Study of ASTX727 vs IV Decitabine in MDS, CMML, and AML

Acute Myeloid Leukemia Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03306264
• Other study ID #: ASTX727-02
• Status: Completed
• Phase: Phase 3
• Start date: February 15, 2018
• Est. completion date: March 28, 2023

Study information

• Verified date: August 2023
• Source: Astex Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Multicenter, randomized, open-label, crossover PK study of ASTX727 versus IV decitabine. Adult subjects who are candidates to receive IV decitabine will be 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, subjects will continue to receive treatment with ASTX727 from Cycle 3 onward (in 28-day cycles) until disease progression, unacceptable toxicity, or the subject discontinues treatment or withdraws from the study.

Description:

This Phase 3 study will establish PK equivalence of ASTX727 to IV decitabine in approximately 118 evaluable subjects. Eligible subjects will receive both study treatments: oral investigational drug ASTX727, and IV decitabine, as follows: subjects will be 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, subjects will receive the ASTX727 tablet Daily×5. Serial PK measurements (blood draws) will be 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. Subjects will be 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, subjects will receive a 1-hour infusion of IV decitabine 20 mg/m^2 Daily×5. Serial PK measurements will be done on Days 1 and 5, along with pre-dose and 1-hour post-infusion assessments on Day 3.

In Cycles ≥3, subjects will receive the ASTX727 tablet Daily×5 in 28-day cycles. (No PK assessments will be done from Cycle 3 onward.)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: March 28, 2023
• Est. primary completion date: July 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Chronic Myelomonocytic Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• ASTX727
ASTX727 is a tablet for oral administration, containing the fixed-dose combination of 100 mg cedazuridine (a cytidine deaminase inhibitor) and 35 mg decitabine, given by mouth Dailyx5 in 28-day cycles (in Cycle 1 or Cycle 2, then in Cycle 3 and beyond).
• Dacogen
Decitabine 20 mg/m^2 one-hour IV infusion Dailyx5 (in one 28-day cycle: either Cycle 1 or Cycle 2).

Locations

Country	Name	City	State
Austria	Uniklinikum Salzburg	Salzburg
Austria	General Hospital Hietzing	Vienna
Austria	Klinikum Wels-Grieskirchen	Wels
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Queen Elizabeth II (QEII) Health Sciences Center	Halifax	Nova Scotia
Canada	Juravinski Hospital & Cancer Center	Hamilton	Ontario
Canada	Centre Intégré Universitaire de Santé et de Services Sociaux (CIUSSS) de l'Est-de-l'Ile-de-Montréal - Hôpital Maisonneuve Rosemont	Montréal	Quebec
Canada	Ottawa Hospital - General Campus	Ottawa	Ontario
Canada	Princess Margaret Cancer Center - University Health Network	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Czechia	University Hospital Brno	Brno
Czechia	FN Ostrava	Ostrava	Poruba
Czechia	Fakultni Nemocnice Kralovske Vinohrady FNKV	Praha 10	Ceská Republika
France	Centre de lutte contre le Cancer Leon Berard	Lyon	Rhone
France	Hospital Emile Muller	Mulhouse
Germany	Staedtisches Klinikum Braunschweig	Braunschweig
Germany	Oberärztin für Innere Medizin, Hämato-/Onkologie und Palliativmedizin	Düsseldorf
Germany	Universitaetsklinikum Freiburg	Freiburg im Breisgau	Baden
Germany	University Hospital Halle	Halle
Germany	University of Leipzig	Leisnig
Germany	UNIVERSITTSKLINIKUM Schleswig-Holstein	Lubeck	Schleswig-Holstein
Germany	Philipps-Universität Marburg, Klinik für Innere medizin, Hämatologie, Onkologie und Immunologie	Marburg	Hesse
Hungary	Debreceni Egyetem Klinikai Kozpont	Debrecen
Hungary	Somogy Megyei KAposi Mor Oktato Korhaz	Kaposvár
Hungary	University of Pecs, 1st Department of Internal Medicine	Pecs
Hungary	University of Szeged	Szeged
Italy	Azienda Ospedaliera Nazionale SS. Antonio e Biagio e C. Arrigo	Alessandria
Italy	AOUC Azienda Ospedaliero-Universitaria Careggi	Firenze
Italy	Fondazione IRCCS C Granda OM Policlinico	Milan
Italy	Azienda Ospedaliero-Universitaria Maggiore della Carità Novara	Novara
Italy	Ospedale S. Eugenio	Rome
Italy	ULSS 8 Vicenza - Ospedale San Bortolo di Vicenza	Vicenza
Spain	Hospital San Pedro de Alcantara	Cáceres
Spain	Hospital Universitario Virgen de las Nieves	Granada
Spain	Hospital Duran i Reynals	L'Hospitalet De Llobregat
Spain	Clinica Universitaria Navarra	Madrid
Spain	Hospital General Universitario Gregorio Marañón	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Universitario Central de Asturias	Oviedo	Asturias
Spain	Clinica Universitaria Navarra	Pamplona
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital U. Marqués de Valdecilla	Santander	Cantabria
Spain	Hospital Universitari I Politècnic La Fe	València
United Kingdom	The Christie NHS Fundation Trust	Manchester
United Kingdom	Oxford University Hopsitals NHS Trust	Oxford	Oxfordshire
United States	Pinnacle Research Group	Anniston	Alabama
United States	Johns Hopkins	Baltimore	Maryland
United States	Regional Cancer Care Associates	Bethesda	Maryland
United States	Boca Raton Clinical Research	Boca Raton	Florida
United States	Montefiore	Bronx	New York
United States	Roswell Park	Buffalo	New York
United States	Gabrail Cancer Center	Canton	Ohio
United States	Charleston Hematology Oncology Associates	Charleston	South Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	Ohio State University	Columbus	Ohio
United States	Baylor Scott & White University Medical Center	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Michigan Center of Medical Research	Farmington Hills	Michigan
United States	Holy Cross Hospital	Fort Lauderdale	Florida
United States	Compassionate Cancer Care Research Group	Fountain Valley	California
United States	Cancer & Hematology Centers of Western Michigan	Grand Rapids	Michigan
United States	Hackensack	Hackensack	New Jersey
United States	Houston Methodist Cancer Center	Houston	Texas
United States	MD Anderson Cancer Center	Houston	Texas
United States	Indiana Blood and Marrow Transplantation	Indianapolis	Indiana
United States	Kadlec Clinic Hematology and Oncology	Kennewick	Washington
United States	Monter Cancer Center	Lake Success	New York
United States	University of Southern California	Los Angeles	California
United States	Norton Cancer Institute	Louisville	Kentucky
United States	Mount Sinai	Miami Beach	Florida
United States	Vanderbilt	Nashville	Tennessee
United States	Yale	New Haven	Connecticut
United States	Weill Cornell Medicine	New York	New York
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	University of Pittsburgh Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	West Penn Allegheny Cancer Institute	Pittsburgh	Pennsylvania
United States	Oregon Health & Sciences University	Portland	Oregon
United States	Quincy Medical Group	Quincy	Illinois
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	Utah Cancer Specialists	Salt Lake City	Utah
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	Arizona Clinical Research Center	Tucson	Arizona
United States	Georgetown University	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Astex Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Austria,  Canada,  Czechia,  France,  Germany,  Hungary,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total 5-day Area Under the Curve (AUC) exposures of decitabine	Primary Endpoint	18 months
Secondary	Number of participants with adverse events (AEs); the severity (intensity) of AEs will be graded according to CTCAE v4.03.	Safety assessment	18 months
Secondary	Long Interspersed Nucleotide Elements (LINE)-1 demethylation	Pharmacodynamics assessment	18 months
Secondary	Maximum plasma concentration (Cmax)	Secondary pharmacokinetics parameter	2 months
Secondary	Time to reach maximum concentration (Tmax)	Secondary pharmacokinetics parameter	2 months
Secondary	Elimination rate constant	Secondary pharmacokinetics parameter	2 months
Secondary	Apparent total systemic clearance	Secondary pharmacokinetics parameter	2 months
Secondary	Apparent elimination half life	Secondary pharmacokinetics parameter	2 months
Secondary	Apparent volume of distribution	Secondary pharmacokinetics parameter	2 months
Secondary	MDS/CMML: Number of participants with complete response (CR), marrow CR, partial response; hematologic improvement based on International Working Group (IWG) 2006 MDS response criteria.	Efficacy analysis - Clinical response	18 months
Secondary	AML: Number of participants with CR, CR with incomplete platelet recovery (CRp) and CR with incomplete blood count recovery (CRi) based on IWG 2003 AML response criteria	Efficacy analysis - Clinical response	18 months
Secondary	Red blood cell (RBC) transfusion independence: defined as no RBC transfusion for 56 consecutive days.	Efficacy analysis - RBC transfusion independence	18 months
Secondary	Platelet transfusion independence: defined as no platelet transfusion for 8 consecutive weeks.	Efficacy analysis - Platelet transfusion independence	18 months
Secondary	Leukemia-free survival in MDS/CMML participants: number of days from date of randomization to date when bone marrow or peripheral blood blasts reach =20%, or death.	Efficacy analysis - Leukemia-free survival	18 months
Secondary	Overall survival: number of days from date subject was randomized to date of death.	Efficacy analysis - Overall survival	18 months