A Study of Gilteritinib, Venetoclax and Azacitidine as a Combined Treatment for People Newly Diagnosed With Acute Myeloid Leukemia

NCT05520567 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: 2215-CL-0203
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 20

Brief Summary

People with acute myeloid leukemia (AML) are usually treated with chemotherapy. Some people with AML have a changed FLT3 gene which causes leukemia cells to grow faster. Therefore, chemotherapy is less suitable to treat AML in people with the changed FLT3 gene. Gilteritinib, given with venetoclax and azacitidine, is a potential new treatment for people with AML with the changed FLT3 gene. They cannot have chemotherapy due to old age or other conditions. Before these combined 3 medicines are available as a treatment, the researchers need to understand how they are processed by and act upon the body when given together. In this study, they do this to find a suitable dose for venetoclax and to check for potential medical problems from the treatment. In this study, people newly diagnosed with AML who have the changed FLT3 gene and cannot have chemotherapy can take part. The main aims of this study are: to find suitable doses of gilteritinib, venetoclax and azacitidine as a combined treatment; to learn how they are processed by and act upon the body; to learn the remission rate; to check for medical problems during this treatment. In the study, people will visit the study clinic many times. The first visit is to check if they can take part. People will be asked about their medical history, have a medical examination, and have their vital signs checked. Also, they will have an ECG to check their heart rhythm and have some blood and urine samples taken for laboratory tests. They will have a chest X-ray and a bone marrow sample will be taken. The changed FLT3 gene will be confirmed, either by the bone marrow or a blood sample. This study will be in 2 phases. In Phase 1, different small groups of people will take venetoclax tablets containing lower to higher doses in the combined treatment. The doses of gilteritinib and azacytidine will be unchanged. This is done to find a suitable dose of venetoclax to use in phase 2 of the study. People will take tablets of gilteritinib and venetoclax once a day on a 28-day cycle. They will be given azacytidine as an infusion or an injection just under the skin. This will be for 7 days at the beginning of each 28-day cycle. They will continue cycles of treatment throughout this phase of the study. In Phase 2, more people newly diagnosed with AML with the changed FLT3 gene will take part. They will be treated with the suitable doses of the combined treatment worked out from Phase 1. Treatment will be on a 28-day cycle. People will continue on cycles of treatment throughout this phase of the study. Researchers will work out the remission rate from this phase of the study. In each phase of the study, people can continue with up to 12 cycles of treatment if they can manage any medical problems. People will visit the study clinic many times during their first treatment cycle, and less often during the next cycles. During these visits, medical problems will be recorded and some blood samples will be taken for laboratory tests. On some visits, people will also have their vital signs checked. Bone marrow samples will be taken during cycle 1, and at the beginning of cycle 3. More samples will be taken during the study from people who are not in remission. When people have finished treatment, those who have responded well to treatment and are in remission will be invited to continue with up to 24 more cycles of gilteritinib plus azacitidine. All people taking part in the study will visit the study clinic for an end-of-treatment visit. During this visit, medical problems will be recorded and some blood samples will be taken for laboratory tests. People will have a medical examination, an ECG, and will have their vital signs checked. Also, a bone marrow sample will be taken. There will be a follow-up visit 30 days later to check for medical problems. Then people will visit the clinic or get a phone call every 3 months for up to 3 years. This is to give an update on their current treatment for AML. Some people can have a stem cell transplant during the study if they meet certain study rules. They will pause their study treatment during the stem cell transplant process and continue study treatment afterwards.

Conditions

Acute Myeloid Leukemia (AML); FLT3-mutated Acute Myeloid Leukemia

Keywords

Cancer; Acute Myeloid Leukemia; AML

Outcome Measures

Primary Outcomes (11)

• Number of Participants with Dose Limiting Toxicities (DLTs)

  A DLT is defined as any of the events meeting DLT criteria that occur with the first dose on Cycle 1 Day 1 (C1D1) and that is considered to be possibly or probably related to the study treatment regimen.

  Up to 42 Days

• Number of Participants with Adverse Events (AEs)

  An AE is any untoward medical occurrence in a patient or clinical study participant temporally associated with the use of study investigational product (IP), whether or not considered related to the study IP. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study IP. This includes events related to the comparator and events related to the (study) procedures.

  Up to 49 months

• Number of Participants with Serious AEs (SAEs)

  An SAE is defined as any untoward medical occurrence that, at any dose: * results in death * is life threatening * requires inpatient hospitalization or prolongation of existing hospitalization * results in persistent or significant disability/incapacity * is a congenital anomaly/birth defect * other situations where medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other situations such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed above. These events should usually be considered serious.

  Up to 49 months

• Number of Participants with laboratory value abnormalities and/or AEs

  Number of participants with potentially clinically significant laboratory values.

  Up to 48 months

• Number or Participants with electrocardiogram (ECG) abnormalities and/or AEs

  Number of participants with potentially clinically significant ECG values.

  Up to 48 months

• Number of Participants with vital sign abnormalities and/or AEs

  Number of participants with potentially clinically significant vital sign values.

  Up to 48 months

• Number of Participants with physical exam abnormalities and/or AEs

  Number of participants with potentially clinically significant physical exam values.

  Up to 48 months

• Number of Participants at each grade of the Eastern Cooperative Oncology Group (ECOG) performance status scores

  The ECOG scale will be used to assess performance status. Grades range from 0 (fully active) to 5 (dead). Negative change scores indicate an improvement. Positive scores indicate a decline in performance.

  Up to 48 months

• Percentage of Participants with Complete Remission (CR)

  CR rate is defined as the number of participants who achieve the best response of CR divided by the number of participants in the analysis population. CR is defined as participants having bone marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free state and must have bone marrow blasts \< 5% by morphological examination, absolute neutrophil count (ANC) \> 1 x 10\^9/L, platelet count \> 100 x 10\^9/L, and an absence of leukemic blasts in the peripheral blood by morphological examination. There should be no evidence of extramedullary disease. Other participants who do not relapse on study are considered nonevents and censored at the last

  Up to 24 months

• Pharmacological activity by Plasma Inhibitory Activity Assay (PIA)

  Inhibition of FLT3 phosphorylation after drug treatment will be determined relative to pretreatment phosphorylated FLT3 levels in participants to assess the relationship with gilteritinib dose. Phosphorylated FLT3 will be measured by plasma inhibitory activity (PIA) assay.

  Up to 2 months

• Pharmacokinetics (PK) of ASP2215 in plasma: concentration

  Concentration will be recorded from the PK plasma samples collected.

  Up to 6 months

Secondary Outcomes (12)

• Percentage of Participants with Complete Remission and Complete Remission with Partial Hematological Recovery (CR/CRh) rate

  Up to 24 months

• Percentage of Participants with Composite Complete Remission (CRc)

  Up to 24 months

• Duration of Remission (DOR)

  Up to 24 months

• Duration of Overall Survival (OS)

  Up to 24 months

• Duration of Event free survival (EFS)

  Up to 24 months

Study Arms (2)

Dose Ranging Cohort (Phase 1)

EXPERIMENTAL

Participants will receive daily dose of gilteritinib and venetoclax for 28 days, and azacitidine for 7 days in each 28-day cycle.

Drug: Gilteritinib; Drug: Venetoclax; Drug: Azacitidine

Dose Expansion Cohort (Phase 2)

EXPERIMENTAL

Participants will receive daily dose of gilteritinib, venetoclax, and azacitidine at an optimized dose established from dose ranging cohort (Phase 1)

Drug: Gilteritinib; Drug: Venetoclax; Drug: Azacitidine

Interventions

Gilteritinib DRUG

Oral

Also known as: ASP2215, XOSPATA®

Dose Expansion Cohort (Phase 2); Dose Ranging Cohort (Phase 1)

Venetoclax DRUG

Oral

Also known as: ABT199, Venclexta

Dose Expansion Cohort (Phase 2); Dose Ranging Cohort (Phase 1)

Azacitidine DRUG

Subcutaneous injection or intravenous infusion

Dose Expansion Cohort (Phase 2); Dose Ranging Cohort (Phase 1)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant has a diagnosis of previously untreated Acute Myeloid Leukemia (AML) according to World Health Organization classification as determined by pathology review at the treating institution.
• Participant is positive for FMS-like tyrosine kinase 3 (FLT3) mutation (internal tandem duplication \[ITD\] and/or tyrosine kinase domain \[TKD\] \[D835/I836\] mutation) in bone marrow or whole blood as determined by the central laboratory. A participant with rapidly proliferative disease and unable to wait for the central laboratory results can be enrolled from a local test result.
• Participant is ineligible for intensive induction chemotherapy by meeting at least 1 of the following criteria:
• Participant is \>= 75 years of age with Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.
• Participant is \>= 18 to 75 years of age and has any of the following comorbidities: ECOG performance status 2 or 3, cardiac history of congestive heart failure requiring treatment or ejection fraction \<= 50% or chronic stable angina, known history of diffusion capacity of lung for carbon monoxide (DLCO) \<= 65% or forced expiratory volume in the first second (FEVI) \<= 65%, creatinine clearance \> 30 mL/min to 45 mL/min, calculated by the Cockcroft Gault formula, moderate hepatic impairment with total bilirubin \> 1.5 to \< 3.0 x upper limit of normal (ULN), any other comorbidity incompatible with intensive chemotherapy during screening and before enrollment.
• Participant must have a projected life expectancy of at least 12 weeks.
• Participant must have adequate organ and bone marrow function prior to enrollment, as specified per protocol's laboratory parameters.
• Participant is suitable for oral administration of study drug (gilteritinib and venetoclax) and is willing/able to swallow oral tablets/capsules.
• Participant with a known history of human immunodeficiency virus (HIV) on effective antiretroviral therapy must have a viral load undetectable for 6 months prior to Cycle 1 Day 1 (C1D1).
• Female participant is eligible to participate if she is not pregnant and at least one of the following conditions apply:
• Not a woman of childbearing potential (WOCBP) OR
• WOCBP agrees to follow the contraceptive guidance starting at screening and continue through the study treatment period, and for at least 180 days after the final study regimen administration.
• WOCBP must have a negative pregnancy test during screening.
• Female participant must agree not to breastfeed starting at screening, throughout the study treatment period and for 60 days after the last dose of the study treatment regimen.
• Female participant must not donate ova starting at screening, throughout the study treatment and for 180 days after the last dose of the study treatment regimen.

You may not qualify if:

• Participant with the following conditions:
• Acute promyelocytic leukemia (APL)
• Active, symptomatic central nervous system (CNS) involvement with AML
• History of myeloproliferative neoplasm (MPN), including myelofibrosis, essential thrombocythemia, polycythemia vera, chronic myeloid leukemia (CML) with or without BCR-ABL1 translocation or AML with BCR-ABL1 translocation
• Participant previously treated with CAR-T cell therapy for AML or MDS. Exceptions for prior treatment of AML are (i.e., the following treatments are allowed):
• Hydroxyurea for increased blast count (No washout period required. It can be continued throughout the first cycle of therapy).
• Leukapheresis for leukocytosis (No washout period required. It can be continued during the study).
• Participant who is receiving treatment with any other investigational agents.
• Participant requires treatment with concomitant drugs that are strong or moderate inducers of cytochrome P450 (CYP)3A or P glycoprotein (P-gp) during study treatment.
• Participant who has consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit \<= 3 days prior to C1D1.
• Participant with a cardiovascular disability status of New York Heart Association (NYHA) Class \>= 3.
• Participant with mean QTcF \> 450 msec at screening based on local reading performed in triplicate.
• Participant with a history of Long QT Syndrome at screening.
• Participant has been diagnosed with another malignancy within 2 years prior to screening for the study, with the following exceptions:
• Adequately treated in situ carcinoma of the cervix uteri or carcinoma in situ of breast;

Sponsors & Collaborators

• Astellas Pharma Global Development, Inc.: lead

Study Sites (20)

City of Hope Nat'l Medical Center

Duarte, California, 91010, United States

Location

Univ. of California - Irvine

Irvine, California, 92697, United States

Location

UCLA Medical Center

Los Angeles, California, 90095, United States

Location

Sarah Cannon Research Institute

Denver, Colorado, 80218, United States

Location

Memorial Cancer Institute

Pembroke Pines, Florida, 33028, United States

Location

University of Chicago

Chicago, Illinois, 60637, United States

Location

Robert H. Lurie Comprehensive Cancer Center

Chicago, Illinois, 61612, United States

Location

University of Maryland

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Weill Cornell Medical College

New York, New York, 10065, United States

Location

Motefiore-Einstein Center for Cancer Care

The Bronx, New York, 10461, United States

Location

Novant Health

Winston-Salem, North Carolina, 27103, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

University of Pennsylvania-Abramson CCC-Dept. of Hem Onc

Philadelphia, Pennsylvania, 19104, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

The University of Texas MD

Houston, Texas, 77030, United States

Location

The Medical College of Wisconsin- Froedtert Hospital

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Neoplasms

Interventions

gilteritinib; venetoclax; Azacitidine

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Medical Director

  Astellas Pharma Global Development, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 26, 2022
• First Posted: August 30, 2022
• Study Start: January 31, 2023
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): July 31, 2028
• Last Updated: March 4, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.

Locations

US (20)