Clinical trial NCT04256317: 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
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Myelodysplastic Syndromes
Acute Myeloid Leukemia
Myelodysplastic Syndrome/Neoplasm
Chronic Myelomonocytic Leukemia
Keywords: ASTX030
Myeloid Neoplasm
Hematologic Disease
Leukemia
Acute Myeloid Leukemia (AML)
Myelodysplastic Syndrome (MDS)
Chronic Myelomonocytic Leukemia (CMML)
Vidaza™
Azacitadine
Azacitadine and cedazuridine drug combination
Lead sponsor: Taiho Oncology, Inc.
Sponsor class: INDUSTRY
First posted: 2020-02-05
Enrollment: 235
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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). 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 this phase 1-3 study is approximately 7 years.

Detailed description: The Phase 1 and Phase 2 arms have completed enrollment. The Phase 3 arm is open for enrollment.

Eligibility criteria: Inclusion Criteria:

Phase 2:

1. Has Confirmed MDS, CMML, MDS/MPN or AML diagnosis who are candidates to receive and benefit from single agent azacitidine and as applicable according to local country approvals and/or local institution standard practice.

Phase 3:

1. Has confirmed MDS or CMML and is a candidate to receive and benefit from single agent azacitidine as applicable according to local country approvals and/or local institution standard practice:

   a) 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), and CMML or MDS with intermediate-2 or high risk MDS according to the International Prognostic Scoring System (IPSS).
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
3. Participants with adequate organ function.
4. For participants with prior allogeneic stem cell transplant, no evidence of graft-versus-host disease (GVHD).
5. Participants with no major surgery within 3 weeks before first study treatment.
6. Participants with no cytotoxic chemotherapy (excluding hydroxyurea) within 4 weeks before first study treatment.
7. Participants with projected life expectancy of at least 12 weeks.

Exclusion Criteria:

Phase 2 and 3:

1. Has an active uncontrolled gastric or duodenal ulcer.
2. Has poor medical risk because of other conditions.
3. Has known human immunodeficiency virus (HIV) infection.
4. Is known to be positive for Hepatitis B or C infection.
5. Has a life-threatening illness.
6. Has a history of other malignancies prior to study entry, with the exception of adequately treated in situ carcinoma of the breast or cervix uteri; localized basal cell carcinoma or squamous cell carcinoma of the skin; previous malignancy confined and surgically resected or adequately treated and controlled with other modalities; and any early stage malignancy for which no definitive therapy is required.
7. Participants with MDS/MPN including CMML who have clinical extramedullary disease including clinically palpable hepatomegaly or splenomegaly.
8. Has previous treatment with more than 1 cycle of decitabine, azacitidine, or guadecitabine (Phases 2 and 3 only).
9. Has been 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.
10. Has a known or suspected hypersensitivity to cedazuridine or azacitidine or any of their excipients.

Primary outcomes:
measure: Phase 1, 2 and 3: Total Cycle Area Under the Curve (AUC) from 0 to 24 Hours (AUC0-24) Exposures
timeFrame: Predose and at multiple timepoints post-dose up to 24 hours
Secondary outcomes:
measure: Phase 1, 2 and 3: Number of Participants with Treatment-emergent Adverse Events (TEAEs)
timeFrame: Up to 36 months
measure: Phase 1, 2 and 3: Change in Deoxyribonucleic Acid (DNA) Methylation
timeFrame: Baseline in Phase 1 to the end of Cycle 2 in Phase 3 (28 days per cycle)
measure: Phase 1, 2 and 3: Best Clinical Response Rate for Participants with MDS, CMML, or MDS/Myeloproliferative Neoplasms (MPN)
timeFrame: Up to 36 months
measure: Phase 1, 2 and 3: AML-free Survival for Participants with MDS, CMML, or MDS/MPN
timeFrame: Up to 36 months
measure: Phase 1, 2 and 3: Duration of Response
timeFrame: Up to 36 months
measure: Phase 1, 2 and 3: Overall Survival
timeFrame: Up to 36 months
measure: Phase 1, 2 and 3: Time to Response
timeFrame: Up to 36 months
measure: Phase 1, 2 and 3: Red Blood Cell (RBC) Transfusion Independence (TI)
timeFrame: Up to 36 months
measure: Phase 1, 2 and 3: Platelet Transfusion Independence (TI)
timeFrame: Up to 36 months
measure: Phase 1, 2 and 3: AUC for Azacitidine, Cedazuridine and Cedazuridine-epimer
timeFrame: Predose and at multiple timepoints post-dose on Days 1, 2 and 7 of Cycle 1 and Cycle 2 (cycle length=28 days)
measure: Phase 1, 2 and 3: Cmax for Azacitidine, Cedazuridine and Cedazuridine-epimer
timeFrame: Predose and at multiple timepoints post-dose on Days 1, 2 and 7 of Cycle 1 and Cycle 2 (cycle length=28 days)
measure: Phase 1, 2 and 3: Time to Reach Cmax (Tmax) for Azacitidine, Cedazuridine and Cedazuridine-epimer
timeFrame: Predose and at multiple timepoints post-dose on Days 1, 2 and 7 of Cycle 1 and Cycle 2 (cycle length=28 days)
measure: Phase 1B, Food Effect Cohort: AUC for Azacitidine, Cedazuridine and Cedazuridine-epimer
timeFrame: Predose and at multiple timepoints post-dose on Day 7 of Cycle 2 (cycle length=28 days)
measure: Phase 1B, Food Effect Cohort: Cmax for Azacitidine, Cedazuridine and Cedazuridine-epimer
timeFrame: Predose and at multiple timepoints post-dose on Day 7 of Cycle 2 (cycle length=28 days)
measure: Phase 1B, Food Effect Cohort: Tmax for Azacitidine, Cedazuridine and Cedazuridine-epimer
timeFrame: Predose and at multiple timepoints post-dose on Day 7 of Cycle 2 (cycle length=28 days)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Keck School of Medicine of USC
state: California
city: Orange
country: United States
facility: UCI Health - Chao Family Comprehensive Cancer Center
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Hackensack
country: United States
facility: John Theurer Cancer Center / Hackensack University
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: Mineola
country: United States
facility: New York University Langone Hospital - Long Island
state: New York
city: New York
country: United States
facility: Perlmutter Cancer Center - 34th Street
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Rochester
country: United States
facility: James P. Wilmot Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center (OSUCCC) - The James Cancer Hospital and Solove Research Institute
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Salem
country: United States
facility: Oregon Oncology Specialists
state: Oregon
city: Charleston
country: United States
facility: Hollings Cancer Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor Research Institute dba Baylor Scott & White Research Institute
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Milwaukee
country: United States
facility: Froedtert & Medical College of Wisconsin
state: Wisconsin
city: St. John's
country: Canada
facility: Eastern Health - Health Sciences Centre
state: Newfoundland and Labrador
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
Study officials:
References: