| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Lower Risk (IPSS Low or Intermediate-1) Myelodysplastic Syndromes (MDS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Myelodysplastic Syndromes (MDS) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028536 |
| E.1.2 | Term | Myelodysplastic syndromes |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028533 |
| E.1.2 | Term | Myelodysplastic syndrome |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
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.
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.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria
Subjects must fulfill all of the following inclusion criteria.
1) Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written 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 <0.5×109/L in at least 2 blood counts prior to randomization.
d) Platelet counts of <50×109/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]*; CTFG 2020) 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.
|
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following exclusion criteria will be excluded from the study:
1. 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.
2. Prior treatment with azacitidine, decitabine or gaudecitabine.
3. 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.
4. Diagnosis of chronic myelomonocytic leukemia (CMML).
5. Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
6. 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.
7. 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.
8. 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.
9. Known active infection with human immunodeficiency virus or hepatitis viruses. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoints
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.
Phase 2
·Hematologic response as defined in the Efficacy Analysis section. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The DSRC will comprise the principal investigators (or nominated deputies), medical monitor, study director, PD director, PK director, and other team members as appropriate. Safety, PD, and other clinical data from this study will be assessed for each dose cohort by the DSRC after at least Cycle 1 of Phase 1 Stage A and after at least Cycle 1 of Phase 1 Stage B. The DSRC will recommend the dose(s)/schedule(s) to be taken forward to Phase 2. In Phase 2, the DSRC will review emerging safety data in the first 6 subjects enrolled into the ASTX727 SD Daily×3 dose regimen and expand this safety evaluation to 12 subjects if necessary. The DSRC will also review the data when at least 20 subjects in each regimen have been followed up for at least 1 cycle of safety data, or earlier if warranted. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints
- RBC transfusion independence, as defined in Efficacy Analysis section;
- Platelet transfusion independence, as defined in Efficacy Analysis section;
- 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;
- %LINE-1 methylation change from baseline;
- 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;
- Safety as determined by incidence of AEs, AEs of Grade ≥3, and serious adverse events (SAEs) (Primary endpoint for Phase 1);
- Hematologic response (Secondary endpoint for Phase 1 only);
- 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;
- 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%;
- 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;
- Overall survival (OS), defined as the number of days from the date of randomization to the date of death from any cause. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the course of the study, emerging safety data will be considered by the DSRC in evaluating the potential risks and benefits of ASTX727 LD. In Phase 1, cohorts in which ≥33% of subjects are observed to have DLTs will stop further enrollment and not be taken forward to Phase 2. During the conduct of the study, cohorts may be discontinued from treatment with study drug for safety (including, but not limited to DLTs) after review by the DSRC. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| phase 1b (safety profile) |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United Kingdom |
| Belgium |
| Germany |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| There is no fixed duration for individual participation in this study. Treatment with ASTX727 will be administered orally for each 28-day cycle until disease progression, death, or unacceptable treatment-related toxicity; subjects elect to discontinue study treatment or withdraw consent to continue study participation; if the investigator determines it is in the subject’s best interest; or until the study is closed by the sponsor. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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