Clinical trial NCT03306264: Study of ASTX727 vs IV Decitabine in Participants With MDS, CMML, and AML
Official title: A Phase 3, Randomized, Open-Label, Crossover Study of ASTX727 (Cedazuridine and Decitabine Fixed-Dose Combination) Versus IV Decitabine in Subjects With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), and Acute Myeloid Leukemia (AML)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
Keywords: MDS
CMML
decitabine
Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
Acute Myeloid Leukemia
AML
Lead sponsor: Astex Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2017-10-11
Enrollment: 227
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Multicenter, randomized, open-label, 2-period, 2-sequence crossover study
Primary purpose: TREATMENT

Brief summary: Multicenter PK study of ASTX727 versus IV decitabine. Adult participants who were candidates to receive IV decitabine were randomized 1:1 to receive the ASTX727 tablet Daily×5 in Cycle 1 followed by IV decitabine 20 mg/m\^2 Daily×5 in Cycle 2, or the converse order. After completion of PK studies during the first 2 treatment cycles, participants continued to receive treatment with ASTX727 from Cycle 3 onward (in 28-day cycles) until disease progression, unacceptable toxicity, or the participants discontinued treatment or withdrew from the study.

Detailed description: This Phase 3 study established PK equivalence of ASTX727 to IV decitabine in approximately 227 evaluable participants. Eligible participants were randomized to receive both study treatments: oral investigational drug ASTX727, and IV decitabine, as follows: participants were randomly assigned 1:1 to receive ASTX727 or IV decitabine in Cycle 1 and then cross over to the other therapy in Cycle 2.

In the ASTX727 cycle, participants received the ASTX727 tablet Daily×5. Serial PK measurements (blood draws) were done on Days 1, 2, and 5, along with pre-dose PK assessments on Days 1-5 and an assessment at 3 hours post-dose on Day 3. Participants were required to fast from food for 4 hours on days when receiving ASTX727: at least 2 hours before and 2 hours after dosing.

In the IV decitabine cycle, participants received a 1-hour infusion of IV decitabine 20 mg/m\^2 Daily×5. Serial PK measurements were done on Days 1 and 5, along with pre-dose and 1-hour post-infusion assessments on Day 3.

In Cycles ≥3, participants received the ASTX727 tablet Daily×5 in 28-day cycles. (No PK assessments were done from Cycle 3 onward.)

Eligibility criteria: 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; specifically able to comply with the PK assessment schedule during the first 2 treatment cycles.
2. Men or women ≥18 years who are candidates to receive IV decitabine according to FDA or European Medicines Agency (EMA) approved indications:

   1. In North America: Participants with MDS previously treated or untreated with de novo or secondary MDS, including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia \[CMML\]), and subjects with MDS International Prognostic Scoring System (IPSS) int-1, -2, or high-risk MDS.
   2. In Europe: Participants with de novo or secondary AML, as defined by the World Health Organization (WHO) criteria, who are not candidates for standard induction chemotherapy.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
4. Adequate organ function defined as follows:

   1. Hepatic: Total or direct bilirubin ≤2 × upper limit of normal (ULN); aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) ≤2.5 × ULN.
   2. Renal: serum creatinine ≤1.5 × ULN or calculated creatinine clearance or glomerular filtration rate \>50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal.
5. No major surgery within 30 days of first study treatment.
6. Life expectancy of at least 3 months.
7. Women of child-bearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of non-childbearing potential are those who have had a hysterectomy or bilateral oophorectomy, or who have completed menopause, defined as no menses for at least 1 year AND either age ≥65 years or follicle-stimulating hormone levels in the menopausal range.
8. Subjects and their partners with reproductive potential must agree to use effective contraceptive measures during the study and for 3 months after the last dose of study treatment. Effective contraception includes methods such as oral contraceptives or double-barrier method (eg, use of a condom AND diaphragm, with spermicide).

Exclusion Criteria:

1. Prior treatment with more than 1 cycle of azacitidine or decitabine. Prior cytotoxic chemotherapy for AML except for hydroxyurea to control high white blood cell (WBC) counts.
2. Hospitalization for more than 2 days for documented febrile neutropenia, pneumonia, sepsis, or systemic infection in the 30 days before screening.
3. Treatment with any investigational drug or therapy within 2 weeks of study treatment, or 5 half-lives, whichever is longer, before the first dose of study treatment, or ongoing clinically significant adverse events (AEs) from previous treatment.
4. Cytotoxic chemotherapy or prior azacitidine or decitabine within 4 weeks of first dose of study treatment.
5. Concurrent MDS therapies, including lenalidomide, erythropoietin, cyclosporine/tacrolimus, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, etc. (Prior treatment with these agents is permitted, provided that completion is at least 1 week before the first dose of study treatment.)
6. Poor medical risk because of other conditions such as uncontrolled systemic diseases, active uncontrolled infections, or comorbidities that may put the patient at risk of not being able to complete at least 2 cycles of treatment.
7. 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.
8. Rapidly progressive or highly proliferative disease (total white blood cell count of \>15 × 10\^9/L) or other criteria that render the subject at high risk of requiring intensive cytotoxic chemotherapy within the next 3 months.
9. Life-threatening illness or severe organ system dysfunction, such as uncontrolled congestive heart failure or chronic obstructive pulmonary disease, 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, or compromise completion of the study or integrity of the study outcomes.
10. 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 2 years.

Primary outcomes:
measure: Total 5-day Area Under the Curve From 0 to 24 Hours (AUC0-24) After Treatment With ASTX727 And IV Decitabine
timeFrame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
Secondary outcomes:
measure: MDS/CMML: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.7 years)
measure: AML: Number of Participants With Treatment-emergent Adverse Events (AEs)
timeFrame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.4 years)
measure: MDS/CMML: Number of Participants With Grade 3 or Higher TEAEs
timeFrame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.7 years)
measure: AML: Number of Participants With Grade 3 or Higher TEAEs
timeFrame: From randomization up to 30 days after last dose of study treatment (up to approximately 2.4 years)
measure: Maximum Percentage of Long Interspersed Nucleotide Elements (LINE)-1 Demethylation
timeFrame: Pre-dose on Day 1 of Cycles 1 and 2 (as Baseline), and Days 8, 15 and 22 of Cycles 1 and 2 (each cycle= 28 days)
measure: Total 5-day Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine
timeFrame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
measure: Total 5-day Area Under the Curve From 0 to Last Quantifiable Concentration (AUC0-last) After Treatment With ASTX727 And IV Decitabine
timeFrame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
measure: Total 5-day Area Under the Curve From 0 to 8 Hours (AUC0-8) After Treatment With ASTX727 And IV Decitabine
timeFrame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 to 5 of Cycle 1 and 2 (each cycle= 28 days)
measure: Area Under the Curve From 0 to Infinity (AUC0-inf) After Treatment With ASTX727 And IV Decitabine
timeFrame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
measure: Maximum Observed Plasma Concentration (Cmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer
timeFrame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Decitabine, Cedazuridine, and Cedazuridine-epimer
timeFrame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
measure: Apparent Oral Clearance (CL/F) of Oral Decitabine and Cedazuridine
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days)
measure: Apparent Elimination Half Life (t1/2) of Decitabine, Cedazuridine, and Cedazuridine-epimer
timeFrame: ASTX727: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2; Decitabine: Pre-dose, 0.25, 0.5, 1, 1.08, 1.5, 2, 3, 4, 6, 8 hours post-dose on Days 1 and 5 of Cycle 1 and 2 (each cycle= 28 days)
measure: Apparent Volume of Distribution (Vz/F) of Oral Decitabine and Cedazuridine
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 24 hours post-dose on Days 1, 2 and 5 of Cycle 1 and 2 (each cycle= 28 days)
measure: MDS/CMML: Percentage of Participants With Complete Response (CR), Marrow CR (mCR), Partial Response (PR), Hematologic Improvement (HI) Based on International Working Group (IWG) 2006 Myelodysplastic Syndromes (MDS) Response Criteria
timeFrame: Up to approximately 2.7 years
measure: AML: Percentage of Participants With CR, CR With Incomplete Blood Count Recovery (CRi), CR With Incomplete Platelet Recovery (CRp), and CR Plus CRp Based on IWG 2003 AML Response Criteria
timeFrame: Up to approximately 2.4 years
measure: AML: Percentage of Participants With CR With Partial Hematologic Recovery (CRh) Based on IWG 2003 AML Response Criteria
timeFrame: Day 1 of Cycle 3 up to approximately 2.4 years (each cycle= 28 days)
measure: AML: Time to First Response, Best Response and Complete Response Based on IWG 2003 AML Response Criteria
timeFrame: Up to approximately 2.4 years
measure: AML: Duration of Complete Response and Combined CR and CRh Based on IWG 2003 AML Response Criteria
timeFrame: Up to approximately 2.4 years
measure: MDS/CMML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI)
timeFrame: Up to approximately 2.7 years
measure: AML: Percentage of Participants With Red Blood Cell (RBC) and Platelet Transfusion Independence (TI)
timeFrame: Up to approximately 2.4 years
measure: MDS/CMML: Leukemia-free Survival (LFS)
timeFrame: From randomization up to approximately 2.7 years
measure: MDS/CMML: Overall Survival (OS)
timeFrame: From randomization up to approximately 2.7 years
measure: AML: Overall Survival (OS)
timeFrame: From randomization up to approximately 2.4 years
measure: AML: Survival Rates at 6 Months, 1 Year, and 2 Years
timeFrame: At Month 6, Year 1 and 2
measure: AML: Event-free Survival (EFS)
timeFrame: From randomization up to approximately 2.4 years
measure: AML: Progression-free Survival (PFS)
timeFrame: From randomization up to approximately 2.4 years
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Pinnacle Research Group
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Tucson
country: United States
facility: Arizona Clinical Research Center
state: Arizona
city: Fountain Valley
country: United States
facility: Compassionate Cancer Care Research Group
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: New Haven
country: United States
facility: Yale
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Boca Raton
country: United States
facility: Boca Raton Clinical Research
state: Florida
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Quincy
country: United States
facility: Quincy Medical Group
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Blood and Marrow Transplantation
state: Indiana
city: Louisville
country: United States
facility: Norton Cancer Institute
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Bethesda
country: United States
facility: Regional Cancer Care Associates
state: Maryland
city: Farmington Hills
country: United States
facility: Michigan Center of Medical Research
state: Michigan
city: Grand Rapids
country: United States
facility: Cancer & Hematology Centers of Western Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack
state: New Jersey
city: Bronx
country: United States
facility: Montefiore
state: New York
city: Buffalo
country: United States
facility: Roswell Park
state: New York
city: Lake Success
country: United States
facility: Monter Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Sciences University
state: Oregon
city: Pittsburgh
country: United States
facility: West Penn Allegheny Cancer Institute
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Hillman Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Charleston Hematology Oncology Associates
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt
state: Tennessee
city: Dallas
country: United States
facility: Baylor Scott & White University Medical Center
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Cancer Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists
state: Utah
city: Kennewick
country: United States
facility: Kadlec Clinic Hematology and Oncology
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Salzburg
country: Austria
facility: Uniklinikum Salzburg
city: Vienna
country: Austria
facility: General Hospital Hietzing
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Halifax
country: Canada
facility: Queen Elizabeth II (QEII) Health Sciences Center
state: Nova Scotia
city: Hamilton
country: Canada
facility: Juravinski Hospital & Cancer Center
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital - General Campus
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center - University Health Network
state: Ontario
city: Montréal
country: Canada
facility: Centre Intégré Universitaire de Santé et de Services Sociaux (CIUSSS) de l'Est-de-l'Ile-de-Montréal - Hôpital Maisonneuve Rosemont
state: Quebec
city: Ostrava
country: Czechia
facility: FN Ostrava
state: Poruba
city: Brno
country: Czechia
facility: University Hospital Brno
city: Praha 10
country: Czechia
facility: Fakultni Nemocnice Kralovske Vinohrady FNKV
state: Česká Republika
city: Lyon
country: France
facility: Centre de lutte contre le Cancer Leon Berard
state: Rhone
city: Mulhouse
country: France
facility: Hospital Emile Muller
city: Freiburg im Breisgau
country: Germany
facility: Universitaetsklinikum Freiburg
state: Baden
city: Marburg
country: Germany
facility: Philipps-Universität Marburg, Klinik für Innere medizin, Hämatologie, Onkologie und Immunologie
state: Hesse
city: Lubeck
country: Germany
facility: UNIVERSITTSKLINIKUM Schleswig-Holstein
state: Schleswig-Holstein
city: Braunschweig
country: Germany
facility: Staedtisches Klinikum Braunschweig
city: Düsseldorf
country: Germany
facility: Oberärztin für Innere Medizin, Hämato-/Onkologie und Palliativmedizin
city: Halle
country: Germany
facility: University Hospital Halle
city: Leisnig
country: Germany
facility: University of Leipzig
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont
city: Kaposvár
country: Hungary
facility: Somogy Megyei KAposi Mor Oktato Korhaz
city: Pecs
country: Hungary
facility: University of Pecs, 1st Department of Internal Medicine
city: Szeged
country: Hungary
facility: University of Szeged
city: Alessandria
country: Italy
facility: Azienda Ospedaliera Nazionale SS. Antonio e Biagio e C. Arrigo
city: Firenze
country: Italy
facility: AOUC Azienda Ospedaliero-Universitaria Careggi
city: Milan
country: Italy
facility: Fondazione IRCCS C Granda OM Policlinico
city: Novara
country: Italy
facility: Azienda Ospedaliero-Universitaria Maggiore della Carità Novara
city: Rome
country: Italy
facility: Ospedale S. Eugenio
city: Vicenza
country: Italy
facility: ULSS 8 Vicenza - Ospedale San Bortolo di Vicenza
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
state: Asturias
city: Santander
country: Spain
facility: Hospital U. Marqués de Valdecilla
state: Cantabria
city: Cáceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: Granada
country: Spain
facility: Hospital Universitario Virgen de las Nieves
city: L'Hospitalet De Llobregat
country: Spain
facility: Hospital Duran i Reynals
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Clinica Universitaria Navarra
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Pamplona
country: Spain
facility: Clinica Universitaria Navarra
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: València
country: Spain
facility: Hospital Universitari I Politècnic La Fe
city: Oxford
country: United Kingdom
facility: Oxford University Hopsitals NHS Trust
state: Oxfordshire
city: Manchester
country: United Kingdom
facility: The Christie NHS Fundation Trust
Study officials:
References: