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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

ConditionsRecurrent Acute Myeloid LeukemiaRecurrent Chronic Myelomonocytic LeukemiaRecurrent Myelodysplastic/Myeloproliferative NeoplasmRefractory Acute Myeloid LeukemiaRefractory Chronic Myelomonocytic LeukemiaRefractory Myelodysplastic/Myeloproliferative Neoplasm
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18+
SponsorM.D. Anderson Cancer Center

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

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)

Trial design

Design model

Single group

Treatments tested in this trial

  • Azacitidine

    Drug

    Given IV

  • Gilteritinib

    Drug

    Given PO

  • Venetoclax

    Drug

    Given PO

Treatment groups

97 Participants
are divided into 1 treatment group
Group A: Treatment (azacitidine, venetoclax, gilteritinib)Experimental treatment 3 interventions

Trial outcomes

Primary outcomes

1

Maximum-tolerated dose (MTD) of gilteritinib (Phase I)

The MTD is the highest dose level in which \< 2 patients of 6 develop first cycle dose-limiting toxicity.

Time frame
Up to 28 days
2

Overall response rate (OR) (Phase II)

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.

Time frame
Up to 56 days (2 cycles)

Secondary outcomes

1

Complete response rate

Will be estimated along with 95% credible interval.

Time frame
Up to 3 years
2

Minimal residual disease negativity

Will be assessed by flow cytometry and estimated along with 95% credible interval.

Time frame
Up to 3 years
3

Relapse-free survival

Will be estimated using the method of Kaplan and Meier.

Time frame
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
4

Overall survival

Will be estimated using the method of Kaplan and Meier.

Time frame
From the start of treatment until death or last follow-up, assessed for up to 3 years

Other outcomes

1

Impact of genomic alterations

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.

Time frame
Baseline
2

Impact of FLT3 allelic ratio

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.

Time frame
Baseline
3

Minimal residual disease negativity rates

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.

Time frame
At time of remission
4

Evaluation of leukemia stem cell populations

Will be examined by Wilcoxon's rank sum test or Fisher's exact test, as appropriate.

Time frame
Up to 3 years

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

M.D. Anderson Cancer Center

Lead sponsor

Source ClinicalTrials.gov
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