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
Conditions
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. 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.
Interventions
Given SC
DRUGVenetoclax
Given PO
Sponsors
M.D. Anderson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 Dose (RP2D) of Omacetaxine in Combination With Venetoclax | Up to 30 days | The RP2D will be selected at the end of the Phase 1b portion based on safety data , in Arms A and B independently. Preliminary efficacy and PK data for each dose level may also be considered as appropriate. |
| Number of Participant to Achieve Complete Remission | At day 28, and 3 cycles. | Complete Remission for AML is defined as: Absolute neutrophil count \> 10\^3/UL, platelets . 10\^5/UL, red cell transfusion independence, absence of extramedullary disease, and bone marrow with \< 5% blasts. Complete Remission for MDS is defined as: Absolute neutrophil count \> 10\^3/UL, platelets . 10\^5/UL, hemoglobin \>11 g/dl, and bone marrow with \< 5% blasts. Peripheral dysplasia will be noted. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | Up to Two years, 8 months, 30 days | Time from date of treatment start until the date of failure or death from any cause. |
| Overall Survival (OS) | Up to Two years, 8 months, 30 days | 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 Two years, 8 months, 30 days | Response date to loss of response or last follow up. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ph 1 Arm A (AML) Dose 0 Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-10 . Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Omacetaxine Mepesuccinate: Given SC
Venetoclax: Given PO | 3 |
| Ph 1 Arm B (MDS) Dose 0 Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-10 . Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Omacetaxine Mepesuccinate: Given SC
Venetoclax: Given PO | 2 |
| Ph 1 Arm A (AML) Dose +1 Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Omacetaxine Mepesuccinate: Given SC
Venetoclax: Given PO | 9 |
| Ph 1 Arm B (MDS) Dose + 1 Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Omacetaxine Mepesuccinate: Given SC
Venetoclax: Given PO | 0 |
| Ph 2 Arm A (AML) Dose +1 Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Omacetaxine Mepesuccinate: Given SC
Venetoclax: Given PO | 10 |
| Ph 2 Arm B (MDS) Dose + 1 Participants receive omacetaxine SC BID on days 2-4, and venetoclax PO on days 1-14. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
Omacetaxine Mepesuccinate: Given SC
Venetoclax: Given PO | 0 |
| Total | 24 |
Baseline characteristics
| Characteristic | Ph 1 Arm B (MDS) Dose 0 | Ph 1 Arm A (AML) Dose +1 | Ph 2 Arm A (AML) Dose +1 | Ph 1 Arm A (AML) Dose 0 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 4 Participants | 7 Participants | 3 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 5 Participants | 3 Participants | 0 Participants | 9 Participants |
| Age, Continuous | 70 years | 65 years | 73 years | 72 years | 72 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 7 Participants | 9 Participants | 2 Participants | 20 Participants |
| Region of Enrollment United States | 2 participants | 9 participants | 10 participants | 3 participants | 24 participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 6 Participants | 0 Participants | 9 Participants |
| Sex: Female, Male Male | 2 Participants | 6 Participants | 4 Participants | 3 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 2 | 1 / 9 | 0 / 0 | 2 / 10 | 0 / 0 |
| other Total, other adverse events | 1 / 3 | 1 / 2 | 5 / 9 | 0 / 0 | 4 / 10 | 0 / 0 |
| serious Total, serious adverse events | 3 / 3 | 2 / 2 | 5 / 9 | 0 / 0 | 7 / 10 | 0 / 0 |
Outcome results
Primary
Number of Participant to Achieve Complete Remission
Complete Remission for AML is defined as: Absolute neutrophil count \> 10\^3/UL, platelets . 10\^5/UL, red cell transfusion independence, absence of extramedullary disease, and bone marrow with \< 5% blasts. Complete Remission for MDS is defined as: Absolute neutrophil count \> 10\^3/UL, platelets . 10\^5/UL, hemoglobin \>11 g/dl, and bone marrow with \< 5% blasts. Peripheral dysplasia will be noted.
Time frame: At day 28, and 3 cycles.
Population: Of the 24 patients enrolled in the study, three were not evaluable for response. One participant in Ph 1 Arm A (AML) Dose 0 was not evaluable for response. Two participants in Ph 2 Arm A (AML) Dose +1 were not available for response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ph 1 Arm A (AML) Dose 0, Arm B (MDS) Dose 0, Arm A (AML) Dose +1 | Number of Participant to Achieve Complete Remission | 0 Participants |
| Ph 1 Arm B (MDS) Dose + 1 | Number of Participant to Achieve Complete Remission | 2 Participants |
| Ph 1 Arm A (AML) Dose +1 | Number of Participant to Achieve Complete Remission | 0 Participants |
| Ph 2 Arm A (AML) Dose +1 | Number of Participant to Achieve Complete Remission | 0 Participants |
Primary
Recommended Phase 2 Dose (RP2D) of Omacetaxine in Combination With Venetoclax
The RP2D will be selected at the end of the Phase 1b portion based on safety data , in Arms A and B independently. Preliminary efficacy and PK data for each dose level may also be considered as appropriate.
Time frame: Up to 30 days
Population: RP2D was only assessed in the phase 1 portion of the study. In the phase 1b portion of the MDS arm, 2 patients were treated at dose level 0 before the study was closed by the sponsor.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ph 1 Arm A (AML) Dose 0, Arm B (MDS) Dose 0, Arm A (AML) Dose +1 | Recommended Phase 2 Dose (RP2D) of Omacetaxine in Combination With Venetoclax | Omacetaxine (days 2-4) | 1.25 mg/m2 |
| Ph 1 Arm A (AML) Dose 0, Arm B (MDS) Dose 0, Arm A (AML) Dose +1 | Recommended Phase 2 Dose (RP2D) of Omacetaxine in Combination With Venetoclax | Venetoclax (days 1-14) | 400 mg/m2 |
Secondary
Duration of Response
Response date to loss of response or last follow up.
Time frame: Up to Two years, 8 months, 30 days
Population: Due to lack of efficacy during an interim analysis, the AML arm was closed. In the phase 1b portion of the MDS arm, 2 patients were treated before the study was closed by the sponsor.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ph 1 Arm A (AML) Dose 0, Arm B (MDS) Dose 0, Arm A (AML) Dose +1 | Duration of Response | NA Month |
| Ph 1 Arm B (MDS) Dose + 1 | Duration of Response | 15.0 Month |
| Ph 1 Arm A (AML) Dose +1 | Duration of Response | NA Month |
| Ph 2 Arm A (AML) Dose +1 | Duration of Response | NA Month |
Secondary
Event-free Survival (EFS)
Time from date of treatment start until the date of failure or death from any cause.
Time frame: Up to Two years, 8 months, 30 days
Population: Due to lack of efficacy during an interim analysis, the AML arm was closed. In the phase 1b portion of the MDS arm, 2 patients were treated before the study was closed by the sponsor.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ph 1 Arm A (AML) Dose 0, Arm B (MDS) Dose 0, Arm A (AML) Dose +1 | Event-free Survival (EFS) | 1.1 Months |
| Ph 1 Arm B (MDS) Dose + 1 | Event-free Survival (EFS) | 16.8 Months |
| Ph 1 Arm A (AML) Dose +1 | Event-free Survival (EFS) | 1.0 Months |
| Ph 2 Arm A (AML) Dose +1 | Event-free Survival (EFS) | 1.1 Months |
Secondary
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.
Time frame: Up to Two years, 8 months, 30 days
Population: Due to lack of efficacy during an interim analysis, the AML arm was closed. In the phase 1b portion of the MDS arm, 2 patients were treated before the study was closed by the sponsor. Survival will be presented by median survival, which is the time point at which the cumulative survival drops below 50%. If there is no median survival (not reached), it means the cumulative survival was more than 50%.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ph 1 Arm A (AML) Dose 0, Arm B (MDS) Dose 0, Arm A (AML) Dose +1 | Overall Survival (OS) | 9.4 Months |
| Ph 1 Arm B (MDS) Dose + 1 | Overall Survival (OS) | NA Months |
| Ph 1 Arm A (AML) Dose +1 | Overall Survival (OS) | 4.0 Months |
| Ph 2 Arm A (AML) Dose +1 | Overall Survival (OS) | 3.4 Months |