Azacitidine, Venetoclax, and Gilteritinib in Treating Patients With Recurrent/Refractory FLT3-Mutated Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or High-Risk Myelodysplastic Syndrome/Myeloproliferative Neoplasm

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04140487

Collaborator

(none)

Enrollment

Location

Arm

56.5

Anticipated Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I/II trial studies the side effects and best dose of gilteritinib and to see how well it works in combination with azacitidine and venetoclax in treating patients with FLT3-mutation positive acute myeloid leukemia, chronic myelomonocytic leukemia, or high-risk myelodysplastic syndrome/myeloproliferative neoplasm that has come back (recurrent) or has not responded to treatment (refractory). Drugs used in chemotherapy, such as azacitidine, 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 azacitidine, venetoclax, and gilteritinib may work better compared to azacitidine and venetoclax alone in treating patients with acute myeloid leukemia, chronic myelomonocytic leukemia, or myelodysplastic syndrome/myeloproliferative neoplasm.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Acute Myeloid Leukemia Recurrent Chronic Myelomonocytic Leukemia Recurrent Myelodysplastic/Myeloproliferative Neoplasm Refractory Acute Myeloid Leukemia Refractory Chronic Myelomonocytic Leukemia Refractory Myelodysplastic/Myeloproliferative Neoplasm	Drug: Azacitidine Drug: Gilteritinib Drug: Venetoclax	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

To establish the maximum tolerated dose (MTD) of the combination of azacitidine, venetoclax and gilteritinib in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML) or high-risk myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN). (Phase I) II. To determine the complete remission/complete remission with incomplete count recovery (CR/CRi) rate of the regimen in patients with newly diagnosed or relapsed/refractory fms-like tyrosine kinase 3 (FLT3)-mutated AML or CMML or high-risk MDS/MPN. (Phase II)

SECONDARY OBJECTIVES:

To assess other efficacy endpoints (CR rate, minimal residual disease negativity by flow cytometry, relapse-free survival, overall survival).
To assess proportion of patients proceeding to hematopoietic stem cell transplantation (HSCT).
To determine the safety of the combination regimen.

EXPLORATORY OBJECTIVES:

To evaluate the impact of baseline genomic alterations on response and survival of the combination regimen.
To determine the impact of baseline FLT3 allelic ratio on response and survival.
To evaluate clonal evolution from diagnosis to relapse using single-cell sequencing.

OUTLINE: This is phase I, dose-escalation study of gilteritinib followed by a phase II study.

Patients receive azacitidine subcutaneously (SC) or intravenously (IV) over 30-60 minutes on days 1-7, venetoclax orally (PO) once daily (QD) on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles, and gilteritinib PO QD on days 1-28. Treatment of azacytidine and venetoclax repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Cycles of gilteritinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 6 months thereafter.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

42 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II Study of Azacitidine, Venetoclax, and Gilteritinib for Patients With Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome With an Activating FLT3 Mutation

Actual Study Start Date :

Dec 17, 2019

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Sep 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (azacitidine, venetoclax, gilteritinib) Patients receive azacitidine SC or IV over 30-60 minutes on days 1-7, venetoclax PO QD on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles, and gilteritinib PO QD on days 1-28. Treatment of azacytidine and venetoclax repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Cycles of gilteritinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Azacitidine Given IV Other Names: 5 AZC 5-AC 5-Azacytidine 5-AZC Azacytidine Azacytidine, 5- Ladakamycin Mylosar Onureg U-18496 Vidaza Drug: Gilteritinib Given PO Other Names: ASP-2215 ASP2215 Drug: Venetoclax Given PO Other Names: ABT-0199 ABT-199 ABT199 GDC-0199 RG7601 Venclexta Venclyxto

Arm

Intervention/Treatment

Experimental: Treatment (azacitidine, venetoclax, gilteritinib)

Patients receive azacitidine SC or IV over 30-60 minutes on days 1-7, venetoclax PO QD on days 1-28 of cycle 1 and on days 1-21 of subsequent cycles, and gilteritinib PO QD on days 1-28. Treatment of azacytidine and venetoclax repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity. Cycles of gilteritinib repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Azacitidine

Given IV

Other Names:

5 AZC

5-AC

5-Azacytidine

5-AZC

Azacytidine

Azacytidine, 5-

Ladakamycin

Mylosar

Onureg

U-18496

Vidaza

Drug: Gilteritinib

Given PO

Other Names:

ASP-2215

ASP2215

Drug: Venetoclax

Given PO

Other Names:

ABT-0199

ABT-199

ABT199

GDC-0199

RG7601

Venclexta

Venclyxto

Outcome Measures

Primary Outcome Measures

Maximum-tolerated dose (MTD) of gilteritinib (Phase I) [Up to 28 days]
The MTD is the highest dose level in which < 2 patients of 6 develop first cycle dose-limiting toxicity.
Overall response rate (OR) (Phase II) [Up to 56 days (2 cycles)]
Will be defined as the complete remission/complete remission with incomplete count recovery (CR/CRi) rate. Will estimate the OR for the combination treatment along with the 95% credible interval.

Secondary Outcome Measures

Complete response rate [Up to 3 years]
Will be estimated along with 95% credible interval.
Minimal residual disease negativity [Up to 3 years]
Will be assessed by flow cytometry and estimated along with 95% credible interval.
Relapse-free survival [The number of days from the date of response to the date of documented relapses from CR or death from any cause, whichever occurs first, assessed up to 3 years]
Will be estimated using the method of Kaplan and Meier.
Overall survival [From the start of treatment until death or last follow-up, assessed for up to 3 years]
Will be estimated using the method of Kaplan and Meier.
Proportion of patients proceeding to hematopoietic stem cell transplantation [Up to 3 years]
Will be estimated along with 95% credible interval.
Incidence of adverse events [Up to 3 years]
Will be summarized using descriptive statistics such as mean, standard deviation, median and range.

Other Outcome Measures

Impact of genomic alterations [Baseline]
The impact of genomic alterations on response and the survival of the combination regimen will be assessed. Will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Impact of FLT3 allelic ratio [Baseline]
The impact of FLT3 allelic ratio on response and the survival will be assessed. Will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Minimal residual disease negativity rates [At time of remission]
Will be assessed by digital droplet polymerase chain reaction. Will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.
Evaluation of leukemia stem cell populations [Up to 3 years]
Will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis:
Phase I cohort: Adults >= 18 years with relapsed/refractory FLT3-mutated AML or CMML or other MDS/MPN 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
Phase II cohort B: Adults >= 18 years with relapsed/refractory FLT3-mutated AML or CMML or other MDS/MPN that is intermediate-2 or high-risk by the International Prognostic Scoring System
For all cohorts, patients with either FLT3-internal tandem duplication (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 principal investigator (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

Exclusion Criteria:

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. 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: No restriction on number of prior therapies
Patients suitable for and willing to receive intensive induction chemotherapy (for Phase II cohort A only)
Congenital long QT syndrome or corrected QT interval by Fridericia (QTcF) > 450 msec. Repeat electrocardiograms (EKGs) after correction of electrolytes or discontinuation of QT prolonging medications are allowed to meet entry criteria. In cases where QTcF > 450 msec is considered to be falsely increased due to inaccurate automated reading and not clinically significant (e.g. due to bundle branch block), patients are still eligible if cardiologist reviews and documents that QTcF is =< 450 msec when manually measured
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 human immunodeficiency virus (HIV) seropositive
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 cytochrome P450, family 3, subfamily A (CYP3A) or p-glycoprotein within 3 days of study enrollment. Agents include but are not limited to: carbamazepine, phenytoin, rifampin, and St. John's wort
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
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 practice 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