A Study of ASTX030 (Cedazuridine in Combination With Azacitidine) in MDS, CMML, or AML

Study Overview
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Brief Summary
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Study ASTX030-01 is designed to move efficiently from Phase 1 to Phase 3. Phase 1 consists of an open-label Dose Escalation Stage (Stage A) using multiple cohorts at escalating dose levels of oral cedazuridine and azacitidine (only one study drug will be escalated at a time) followed by a Dose Expansion Stage (Stage B) of ASTX030. Phase 2 is a randomized open-label crossover study to compare oral ASTX030 to subcutaneous (SC) azacitidine. Phase 3 is a randomized open-label crossover study comparing the final oral ASTX030 dose to SC azacitidine. The duration of the study is expected to be approximately 48 months.

Official Title
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A Multi-phase, Dose-Escalation Followed by an Open-label, Randomized, Crossover Study of Oral ASTX030 (Cedazuridine and Azacitidine Given in Combination) Versus Subcutaneous Azacitidine in Subjects With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)

Conditions
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Myelodysplastic Syndromes, Chronic Myelocytic Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndrome/Neoplasm

Intervention / Treatment
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* Drug: Azacitidine
* Drug: ASTX030 (cedazuridine + azacitidine)
* Drug: Cedazuridine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed MDS, CMML, MDS/MPN, or AML who are candidates to receive and benefit from single agent azacitidine as follows and as applicable according to local country approvals and/or local institution standard practice: French-American-British myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), or MDS with intermediate-2 or high risk MDS according to the International Prognostic Scoring System (IPSS). MDS/MPN patients including CMML according to the World Health Organization (WHO) 2016 classification are also eligible if they are candidates to receive single agent azacitidine per local institution standards; or Previously untreated AML with 20% to 30% blasts present in bone marrow and multi-lineage dysplasia (Phase 2 and 3 only); or Previously untreated AML with >30% blasts present in bone marrow, who are not eligible for stem cell transplant and unfit for intensive chemotherapy induction (Phase 2 and 3 only). Participants with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Participants with adequate organ function defined as: Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) ≤2.5 × ULN. Renal: Calculated creatinine clearance >50 mL/min/1.73 m^2 by Cockcroft-Gault formula or other medically acceptable formulas. For participants with prior allogeneic stem cell transplant, no evidence of graft-versus-host disease (GVHD) and must be ≥2 weeks off systemic immunosuppressive therapy before start of study treatment. Participants with no major surgery within 2 weeks before first study treatment. Participants with no cytotoxic chemotherapy within 4 weeks before first study treatment. Able to swallow the number of tablets/capsules required for the treatment assignment within a 10-minute period and tolerate 4 hours of fasting. Participants with projected life expectancy of at least 12 weeks. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Exclusion Criteria: Active uncontrolled gastric or duodenal ulcer. Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled bacterial, viral, or fungal infections. Life-threatening illness (e.g., uncontrolled bleeding and patients at risk for or are experiencing leukostasis [AML]), uncontrolled medical condition or organ system dysfunction, or other reasons, which, in the investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of oral cedazuridine + azacitidine or compromise the integrity of the study outcomes. 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 participant has been disease free for at least 2 years. Participants with MDS/MPN who have clinical extramedullary disease including clinically palpable hepatomegaly or splenomegaly. Previous treatment with more than 1 cycles of decitabine, azacitidine, or guadecitabine (Phases 2 and 3 only). Treated with any investigational drug or therapy within 2 weeks, or 5 half lives, whichever is longer, before the protocol-defined first dose of study treatment, or ongoing clinically significant adverse events from previous treatment with investigational drug or therapy. Known or suspected hypersensitivity to cedazuridine or azacitidine, or any of their excipients.

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1, Stage A (Dose Escalation)<br>In Cycle 1 (28 days per cycle), single dose oral azacitidine will be administered, followed by subcutaneous (SC) azacitidine, ASTX030 and oral cedazuridine on a specific dosing schedule; in Cycle 2, oral ASTX030 (cedazuridine + azacitidine) will be administered | Drug: Azacitidine<br>* Tablets/Capsules for oral administration and powder for reconstitution to aqueous suspension for subcutaneous administration<br>* Other names: Vidaza;Drug: ASTX030 (cedazuridine + azacitidine)<br>* Tablets/Capsules for oral administration<br>Drug: Cedazuridine<br>* Tablets for oral administration<br>|
| Experimental: Phase 1, Stage B (Dose Expansion)<br>Oral cedazuridine + azacitidine will be administered separately at the recommended dose for expansion (RDE) | Drug: ASTX030 (cedazuridine + azacitidine)<br>* Tablets/Capsules for oral administration<br>|
| Experimental: Phase 2, Sequence A<br>Oral ASTX030 (cedazuridine + azacitidine) will be administered in Cycle 1, followed by SC azacitidine in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3) | Drug: Azacitidine<br>* Tablets/Capsules for oral administration and powder for reconstitution to aqueous suspension for subcutaneous administration<br>* Other names: Vidaza;Drug: ASTX030 (cedazuridine + azacitidine)<br>* Tablets/Capsules for oral administration<br>|
| Experimental: Phase 2, Sequence B<br>SC azacitidine will be administered in Cycle 1, followed by oral cedazuridine + azacitidine tablets/capsules in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3) | Drug: Azacitidine<br>* Tablets/Capsules for oral administration and powder for reconstitution to aqueous suspension for subcutaneous administration<br>* Other names: Vidaza;Drug: ASTX030 (cedazuridine + azacitidine)<br>* Tablets/Capsules for oral administration<br>|
| Experimental: Phase 3, Sequence A<br>Participants will receive ASTX030 in Cycle 1, followed by SC azacitidine in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3) | Drug: Azacitidine<br>* Tablets/Capsules for oral administration and powder for reconstitution to aqueous suspension for subcutaneous administration<br>* Other names: Vidaza;Drug: ASTX030 (cedazuridine + azacitidine)<br>* Tablets/Capsules for oral administration<br>|
| Experimental: Phase 3, Sequence B<br>Participants will receive SC azacitidine in Cycle 1 followed by ASTX030 in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3) | Drug: Azacitidine<br>* Tablets/Capsules for oral administration and powder for reconstitution to aqueous suspension for subcutaneous administration<br>* Other names: Vidaza;Drug: ASTX030 (cedazuridine + azacitidine)<br>* Tablets/Capsules for oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total cycle area under the curve (AUC)0-24 exposures | Ratio of azacitidine total cycle AUC0-24 exposures after oral ASTX030 over SC azacitidine | Up to 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Number of TEAEs | Number of participants with treatment-emergent adverse events (TEAEs) | Up to 36 months | 
| Change in DNA methylation | Percent long interspersed nuclear elements 1 (LINE-1) methylation change (demethylation) from baseline in Cycle 1 (Phase 1) and compared between SC azacitidine and ASTX030 in Cycles 1 and 2 (Phase 2 and 3) | Baseline in Phase 1 to the end of Cycle 2 in Phase 3 (28 days per cycle) | 
| Best clinical response rate for participants with MDS, CMML, or MDS/myeloproliferative neoplasms (MPN) | The number of participants with a complete response (CR), marrow complete response (mCR), partial response (PR), and hematologic improvement (HI) will be evaluated using International Working Group (IWG) 2006 MDS response criteria | Up to 36 months | 
| Best clinical response rate for participants with AML | The number of participants with CR, CRi (CR with incomplete hematologic recovery), CRh (complete response with partial hematological recovery), and PR will be evaluated using European LeukemiaNet (ELN) 2017 AML response criteria and Kantarjian et al. (2017) | Up to 36 months | 
| AML-free survival for participants with MDS, CMML, or MDS/MPN | Number of days from the date of randomization (date of first treatment in Phase 1) to either the date of MDS, CMML, or MDS/MPN progression to AML or the date of death from any cause | Up to 36 months | 
| Duration of response | Number of days from the date that criteria are met for response until the first date that recurrent or progressive disease is documented by the investigating physician | Up to 36 months | 
| Overall survival | Number of days from the date the participant was randomized (date of first treatment in Phase 1) to the date of death, regardless of cause | Up to 36 months | 
| Time to response | Number of days from the start of treatment until the participant's first day of best response | Up to 36 months | 
| Red blood cell (RBC) transfusion independence (TI) | Number of participants with RBC TI, defined as no RBC transfusion for 56 consecutive days while maintaining hemoglobin ≥8 g/dL | Up to 36 months | 
| Platelet transfusion independence (TI) | Number of participants with platelet TI, defined as no platelet transfusion for 56 consecutive days while maintaining platelets ≥20×10^9/L | Up to 36 months | 
| Pharmacokinetic parameter AUC | Area under the curve (AUC) | Up to Day 8 in Cycle 2 (28 days per cycle) | 
| Pharmacokinetic parameter Cmax | Maximum plasma concentration (Cmax) | Up to Day 8 in Cycle 2 (28 days per cycle) | 
| Pharmacokinetic parameter Tmax | Time to reach maximum plasma concentration (Tmax) | Up to Day 8 in Cycle 2 (28 days per cycle) |