This phase I trial tests the safety, side effects, and best dose of miRisten in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). MiRisten may stop the growth of cancer cells by blocking some of the molecules needed for cell growth. Giving miRisten may be safe, tolerable and/or effective in treating patients with relapsed or refractory AML.
PRIMARY OBJECTIVES: I. Evaluate the safety and tolerability of miR-126 inhibitor miRisten (miRisten) given intravenously (i.v.) twice daily. II. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). SECONDARY OBJECTIVES: I. Evaluate the anti-leukemic activity, as assessed by complete remission (complete response \[CR\]+complete response with Incomplete hematopoietic recovery \[CRi\]+CR with partial hematologic recovery \[CRh\]), overall response (overall response rate \[ORR\]: CR+CRi+CRh+partial response \[PR\]) and minimal residual disease negative (MRD-) rate and duration over the study period. II. Estimate overall survival (OS), progression-free survival (PFS) and duration of response (DOR) rate at 6 months. III. Describe the pharmacokinetics (PK) of miRisten. EXPLORATORY STUDY OBJECTIVES: I. Evaluate pharmacodynamics (PD) of miRisten therapy to identify biomarkers of clinical response and resistance. II. Estimate miR-126 level in the bone marrow and blood pre-, post-therapy. III. Evaluate the impact of miRisten on miR-126 and its targets (e.g., SPRED1, CDK3, PIK3R2) in bone marrow. IV. Estimate leukemia stem cell burden in bone marrow pre-, post-therapy. V. Monitor levels of cytokines and complement over time. VI. Dissect the mechanisms of miR-126-dependent leukemia stem cell (LSC) survival and self-renewal. VII. Estimate the anti-leukemogenic force, therapeutic work induced by miRisten using the microRNA (miRNA)-based state transition model. OUTLINE: This is a dose-escalation study. Patients receive miRisten IV over 30 minutes twice a day (BID) on days 1-5, 8-12 and 15-19 in the absence of disease progression or unacceptable toxicity. Patients also undergo echocardiography (ECHO) during screening and bone marrow and blood sample collection throughout the trial. After completion of study treatment, patients are followed up at 30 days and then at 3 and 6 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Undergo bone marrow and blood sample collection
Undergo ECHO
Given IV
City of Hope Medical Center
Duarte, California, United States
RECRUITINGIncidence of adverse events (AEs)
Toxicity data collection will include incidence and nature of adverse events (AEs) (including grade 3 and 4 AEs, treatment-related AEs, serious adverse events, dose limiting and moderate toxicities, AEs requiring discontinuation of miRisten, and changes in laboratory values.
Time frame: Up to 30 days after completion of study treatment
Disease response
Will be assessed according to the European LeukemiaNet Criteria.
Time frame: Up to 6 months after completion of study treatment
Duration of response
Will be estimated using the product-limit method of Kaplan and Meier.
Time frame: From the date of first documented response to documented disease relapse, progression or death whichever occurs first, assessed p to 6 months after completion of study treatment
Progression-free survival
Will be estimated using the product-limit method of Kaplan and Meier.
Time frame: From date of first dose of study drug to first documented evidence of disease progression or death from any cause, whichever occurs first, assessed up to 6 months after completion of study treatment
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