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

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04874194

Collaborator

(none)

Enrollment

Location

Arm

31.5

Anticipated Duration (Months)

2.7

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Omacetaxine Mepesuccinate Drug: Venetoclax	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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:

To determine duration of response (DOR), event-free survival (EFS), and overall survival (OS).
To evaluate occurrence of minimal residual disease (MRD) negative status by multiparameter flow cytometry and molecular evaluation.

EXPLORATORY OBJECTIVE:

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

84 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase Ib/II Study of Omacetaxine and Venetoclax for Patients With Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome Harboring Mutant RUNX1

Actual Study Start Date :

Dec 17, 2021

Anticipated Primary Completion Date :

Aug 1, 2024

Anticipated Study Completion Date :

Aug 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (omacetaxine, venetoclax) 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.	Drug: Omacetaxine Mepesuccinate Given SC Other Names: Ceflatonin Cephalotaxine, 4-methyl 2-hydroxy-2-(4-hydroxy-4-methylpentyl)butanedioate (ester), [3(R)]- (9CI) CGX-635 HHT homoharringtonine Synribo Drug: Venetoclax Given PO Other Names: ABT-0199 ABT-199 ABT199 GDC-0199 RG7601 Venclexta Venclyxto

Arm

Intervention/Treatment

Experimental: Treatment (omacetaxine, venetoclax)

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.

Drug: Omacetaxine Mepesuccinate

Given SC

Other Names:

Ceflatonin

Cephalotaxine, 4-methyl 2-hydroxy-2-(4-hydroxy-4-methylpentyl)butanedioate (ester), [3(R)]- (9CI)

CGX-635

HHT

homoharringtonine

Synribo

Drug: Venetoclax

Given PO

Other Names:

ABT-0199

ABT-199

ABT199

GDC-0199

RG7601

Venclexta

Venclyxto

Outcome Measures

Primary Outcome Measures

Incidence of adverse events [Up to 30 days post-treatment]
Safety data will be summarized using frequency and percentage, by category and severity.
Overall response rate [Within 3 months of treatment initiation]
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) [From date of treatment start and the date of treatment failure, relapse or death from any cause, assessed up to 3 years]
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) [Up to 3 years]
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 [Up to 3 years]
The Kaplan-Meier method will be used to estimate the probabilities.

Other Outcome Measures

Biomarker analysis [Up to 3 years]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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)