search
Back to results

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

Primary Purpose

Myelodysplastic Syndromes, Chronic Myelocytic Leukemia, Acute Myeloid Leukemia

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Azacitidine
ASTX030 (cedazuridine + azacitidine)
Cedazuridine
Sponsored by
Astex Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • John Theurer Cancer Center / Hackensack UniversityRecruiting
  • Roswell Park Comprehensive Cancer CenterRecruiting
  • New York University Langone Hospital - Long Island Site# 153Recruiting
  • Weill Cornell Medical CenterRecruiting
  • Oregon Health and Science UniversityRecruiting
  • Oregon Oncology SpecialistsRecruiting
  • Vanderbilt University Medical CenterRecruiting
  • MD Anderson Cancer CenterRecruiting
  • Seattle Cancer Care AllianceRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Phase 1, Stage A (Dose Escalation)

Phase 1, Stage B (Dose Expansion)

Phase 2, Sequence A

Phase 2, Sequence B

Phase 3, Sequence A

Phase 3, Sequence B

Arm Description

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

Oral cedazuridine + azacitidine will be administered separately at the recommended dose for expansion (RDE)

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)

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)

Participants will receive ASTX030 in Cycle 1, followed by SC azacitidine in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3)

Participants will receive SC azacitidine in Cycle 1 followed by ASTX030 in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3)

Outcomes

Primary Outcome Measures

Total cycle area under the curve (AUC)0-24 exposures
Ratio of azacitidine total cycle AUC0-24 exposures after oral ASTX030 over SC azacitidine

Secondary Outcome Measures

Safety: Number of TEAEs
Number of participants with treatment-emergent adverse events (TEAEs)
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)
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
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)
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
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
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
Time to response
Number of days from the start of treatment until the participant's first day of best response
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
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
Pharmacokinetic parameter AUC
Area under the curve (AUC)
Pharmacokinetic parameter Cmax
Maximum plasma concentration (Cmax)
Pharmacokinetic parameter Tmax
Time to reach maximum plasma concentration (Tmax)

Full Information

First Posted
January 31, 2020
Last Updated
September 29, 2023
Sponsor
Astex Pharmaceuticals, Inc.
search

1. Study Identification

Unique Protocol Identification Number
NCT04256317
Brief Title
A Study of ASTX030 (Cedazuridine in Combination With Azacitidine) in MDS, CMML, or AML
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)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 21, 2020 (Actual)
Primary Completion Date
December 2025 (Anticipated)
Study Completion Date
April 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Astex Pharmaceuticals, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndromes, Chronic Myelocytic Leukemia, Acute Myeloid Leukemia, Myelodysplastic Syndrome/Neoplasm

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
317 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Phase 1, Stage A (Dose Escalation)
Arm Type
Experimental
Arm Description
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
Arm Title
Phase 1, Stage B (Dose Expansion)
Arm Type
Experimental
Arm Description
Oral cedazuridine + azacitidine will be administered separately at the recommended dose for expansion (RDE)
Arm Title
Phase 2, Sequence A
Arm Type
Experimental
Arm Description
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)
Arm Title
Phase 2, Sequence B
Arm Type
Experimental
Arm Description
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)
Arm Title
Phase 3, Sequence A
Arm Type
Experimental
Arm Description
Participants will receive ASTX030 in Cycle 1, followed by SC azacitidine in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3)
Arm Title
Phase 3, Sequence B
Arm Type
Experimental
Arm Description
Participants will receive SC azacitidine in Cycle 1 followed by ASTX030 in Cycle 2; all participants will receive ASTX030 in subsequent cycles (Cycles ≥3)
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Other Intervention Name(s)
Vidaza
Intervention Description
Tablets/Capsules for oral administration and powder for reconstitution to aqueous suspension for subcutaneous administration
Intervention Type
Drug
Intervention Name(s)
ASTX030 (cedazuridine + azacitidine)
Intervention Description
Tablets/Capsules for oral administration
Intervention Type
Drug
Intervention Name(s)
Cedazuridine
Intervention Description
Tablets for oral administration
Primary Outcome Measure Information:
Title
Total cycle area under the curve (AUC)0-24 exposures
Description
Ratio of azacitidine total cycle AUC0-24 exposures after oral ASTX030 over SC azacitidine
Time Frame
Up to 2 months
Secondary Outcome Measure Information:
Title
Safety: Number of TEAEs
Description
Number of participants with treatment-emergent adverse events (TEAEs)
Time Frame
Up to 36 months
Title
Change in DNA methylation
Description
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)
Time Frame
Baseline in Phase 1 to the end of Cycle 2 in Phase 3 (28 days per cycle)
Title
Best clinical response rate for participants with MDS, CMML, or MDS/myeloproliferative neoplasms (MPN)
Description
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
Time Frame
Up to 36 months
Title
Best clinical response rate for participants with AML
Description
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)
Time Frame
Up to 36 months
Title
AML-free survival for participants with MDS, CMML, or MDS/MPN
Description
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
Time Frame
Up to 36 months
Title
Duration of response
Description
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
Time Frame
Up to 36 months
Title
Overall survival
Description
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
Time Frame
Up to 36 months
Title
Time to response
Description
Number of days from the start of treatment until the participant's first day of best response
Time Frame
Up to 36 months
Title
Red blood cell (RBC) transfusion independence (TI)
Description
Number of participants with RBC TI, defined as no RBC transfusion for 56 consecutive days while maintaining hemoglobin ≥8 g/dL
Time Frame
Up to 36 months
Title
Platelet transfusion independence (TI)
Description
Number of participants with platelet TI, defined as no platelet transfusion for 56 consecutive days while maintaining platelets ≥20×10^9/L
Time Frame
Up to 36 months
Title
Pharmacokinetic parameter AUC
Description
Area under the curve (AUC)
Time Frame
Up to Day 8 in Cycle 2 (28 days per cycle)
Title
Pharmacokinetic parameter Cmax
Description
Maximum plasma concentration (Cmax)
Time Frame
Up to Day 8 in Cycle 2 (28 days per cycle)
Title
Pharmacokinetic parameter Tmax
Description
Time to reach maximum plasma concentration (Tmax)
Time Frame
Up to Day 8 in Cycle 2 (28 days per cycle)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
General Inquiries
Phone
925-560-0100
Email
clinicaltrials@astx.com
Facility Information:
Facility Name
John Theurer Cancer Center / Hackensack University
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Individual Site Status
Recruiting
Facility Name
Roswell Park Comprehensive Cancer Center
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Individual Site Status
Recruiting
Facility Name
New York University Langone Hospital - Long Island Site# 153
City
Mineola
State/Province
New York
ZIP/Postal Code
11501
Country
United States
Individual Site Status
Recruiting
Facility Name
Weill Cornell Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Name
Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Individual Site Status
Recruiting
Facility Name
Oregon Oncology Specialists
City
Salem
State/Province
Oregon
ZIP/Postal Code
97301
Country
United States
Individual Site Status
Recruiting
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Individual Site Status
Recruiting
Facility Name
MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Name
Seattle Cancer Care Alliance
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

We'll reach out to this number within 24 hrs