ASTX727, Venetoclax, and Gilteritinib for the Treatment of Newly Diagnosed, Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

NCT05010122 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 2021-0082NCI-2021-06095
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I/II trial studies the best dose of gilteritinib given together with ASTX727 and venetoclax and the effect of ASTX727, venetoclax, and gilteritinib in treating patients with FLT3-mutated acute myeloid leukemia that is newly diagnosed, has come back (relapsed) or does not respond to treatment (refractory) or high-risk myelodysplastic syndrome. Chemotherapy drugs, such as ASTX727, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Gilteritinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving ASTX727, venetoclax, and gilteritinib may help to control the disease.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndrome; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (Phase I)

  Up to 28 days

• Overall response (OR) rate (Phase II)

  Will estimate the OR for the combination treatment (defined as the proportion of patients achieving complete response (CR) or incomplete hematologic recovery (CRi) within 2 cycles of treatment), along with the 95% credible interval.

  Up to 2 cycles of treatment (1 cycle = 28 days)

Secondary Outcomes (6)

• Complete response rate

  Up to 2 years

• To assess minimal residual disease negativity by flow cytometry

  Up to 2 years

• Relapse-free survival

  From the date of response to the date of documented relapses from CR or death from any cause, whichever occurs first, assessed up to 2 years

• Overall survival

  From treatment start till death or last follow-up, assessed up to 2 years

• Proportion of patients proceeding to hematopoietic stem cell transplantation

  Up to 2 years

Study Arms (1)

Treatment (decitabine, cedazuridine, venetoclax, gilteritib)

EXPERIMENTAL

INDUCTION (CYCLE 1): Patients receive decitabine and cedazuridine PO QD on days 1-5, venetoclax PO QD on days 1-28, and gilteritinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity CONSOLIDATION (CYCLES 2-24): Patients receive decitabine and cedazuridine PO QD on days 1-5, gilteritinib PO QD on days 1-28, and venetoclax PO QD on days 1-14. Treatment repeats every 28 days. MAINTENANCE (CYCLES 24+): Patients receive gilteritinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Decitabine and Cedazuridine; Drug: Gilteritinib; Drug: Venetoclax

Interventions

Decitabine and Cedazuridine DRUG

Given PO

Also known as: ASTX727, C-DEC, CDA Inhibitor E7727/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Combination Agent ASTX727, Cedazuridine/Decitabine Tablet, DEC-C, Inqovi

Treatment (decitabine, cedazuridine, venetoclax, gilteritib)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Treatment (decitabine, cedazuridine, venetoclax, gilteritib)

Gilteritinib DRUG

Given PO

Also known as: ASP-2215, ASP2215

Treatment (decitabine, cedazuridine, venetoclax, gilteritib)

Eligibility Criteria

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

You may qualify if:

• Diagnosis:
• Phase I cohort: Adults \>= 18 years with relapsed/refractory FLT3-mutated AML or myelodysplastic syndrome (MDS) that is intermediate-2 or high-risk by the International Prognostic Scoring System
• Phase II cohort A: Adults \>= 18 years with newly diagnosed FLT3-mutated AML. Patients should meet the following criteria:
• Confirmed newly diagnosed AML with FLT3 mutation
• Ineligible for induction therapy defined as
• Either age \>= 75
• Or 18-74 with at least one comorbidity (congestive heart failure \[CHF\] requiring therapy or ejection fraction \[EF\] =\< 50%, diffusion capacity of the lung for carbon monoxide \[DLCO\] =\< 65% or forced expiratory volume in 1 second \[FEV1\] =\< 65%, or Eastern Cooperative Oncology Group \[ECOG\] 2 or 3, or other significant co-morbidity precluding use of cytotoxic chemotherapy as approved by the principal investigator (PI)
• Phase II cohort B: Adults \>= 18 years with relapsed/refractory FLT3-mutated AML or MDS that is intermediate-2 or high-risk by the International Prognostic Scoring System who have received 1 prior therapy
• For all cohorts, patients with either FLT3-ITD or FLT3 D835 mutations will be eligible
• Performance status =\< 3 (Eastern Cooperative Oncology Group \[ECOG\] scale)
• Total serum bilirubin =\< 2.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the PI
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =\< 3 x ULN, unless due to the underlying leukemia approved by the PI
• Creatinine clearance \>= 30 mL/min
• Ability to swallow
• Signed informed consent

You may not qualify if:

• Prior therapies
• Phase I cohort: No restriction based on prior therapies
• Phase II cohort A: Patients with prior therapy for AML are not eligible. Prior therapy for antecedent hematologic disorder is allowed including prior hypomethylating agent (HMA) therapy for MDS. Prior hydroxyurea or cytarabine given for purposes of cytoreduction is also allowed. Prior all trans-retinoic acid given for presumed acute promyelocytic leukemia is also allowed
• Phase II cohort B: Patients with \>= 3 prior lines of therapy are not eligible. Stem cell transplantation, treatment given only for cytoreductive purposes (e.g. hydroxyurea), and growth factors do not count as lines of therapy for this purpose. Prior therapy with venetoclax and gilteritinib is allowed
• Patients suitable for and willing to receive intensive induction chemotherapy (for Phase II cohort A only)
• Congenital long QT syndrome or corrected QT (QTc) \> 450 msec. Repeat electrocardiograms (EKGs) after correction of electrolytes or discontinuation of QT prolonging medications are allowed to meet entry criteria
• Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of improvement despite antimicrobial treatment)
• Active grade III-V cardiac failure as defined by the New York Heart Association Criteria
• Active central nervous system leukemia
• Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection
• Note: Patients who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Patients who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the PI
• Consumed strong inducer of CYP3A or p-glycoprotein within 3 days of study enrollment. Agents include but are not limited to: carbamazepine, phenytoin, rifampin, and St. John's wart
• Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator. Prior recent treatment with corticosteroids, hydroxyurea and/or cytarabine (given for cytoreduction) permitted. Use of hydroxyurea or one dose cytarabine to reduce WBC below 25 prior to initiation of study treatment is recommended
• Pregnant women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to use effective methods of contraception throughout the study period and for at least 6 months after the last dose of study drugs. Women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 12 months. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control throughout the study period and for at least 4 months after the last dose of study drugs. Lactating women (or those planning to breastfeed) should not breastfeed during treatment of gilteritinib and for at least 2 months after the last dose of gilteritinib

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

decitabine and cedazuridine drug combination; gilteritinib; venetoclax

Condition Hierarchy (Ancestors)

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

Study Officials

• Farhad Ravandi-Kashani

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 22, 2021
• First Posted: August 18, 2021
• Study Start: July 8, 2021
• Primary Completion (Estimated): January 30, 2028
• Study Completion (Estimated): January 30, 2028
• Last Updated: February 18, 2026

Record last verified: 2026-02

Locations

US (1)