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Omacetaxine and Venetoclax for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Harboring Mutant RUNX1

Primary Purpose

Hematopoietic and Lymphoid Cell Neoplasm, Recurrent Acute Biphenotypic Leukemia, Recurrent Acute Myeloid Leukemia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Omacetaxine Mepesuccinate
Venetoclax
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hematopoietic and Lymphoid Cell Neoplasm

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with a diagnosis of relapsed or refractory acute myeloid leukemia (AML) (or biphenotypic or bilineage leukemia including a myeloid component) or myelodysplastic syndrome
  • For myelodysplastic syndrome (MDS) patients, patients must have no response, progression, or relapse following at least 4 cycles of azacytidine or decitabine; and/or intolerance defined as grade >= 3 drug-related toxicity precluding continued therapy
  • Age >= 18 years
  • Subjects must have documented RUNX1 gene mutation
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Creatinine < 2 unless related to the disease
  • Direct bilirubin < 2x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3x ULN unless considered due to leukemic involvement
  • In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (i.e. immunotherapy) agents. Oral hydroxyurea and/or cytarabine (up to 2 g/m^2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principal investigator (PI)
  • Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug
  • Willing and able to provide informed consent

Exclusion Criteria:

  • Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)
  • Patients with any concurrent uncontrolled clinically significant medical condition including active infection or psychiatric illness, which could place the patient at unacceptable risk of study treatment
  • Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI)
  • Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications
  • Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or known human immunodeficiency virus (HIV) infection
  • Subject has a white blood cell count > 25 x 10^9/L. (Note: Hydroxyurea is permitted to meet this criterion.)

  • Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception

    • Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)

Sites / Locations

  • M D Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (omacetaxine, venetoclax)

Arm Description

Patients receive omacetaxine SC BID on days 2-3 or 2-4, and venetoclax PO on days 1-7, 1-10 or 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Incidence of adverse events
Safety data will be summarized using frequency and percentage, by category and severity.
Overall response rate
Defined as the proportion of patients who had complete remission, complete remission with incomplete hematologic recovery, complete remission with incomplete count recovery, partial response or marrow clearance of blasts within 3 months of treatment initiation among adult patients with acute myeloid leukemia. Analyses will be performed for enrolled subjects, with laboratory response assessment occurring +/- 7 days from bone marrow evaluations. The depth of remission such as with exploratory analyses of minimal residual disease negativity by flow cytometry and/or concomitant molecular analysis will also be performed.

Secondary Outcome Measures

Event-free survival (EFS)
The Kaplan-Meier method will be used to estimate the probabilities. Log-rank tests will be used to compare among subgroups of patients in terms of EFS.
Overall survival (OS)
The Kaplan-Meier method will be used to estimate the probabilities. Log-rank tests will be used to compare among subgroups of patients in terms of OS.
Duration of response
The Kaplan-Meier method will be used to estimate the probabilities.

Full Information

First Posted
May 1, 2021
Last Updated
August 29, 2023
Sponsor
M.D. Anderson Cancer Center
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1. Study Identification

Unique Protocol Identification Number
NCT04874194
Brief Title
Omacetaxine and Venetoclax for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Harboring Mutant RUNX1
Official Title
Phase Ib/II Study of Omacetaxine and Venetoclax for Patients With Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Harboring Mutant RUNX1
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 17, 2021 (Actual)
Primary Completion Date
August 1, 2024 (Anticipated)
Study Completion Date
August 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase Ib/II trial best dose, possible benefits and/or side effects of omacetaxine and venetoclax in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back (recurrent) or does not respond to treatment (refractory) and have a genetic change RUNX1. Drugs used in chemotherapy, such as omacetaxine, work in different ways to stop the growth of tumor 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. Giving omacetaxine and venetoclax may help to control the disease.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the safety and tolerability and recommended phase 2 dose (RP2D) of omacetaxine in combination with venetoclax for patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome harboring a RUNX1 mutation. (Phase 1b) II. To determine the efficacy of omacetaxine in combination with venetoclax for patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome harboring a RUNX1 mutation. (Phase II) SECONDARY OBJECTIVES: I. To determine duration of response (DOR), event-free survival (EFS), and overall survival (OS). II. To evaluate occurrence of minimal residual disease (MRD) negative status by multiparameter flow cytometry and molecular evaluation. EXPLORATORY OBJECTIVE: I. To investigate global gene expression profiles, deoxyribonucleic acid (DNA) methylation profiles, BH3 profiling and other potential prognostic markers to explore predictors of antitumor activity and/or resistance to treatment. OUTLINE: This is a phase I, dose de-escalation study followed by a phase II study. Patients receive omacetaxine subcutaneously (SC) twice daily (BID) on days 2-3 or 2-4, and venetoclax orally (PO) on days 1-7, 1-10 or 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up within 30 days, then every 3 months for 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hematopoietic and Lymphoid Cell Neoplasm, Recurrent Acute Biphenotypic Leukemia, Recurrent Acute Myeloid Leukemia, Recurrent Myelodysplastic Syndrome, Refractory Acute Biphenotypic Leukemia, Refractory Acute Myeloid Leukemia, Refractory Myelodysplastic Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
84 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (omacetaxine, venetoclax)
Arm Type
Experimental
Arm Description
Patients receive omacetaxine SC BID on days 2-3 or 2-4, and venetoclax PO on days 1-7, 1-10 or 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Omacetaxine Mepesuccinate
Other Intervention Name(s)
Ceflatonin, Cephalotaxine, 4-methyl 2-hydroxy-2-(4-hydroxy-4-methylpentyl)butanedioate (ester), [3(R)]- (9CI), CGX-635, HHT, homoharringtonine, Synribo
Intervention Description
Given SC
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Incidence of adverse events
Description
Safety data will be summarized using frequency and percentage, by category and severity.
Time Frame
Up to 30 days post-treatment
Title
Overall response rate
Description
Defined as the proportion of patients who had complete remission, complete remission with incomplete hematologic recovery, complete remission with incomplete count recovery, partial response or marrow clearance of blasts within 3 months of treatment initiation among adult patients with acute myeloid leukemia. Analyses will be performed for enrolled subjects, with laboratory response assessment occurring +/- 7 days from bone marrow evaluations. The depth of remission such as with exploratory analyses of minimal residual disease negativity by flow cytometry and/or concomitant molecular analysis will also be performed.
Time Frame
Within 3 months of treatment initiation
Secondary Outcome Measure Information:
Title
Event-free survival (EFS)
Description
The Kaplan-Meier method will be used to estimate the probabilities. Log-rank tests will be used to compare among subgroups of patients in terms of EFS.
Time Frame
From date of treatment start and the date of treatment failure, relapse or death from any cause, assessed up to 3 years
Title
Overall survival (OS)
Description
The Kaplan-Meier method will be used to estimate the probabilities. Log-rank tests will be used to compare among subgroups of patients in terms of OS.
Time Frame
Up to 3 years
Title
Duration of response
Description
The Kaplan-Meier method will be used to estimate the probabilities.
Time Frame
Up to 3 years
Other Pre-specified Outcome Measures:
Title
Biomarker analysis
Description
MRD negative status and exploratory biomarkers will be summarized graphically and with descriptive statistics. The association between molecular and cellular markers and overall response and/or resistance will be assessed through logistic regression analyses. Paired t-test or Wilcoxon signed rank test will be used to assess the marker change over time.
Time Frame
Up to 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with a diagnosis of relapsed or refractory acute myeloid leukemia (AML) (or biphenotypic or bilineage leukemia including a myeloid component) or myelodysplastic syndrome For myelodysplastic syndrome (MDS) patients, patients must have no response, progression, or relapse following at least 4 cycles of azacytidine or decitabine; and/or intolerance defined as grade >= 3 drug-related toxicity precluding continued therapy Age >= 18 years Subjects must have documented RUNX1 gene mutation Eastern Cooperative Oncology Group (ECOG) performance status =< 2 Creatinine < 2 unless related to the disease Direct bilirubin < 2x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3x ULN unless considered due to leukemic involvement In the absence of rapidly proliferative disease, the interval from prior treatment to time of initiation will be at least 7 days for cytotoxic or non-cytotoxic (i.e. immunotherapy) agents. Oral hydroxyurea and/or cytarabine (up to 2 g/m^2) for patients with rapidly proliferative disease is allowed before the start of study therapy, as needed, for clinical benefit and after discussion with the principal investigator (PI) Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug Willing and able to provide informed consent Exclusion Criteria: Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML) Patients with any concurrent uncontrolled clinically significant medical condition including active infection or psychiatric illness, which could place the patient at unacceptable risk of study treatment Patients with active graft-versus-host-disease (GVHD) status post stem cell transplant (patients without active GVHD on chronic suppressive immunosuppression and/or phototherapy for chronic skin GVHD are permitted after discussion with the PI) Patients with any severe gastrointestinal or metabolic condition which could interfere with the absorption of oral study medications Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or known human immunodeficiency virus (HIV) infection Subject has a white blood cell count > 25 x 10^9/L. (Note: Hydroxyurea is permitted to meet this criterion.) Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception Appropriate highly effective method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Courtney DiNardo
Phone
713-794-1141
Email
cdinardo@mdanderson.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Courtney DiNardo
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Courtney DiNardo
Phone
713-794-1141
Email
cdinardo@mdanderson.org
First Name & Middle Initial & Last Name & Degree
Courtney DiNardo

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
M D Anderson Cancer Center

Learn more about this trial

Omacetaxine and Venetoclax for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Harboring Mutant RUNX1

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