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

  • STATUS
    Recruiting
  • End date
    Sep 1, 2024
  • participants needed
    42
  • sponsor
    M.D. Anderson Cancer Center
Updated on 28 March 2021

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.

Description

PRIMARY OBJECTIVES:

I. 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:

I. To assess other efficacy endpoints (CR rate, minimal residual disease negativity by flow cytometry, relapse-free survival, overall survival).

II. To assess proportion of patients proceeding to hematopoietic stem cell transplantation (HSCT).

III. To determine the safety of the combination regimen.

EXPLORATORY OBJECTIVES:

I. To evaluate the impact of baseline genomic alterations on response and survival of the combination regimen.

II. To determine the impact of baseline FLT3 allelic ratio on response and survival.

III. 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.

Details
Condition Refractory Acute Myeloid Leukemia, FLT3 Tyrosine Kinase Domain Point Mutation, Recurrent High Risk Myelodysplastic Syndrome, Refractory High Risk Myelodysplastic Syndrome, Recurrent Acute Myeloid Leukemia, Recurrent Chronic Myelomonocytic Leukemia, Recurrent Myelodysplastic Syndrome, Refractory Chronic Myelomonocytic Leukemia, Refractory Myelodysplastic Syndrome, FLT3 Internal Tandem Duplication, refractory acute myeloid leukemia (aml), Recurrent Myelodysplastic/Myeloproliferative Neoplasm, Refractory Myelodysplastic/Myeloproliferative Neoplasm, Recurrent Myelodysplastic/Myeloproliferative Neoplasm, Refractory Myelodysplastic/Myeloproliferative Neoplasm
Treatment Azacitidine, Gilteritinib, venetoclax, Gilteritinib Fumarate
Clinical Study IdentifierNCT04140487
SponsorM.D. Anderson Cancer Center
Last Modified on28 March 2021

Eligibility

Yes No Not Sure

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
Clear my responses

How to participate?

Step 1 Connect with a site
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar
Name

Primary Contact

site
Name

Phone Email

0/250
Preferred Language
Other Language
Please verify that you are not a bot.

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note