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

Acute Myeloid Leukemia Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04256317
• Other study ID #: ASTX030-01
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: May 21, 2020
• Est. completion date: April 2026

Study information

• Verified date: May 2024
• Source: Astex Pharmaceuticals, Inc.
• Contact: General Inquiries
• Phone: 925-560-0100
• Email: clinicaltrials[@]astx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 317
• Est. completion date: April 2026
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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:

1. 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

2. Previously untreated AML with 20% to 30% blasts present in bone marrow and multi-lineage dysplasia (Phase 2 and 3 only); or

3. 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).

2. Participants with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

3. Participants with adequate organ function defined as:

1. 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.

2. Renal: Calculated creatinine clearance >50 mL/min/1.73 m^2 by Cockcroft-Gault formula or other medically acceptable formulas.

4. 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.

5. Participants with no major surgery within 2 weeks before first study treatment.

6. Participants with no cytotoxic chemotherapy within 4 weeks before first study treatment.

7. Able to swallow the number of tablets/capsules required for the treatment assignment within a 10-minute period and tolerate 4 hours of fasting.

8. Participants with projected life expectancy of at least 12 weeks.

9. 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:

1. Active uncontrolled gastric or duodenal ulcer.

2. Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled bacterial, viral, or fungal infections.

3. 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.

4. 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.

5. Participants with MDS/MPN who have clinical extramedullary disease including clinically palpable hepatomegaly or splenomegaly.

6. Previous treatment with more than 1 cycles of decitabine, azacitidine, or guadecitabine (Phases 2 and 3 only).

7. 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.

8. Known or suspected hypersensitivity to cedazuridine or azacitidine, or any of their excipients.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Chronic Myelocytic Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome/Neoplasm
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Azacitidine
Tablets/Capsules for oral administration and powder for reconstitution to aqueous suspension for subcutaneous administration
• ASTX030 (cedazuridine + azacitidine)
Tablets/Capsules for oral administration
• Cedazuridine
Tablets for oral administration

Locations

Country	Name	City	State
Canada	Eastern Health Sciences Centre - General Hospital	St. John's	Newfoundland and Labrador
Canada	Princess Margaret Cancer Centre	Toronto	Ontario
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	Hollings Cancer Center	Charleston	South Carolina
United States	Ohio State University Comprehensive Cancer Center (OSUCCC) - The James Cancer Hospital and Solove Research Institute	Columbus	Ohio
United States	Baylor Research Institute dba Baylor Scott & White Research Institute	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Duke University	Durham	North Carolina
United States	John Theurer Cancer Center / Hackensack University	Hackensack	New Jersey
United States	MD Anderson Cancer Center	Houston	Texas
United States	Keck School of Medicine of USC	Los Angeles	California
United States	New York University Langone Hospital - Long Island Site# 153	Mineola	New York
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Perlmutter Cancer Center - 34th Street	New York	New York
United States	Weill Cornell Medical Center	New York	New York
United States	Oregon Health and Science University	Portland	Oregon
United States	Oregon Oncology Specialists	Salem	Oregon
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	MedStar Georgetown University Hospital	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Astex Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Safety: Number of TEAEs	Number of participants with treatment-emergent adverse events (TEAEs)	Up to 36 months
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Time to response	Number of days from the start of treatment until the participant's first day of best response	Up to 36 months
Secondary	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
Secondary	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
Secondary	Pharmacokinetic parameter AUC	Area under the curve (AUC)	Up to Day 8 in Cycle 2 (28 days per cycle)
Secondary	Pharmacokinetic parameter Cmax	Maximum plasma concentration (Cmax)	Up to Day 8 in Cycle 2 (28 days per cycle)
Secondary	Pharmacokinetic parameter Tmax	Time to reach maximum plasma concentration (Tmax)	Up to Day 8 in Cycle 2 (28 days per cycle)