A Phase 1B/2A Trial of Combination of ASTX727 With ASTX029 in Acute Myeloid Leukemia
Overview
- Phase
- Phase 1
- Intervention
- ASTX727
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 42
- Primary Endpoint
- Primary Outcome Measure
- Status
- Withdrawn
- Last Updated
- last year
Overview
Brief Summary
To find the recommended dose of the study drugs ASTX727 and ASTX029 that can be given to patients with relapsed/refractory AML. The goal of Part 2 of the study is to learn if the dose of study drugs found in Part 1B can help to control AML.
Detailed Description
Primary Objectives: To determine the safety and recommended phase 2 dose (RP2D) of ASTX727 in combination with ASTX029 in patients with relapsed/refractory AML. Secondary Objectives: * To assess the CR+CRi+PR and MLFS rate within 6 cycles of treatment initiation of ASTX727 in combination with ASTX029 in patients with relapsed refractory AML. * To determine the duration of response (DOR), event-free survival (EFS), overall survival (OS), minimal/measurable residual disease (MRD) status at response and best MRD response attained by flow-cytometry, 4- and 8-week mortality * To investigate correlations of response to these combinations with a pre- therapy, on-therapy, and progression 81-gene panel of gene mutations in AML. Exploratory Objectives: * To investigate possible relationships between response and non-response to the combinations with myeloid mutation panel. * To identify leukemic subpopulations and how their signaling state in disease relates to clinical outcomes by Flow cytometry or CyTOF (mass cytometry) on patients' bone marrow samples and/or peripheral blood baseline, on treatment, remission and relapse and potentially other time-points on study. * To store and/or analyze surplus blood or tissue including bone marrow, if available, for potential future exploratory research into factors that may influence development of AML and/or response to the combination (where response is defined broadly to include efficacy, tolerability or safety).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Phase 1B: Diagnosis of relapsed/refractory AML (excluding acute promyelocytic leukemia)
- •Phase 2A: Diagnosis of relapsed/refractory AML (excluding acute promyelocytic leukemia) with MAPK pathway mutations e.g. N or KRAS, PTPN11, NF1 etc.
- •Patients aged ≥18 years old with relapsed/refractory AML with MAPK pathway mutations e.g. N or KRAS, PTPN11, NF1 etc. are eligible if they are not eligible for potentially curative therapy such as more effective salvage therapy or hematopoietic stem cell transplantation or who refuse these options at the time of enrollment.
- •Patient must be receiving protocol therapy as salvage 1 or
- •Phase 1B: Diagnosis of relapsed/refractory AML (excluding acute promyelocytic leukemia)
- •Phase 2A: Diagnosis of relapsed/refractory AML (excluding acute promyelocytic leukemia) with MAPK pathway mutations e.g. N or KRAS, PTPN11, NF1 etc.
- •Patients aged ≥18 years old with relapsed/refractory AML with MAPK pathway mutations e.g. N or KRAS, PTPN11, NF1 etc. are eligible if they are not eligible for potentially curative therapy such as more effective salvage therapy or hematopoietic stem cell transplantation or who refuse these options at the time of enrollment.
- •Patient must be receiving protocol therapy as salvage 1 or
- •Patients aged ≥ 18 years old, with MDS or CMML treated with hypomethylating agent (HMA) therapies who progress to AML and have no available therapies or are not candidates for available therapies, will be eligible at the time of progression to AML.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2
Exclusion Criteria
- •Patients with known allergy or hypersensitivity to ASTX727(Inqovi), ASTX029 or any of their components.
- •Patients with known allergy or hypersensitivity to ASTX727(Inqovi), ASTX029 or any of their components.
- •Patients with any other known concurrent severe and/or uncontrolled medical condition including but not limited to diabetes, cardiovascular disease including hypertension, renal disease, or active uncontrolled infection, which could compromise participation in the study.
- •Patients on active antineoplastic or radiation therapy for a concurrent malignancy at the time of screening. Maintenance therapy, hormonal therapy, or steroid therapy for well-controlled malignancy is allowed.
- •Prior organ transplantation including allogenic stem-cell transplantation within 3 months prior to planned enrollment, active graft versus host disease (GVHD) \>Grade 1 or requiring transplant-related immunosuppression with the exception of low dose cyclosporine and tacrolimus.
- •Prior treatment with an ERK inhibitor.
- •History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including:
- •A) Presence of predisposing factors to RVO or CSR (eg, uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus) or b) Visible retinal pathology as assessed by ophthalmic examination at screening that is considered a risk factor for RVO or CSR such as:
- •Evidence of optic disc cupping or
- •Evidence of new visual field defects on automated perimetry or
Arms & Interventions
Part 1B
During cycle 1: Participants will take: ASTX029 tablets daily by mouth on days 1-42. ASTX727 tablets by mouth 1 time every day on Days 15-19. You should take ASTX727 and ASTX029 fasting (about 2 hours before a meal, and 2 hours after a meal). Cycles 2 and beyond: Participants will take ASTX029 tablets by mouth every day (days 1-28) fasting, (2 hours before and 2 hours after a meal). You will also take ASTX727 tablets by mouth 1 time every day on days 1-5 of each cycle, fasting (2 hours before and 2 hours after a meal).
Intervention: ASTX727
Part 1B
During cycle 1: Participants will take: ASTX029 tablets daily by mouth on days 1-42. ASTX727 tablets by mouth 1 time every day on Days 15-19. You should take ASTX727 and ASTX029 fasting (about 2 hours before a meal, and 2 hours after a meal). Cycles 2 and beyond: Participants will take ASTX029 tablets by mouth every day (days 1-28) fasting, (2 hours before and 2 hours after a meal). You will also take ASTX727 tablets by mouth 1 time every day on days 1-5 of each cycle, fasting (2 hours before and 2 hours after a meal).
Intervention: ASTX029-01
Part 2
During cycle 1: Participants will take: ASTX029 tablets daily by mouth on days 1-42. ASTX727 tablets by mouth 1 time every day on Days 15-19. You should take ASTX727 and ASTX029 fasting (about 2 hours before a meal, and 2 hours after a meal). Cycles 2 and beyond: Participants will take ASTX029 tablets by mouth every day (days 1-28) fasting, (2 hours before and 2 hours after a meal). You will also take ASTX727 tablets by mouth 1 time every day on days 1-5 of each cycle, fasting (2 hours before and 2 hours after a meal).
Intervention: ASTX727
Part 2
During cycle 1: Participants will take: ASTX029 tablets daily by mouth on days 1-42. ASTX727 tablets by mouth 1 time every day on Days 15-19. You should take ASTX727 and ASTX029 fasting (about 2 hours before a meal, and 2 hours after a meal). Cycles 2 and beyond: Participants will take ASTX029 tablets by mouth every day (days 1-28) fasting, (2 hours before and 2 hours after a meal). You will also take ASTX727 tablets by mouth 1 time every day on days 1-5 of each cycle, fasting (2 hours before and 2 hours after a meal).
Intervention: ASTX029-01
Outcomes
Primary Outcomes
Primary Outcome Measure
Time Frame: Through study completion; an average of 1 year.
Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0 \[Time Frame: through study completion; an average of 1 year.\]