Pharmacokinetics, Safety, and Efficacy of ASTX727 in Combination With Venetoclax in Acute Myeloid Leukemia (AML)

Acute Myeloid Leukemia Clinical Trial

Official title:

A Single-Arm, Open-Label Pharmacokinetic, Safety, and Efficacy Study of ASTX727 in Combination With Venetoclax in Adult Patients With Acute Myeloid Leukemia

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04657081
• Other study ID #: ASTX727-07
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: February 9, 2021
• Est. completion date: December 31, 2025

Study information

• Verified date: May 2024
• Source: Astex Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The Phase 1 portion of this study is a single-arm, open-label, multicenter, non-randomized interventional study to evaluate the pharmacokinetic (PK) interaction, safety, and efficacy of ASTX727 when given in combination with venetoclax for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. The primary purpose of the study is to rule out drug-drug interactions between ASTX727 and venetoclax combination therapy by evaluating area under the curve (AUC) and maximum plasma concentration (Cmax) exposure. The Phase 2 portion of the study is to assess the efficacy of ASTX727 and venetoclax when given in combination and to evaluate potential PK interactions. Phase 2 will follow the same overall study design as Phase 1 and has two parts, Part A and Part B.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 188
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Participant must be 18 years of age or older.

2. Histological confirmation of newly diagnosed AML by World Health Organization (WHO) 2016 criteria.

3. Projected life expectancy of at least 3 months.

4. Participants must be considered ineligible for intensive induction chemotherapy defined by the following: a) Age 75 years or older, or b) Age 18 to 74 years with at least one of the following comorbidities: i) Severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction =50%, or chronic stable angina), ii) Severe pulmonary disorder (eg, diffusing lung capacity for carbon monoxide DLCO =65% or forced expiratory volume in 1 second [FEV1] =65%), iii) Creatinine clearance =30 mL/min to <45 mL/min, iv) Moderate hepatic impairment with total bilirubin >1.5 to =3.0 × upper limit of normal (ULN), v) Phase 1: Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 (participants with ECOG =3 are not eligible); Phase 2, Parts A and B: ECOG Performance Status of 2 or 3 (participants with ECOG 4 are not eligible).

5. Phase 1: ECOG Performance Status of 0-2; Phase 2, Parts A and B: ECOG 0-3.

6. Women of child-bearing potential (according to recommendations of the Clinical Trial Facilitation Group [CTFG]) must not be pregnant or breastfeeding and must have a negative pregnancy test at screening.

7. Participants and their partners with reproductive potential must agree to use a highly effective contraceptive measure during the study and for 3 months after the last dose of study treatment, including refraining from sperm donation. Effective contraception includes methods such as oral contraceptives or double-barrier method (eg, use of a condom AND diaphragm, with spermicide).

8. Capable of giving legally effective informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and protocol, and willing to participate in the study.

Exclusion Criteria:

1. History of myeloproliferative neoplasm including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation.

2. The following karyotype abnormalities: t(8;21), inv(16) or t(15;17), or other acute promyelocytic leukemia variants that remain sensitive to all-trans retinoic acid (ATRA) therapy.

3. Known active central nervous system involvement from AML.

4. Known human immunodeficiency virus (HIV) infection (due to potential drug-drug interactions between antiretroviral medications and venetoclax). Human immunodeficiency virus testing will be performed at Screening, only if indicated per local guidelines or institutional standards.

5. Known active hepatitis B or C infection (detectable viral load). Hepatitis B or C testing will be performed at Screening, only if indicated per local guidelines or institutional standards.

6. Severe hepatic impairment defined as: bilirubin >1.5×upper limit of normal (ULN) for participants =75 years or >3×ULN for participants <75 years; or aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) >3×ULN (unless considered to be due to leukemic organ involvement).

7. Severe renal impairment defined as: calculated creatinine clearance or glomerular filtration rate <30 mL/min.

8. A malabsorption syndrome or other condition that precludes enteral route of administration.

9. Cardiovascular disability status of New York Heart Association Class >2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea, or anginal pain.

10. Chronic respiratory disease that requires continuous oxygen, or significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, any other medical condition or known hypersensitivity to any of the study medications that in the opinion of the investigator would adversely affect his/her participating in this study.

11. Clinically significant uncontrolled systemic infection requiring therapy (viral, bacterial, or fungal).

12. 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.

13. White blood cell (WBC) count >25,000/µL (Hydroxyurea treatment is permitted to meet this criterion).

14. Treatment with the following: a) A hypomethylating agent (azacitidine or decitabine), or venetoclax including prior treatment for myelodysplastic syndrome (MDS), b) Chimeric Antigen Receptor (CAR)-T cell therapy, c) Investigational therapies for MDS or AML.

15. Participants who cannot discontinue concomitant prophylactic antifungal therapy with CYP3A inhibitor activity or other concomitant medications with moderate or strong CYP3A inhibitor activity =7 days or 5 half-lives, whichever is greater, prior to cycle 1 day 1 (C1D1).

16. Participants who cannot discontinue concomitant drugs that are strong CYP3A or P-gp inhibitors =7 days or 5 half-lives, whichever is greater, prior to C1D1.

17. Participants who cannot avoid concomitant drugs known as moderate or strong CYP3A inducers.

18. Current participation in another research study requiring interventions such as drug therapy or study procedures.

19. Known or suspected hypersensitivity to decitabine, cedazuridine, venetoclax, or any of their excipients.

20. 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 participant to high risk of noncompliance with the protocol.

21. Participants who consume grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit =7 days prior to C1D1.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Decitabine and Cedazuridine (ASTX727)
Route of administration: oral in the form of a tablet
• Venetoclax
Route of administration: oral in the form of a tablet

Locations

Country	Name	City	State
Canada	University of Calgary - Health Sciences Centre	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	Jewish General Hospital	Montréal
Canada	The Ottawa Hospital, General Campus	Ottawa	Ontario
Spain	Institut Catala d'Oncologia-Hospital Duran i Reynals	L'Hospitalet De Llobregat	Barcelona
Spain	Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario Central de Asturias	Oviedo	Austrias
Spain	Clinica Universidad de Navarra, Pamplona	Pamplona	Navarra
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Hospital Universitari i Politecnic La Fe	Valencia
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	The Ohio State University	Columbus	Ohio
United States	East Carolina University	Greenville	North Carolina
United States	Hackensack University of Medical Center	Hackensack	New Jersey
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	MD Anderson Cancer Center	Houston	Texas
United States	Indiana University Simon Cancer Center	Indianapolis	Indiana
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Health Midwest Ventures Group, Inc.	Kansas City	Missouri
United States	USC Norris Comprehensive Cancer Center	Los Angeles	California
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Weill Cornell Medical College	New York	New York
United States	Stanford University	Palo Alto	California
United States	UPMC Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	Boca Raton Clinical Research	Plantation	Florida
United States	University of Rochester	Rochester	New York
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	The Research Foundation of the State University of New York (SUNY)	Syracuse	New York
United States	Baylor Scott & White Research Institute	Temple	Texas
United States	University of Massachusetts, Memorial Medical Center	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Astex Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Canada,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pharmacokinetic parameter: AUC0-24	Venetoclax area under the curve from time 0 to 24 hours (AUC0-24) with and without ASTX727 in Phase 1 and Phase 2, Part A.	On Days 5 and 15 in Cycle 2 (28 days per cycle)
Primary	Pharmacokinetic parameter: Cmax	Venetoclax maximum observed concentration (Cmax) with and without ASTX727 in Phase 1 and Phase 2, Part A.	On Days 5 and 15 in Cycle 2 (28 days per cycle)
Primary	Complete Response (CR)	Number of participants with CR in Phase 2, Parts A and B.	Up to 36 months
Secondary	Pharmacokinetic parameter: AUC0-24	Decitabine and cedazuridine area under the curve from time 0 to 24 hours (AUC0-24) in Phase 1 and Phase 2, Parts A and B.	Cycle 1, 2 and 3 (28 days per cycle)
Secondary	Pharmacokinetic parameter: Cmax	Decitabine and cedazuridine maximum observed concentration (Cmax) in Phase 1 and Phase 2, Parts A and B.	Cycle 1, 2 and 3 (28 days per cycle)
Secondary	Pharmacokinetic parameter: AUC0-8	Decitabine and cedazuridine area under the curve from time 0 to 8 hours (AUC0-8) in Phase 1 and 2, Parts A and B.	Cycle 1, 2 and 3 (28 days per cycle)
Secondary	Pharmacokinetic parameter: AUC0-inf	Decitabine and cedazuridine area under the curve from time 0 to infinity (AUC0-inf) in Phase 2, Parts A and B.	Cycle 1, 2 and 3 (28 days per cycle)
Secondary	Pharmacokinetic parameter: 5-day AUC	Decitabine 5-day cumulative AUC in Phase 1.	Cycle 2 (28 days per cycle)
Secondary	Safety: Participants with TEAEs	Number of participants with treatment-emergent adverse events (TEAEs) in Phase 1 and 2, Parts A and B.	Up to 36 months
Secondary	Complete response (CR)	Number of participants with CR (Phase 1), CR + complete response with partial hematological recovery (CRh), and CR + incomplete blood count recovery (CRi) in Phase 1 and 2, Parts A and B.	Up to 36 months
Secondary	Time to Response	Number of days from the first dose to the first documented evidence of complete response or CRh in Phase 1 and 2, Parts A and B.	Up to 36 months
Secondary	Duration of Response	Number of days from the start of response (CR or CRh) until disease progression, start of alternative antileukemia therapy, or death in Phase 1 and 2, Parts A and B.	Up to 36 months
Secondary	Overall Survival	Number of days from date of first dose until death due to any cause in Phase 1 and 2, Parts A and B.	Up to 36 months
Secondary	Pharmacokinetic parameter: Cmin	Venetoclax, decitabine and cedazuridine minimum observed concentration (Cmin) in Phase 1 and Phase 2, Parts A and B.	Cycle 1, 2 and 3 (28 days per cycle)
Secondary	Pharmacokinetic parameter: Tmax	Venetoclax, decitabine and cedazuridine time to maximum observed concentration in Phase 1 and Phase 2, Parts A and B.	Cycle 1, 2 and 3 (28 days per cycle)
Secondary	Pharmacokinetic Parameter: Apparent Elimination Half-life (T1/2)	Venetoclax, decitabine and cedazuridine T1/2 in Phase 1 and Phase 2, Parts A and B.	Cycle 1, 2 and 3 (28 days per cycle)