ≤ 1.5 × ULN Creatinine clearance or glomerular filtration rate ≥ 50 mL/min Respiratory function: percutaneous arterial oxygen saturation (SpO2) ≥ 90% Patients who are expected to survive for at least 3 months Patients who give written consent to participate in the trial using the informed consent form approved by the institutional review board Exclusion Criteria: Patients who are unlikely to respond to AZA Patients who have received chemotherapy, hormone therapy, antibody therapy, radiotherapy, or other exploratory anti-cancer treatments for the primary disease within 3 weeks prior to the first administration of the investigational medicinal product (IMP) Patients who have used any other IMP or any privately imported medicine within 4 weeks prior to the first administration of IMP Patients with heart disease of Class 3 or 4 according to the New York Heart Association classification Patients with uncontrolled systemic disease or active infection Patients with uncontrolled gastric or duodenal ulcer Patients with prior or current interstitial lung disease Patients with a history of surgical gastrectomy Patients with life-threatening conditions/symptoms, multiple organ failure, or other factors (including laboratory abnormalities) that, in the opinion of the investigator, are likely to affect their safety or the absorption and metabolism of AZA and cedazuridine (CED), or influence the trial evaluation Patients with other malignancies (except appropriately treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ; prostate or breast cancer stabilized by endocrine therapies; and malignancies that have not relapsed for at least 1 year since the last successful treatment) Patients who are positive for HIV antibody, HBV-DNA, or HCV antibody Patients with any ≥ Grade 2 AE (except alopecia) associated with prior treatment of the primary disease. However, the parameters defined in inclusion criterion above are excluded. Patients who have undergone a highly invasive and extensive surgical procedure within 4 weeks prior to the first administration of IMP Patients who previously underwent or plan on undergoing hematopoietic stem cell transplantation Patients with a history of hypersensitivity to the active ingredient or any excipient of IMP Patients who are, in the opinion of the investigator, at high risk for being unable to comply with the trial protocol because of mental disorders or other medical conditions (alcohol/substance abuse or addiction) Pregnant or nursing female patients, or female patients with a positive pregnancy test at screening. Nursing patients cannot participate in the trial even if they discontinue breastfeeding. Female patients must undergo a pregnancy test to confirm that they are not pregnant at screening. However, a pregnancy test is not necessary for female patients without childbearing potential (ie, patients with a history of bilateral oophorectomy or hysterectomy or who have been postmenopausal for at least 12 months except for cases where menopause could be due to the effect of antineoplastic treatment). Sexually active males (except those with a history of bilateral orchiectomy) or females of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 3 months (males) and 6 months (females) after the last dose of IMP. If birth control is employed, 2 of the following precautions must be used: vasectomy, tubal ligation, intrauterine device, oral contraceptive, and condom (all methods approved or certified in Japan) Patients who, in the opinion of the investigator, are otherwise ineligible to participate in the trial

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azacitidine + Cedazuridine<br>Drug: Azacitidine Tablets or capsules for oral administration and powder for reconstitution to aqueous suspension for subcutaneous administration Drug: Cedazuridine Tablets for oral administration | Drug: ASTX030<br>* In Cycle 1 (28 days per cycle), single dose oral azacitidine formulations will be administered on day -3, followed by subcutaneous (SC) azacitidine on day 1, oral azacitidine formulations and cedazuridine tablets on day 2-7; in Cycle 2 and onward, oral azacitidine formulations and cedazuridine tablets will be administered on day 1-7<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • AUC ratio of AZA after administration of oral azacitidine formultions in combination with CED tablets compared with subcutaneous (SC) administration of AZA injection |  | Up to 1 month |