A Multicenter, Open, Dose Escalation and Dose Expansion Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of STI-8591 in Subjects With Advanced Acute Myeloid Leukemia (AML)
Overview
- Phase
- Phase 1
- Intervention
- STI-8591
- Conditions
- AML, Adult
- Sponsor
- Zhejiang ACEA Pharmaceutical Co. Ltd.
- Enrollment
- 84
- Locations
- 1
- Primary Endpoint
- Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This is a first-in-human, dose-escalation and dose-expansion Phase I study to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of STI-8591 in subjects with advanced AML who have signed an informed consent form (ICF) and have been screened for enrollment in this study.
- Dose escalation phase: rapid titration and conventional 3+3 test design were used to evaluate the safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and PK characteristics of STI-8591.
- Dose Expansion Phase: Evaluate the safety, preliminary efficacy and determine the recommended phase II dose (RP2D) of STI-8591 for the treatment of subjects with advanced AML under the conditions of reaching the expanded dose.
Detailed Description
Dose escalation phase:Based on the preclinical trial data and with reference to the modified Fibonacci method, the dose escalation ratios are 100%, 100%, 50% and 6.7%, and the initial 5 dose groups for STI-8591 dose escalation are 40, 80, 160, 240 and 280 mg/day, respectively. Screened subjects will be entered into the 5 dose groups in order of succession from lowest to highest dose.This test dose increment will be performed using the rapid titration method and the traditional 3+3 test design. Dose expansion phase:During dose escalation, for dose groups (except for ≥2 DLT dose groups) when the following dose signals suggesting initial efficacy are present. 1) CR, CRh or CRi in ≥1 subject in either dose group.2) Median decrease in FLT3 phosphorylation was ≥90% in ≥3 subjects in either dose group.The SRC will decide whether to initiate an extension study for that dose group and its subsequent dose groups at the same time as the dose escalation to the next dose group. Subjects in the dose escalation phase will be administered BID every 28 days in 1 cycle, with ≥8h between doses, fasting for at least 2 hours before and at least 1 hour after dosing with approximately 240mL of water (subject to adjustment based on data results from the dose escalation phase) . If initiation was determined, the dose group identified for initiation and its subsequent dose group extension studies were further enrolled in 14 to 17 cases \[a total of 20 cases in each dose group, with FLT3 mutation-positive (FLT3 internal tandem repeat (ITD) and/or FLT3 tyrosine kinase structural domain (TKD) mutation-positive subjects enrolled in at least 10 cases\] to further define the final RP2D.
Investigators
Eligibility Criteria
Inclusion Criteria
- •To be enrolled in this study, subjects must meet all of the following inclusion criteria.
- •Voluntary signing of ICF.
- •Age ≥ 18 years old.
- •Expected survival \>12 weeks.
- •Dose escalation component: Advanced primary AML or myelodysplastic neoplasm (MDS) secondary to AML or MDS/myeloproliferative neoplasm (MPN)-associated AML (AML-MR) diagnosed by 2022 WHO AML typing and with diagnostic criteria that have failed standard therapy or are intolerant of standard therapy may be considered for inclusion in this component of the study. Dose extension section: Advanced primary AML or MDS secondary to AML or AML-MR diagnosed according to the 2022 WHO AML typing and associated diagnostic criteria, who have failed or are intolerant to standard therapy, or who are unable to access standard therapy for various reasons, may only be considered for inclusion in this part of the study.
- •ECOG scores physical fitness status 0 to
- •Subjects are willing to undergo a bone marrow aspiration/biopsy as required by the protocol, which is used to assess the subject's response to treatment.
- •Laboratory test index requirements within 7 days prior to the first dose, including:
- •White blood cell count (WBC) ≤ 20 x 109 /L \[(hydroxyurea is allowed up to the first dose to stabilize the WBC count up to a maximum dose of 5 g/day. Hydroxyurea may be continued for up to 28 days after the first dose (i.e., the first dosing cycle) at the discretion of the investigator, but generally not beyond 28 days)\].
- •Alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if liver involvement is known).
Exclusion Criteria
- •To be enrolled in this study, subjects must not meet any of the following exclusion criteria.
- •Known hypersensitivity to any component of the study drug formulation.
- •Subjects were diagnosed with acute promyelocytic leukemia (APL).
- •Subjects have BCR-ABL positive leukemia (chronic myelogenous leukemia acute).
- •Subjects developed secondary AML after previous antitumor therapy for other tumors (except MDS, MDS/MPN).
- •Subjects had CNS leukemia with associated clinical symptoms.
- •Enrolled in any therapeutic clinical study within 28 days prior to the first dose and enrolled in treatment, except in the survival follow-up phase of the interventional study.
- •Received anti-tumor therapy (including chemotherapy, immunotherapy, endocrine therapy, targeted therapy, etc.) within 28 days or 5 half-lives (whichever is shorter) prior to the first dose. Received radiotherapy within 14 days prior to the first dose. Palliative radiotherapy for symptom control is allowed to be completed at least 7 days prior to the first dose. Have received herbal therapy with approved indications for antitumor use within 7 days prior to the first dose.
- •≥ Grade 2 graft-versus-host disease (GvHD), including acute, chronic or overlapping or escalating GvHD therapy within 14 days prior to first dose or being treated with systemic cortisol hormone for GvHD.
- •Received chimeric antigen receptor T-cell immunotherapy (CAR-T) within 3 months prior to the first dose.
Arms & Interventions
STI-8591 in Advanced Acute Myeloid Leukemia (AML)
Subjects with Advanced primary AML or MDS secondary to AML or AML-MR.
Intervention: STI-8591
Outcomes
Primary Outcomes
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
Time Frame: Up to 3 years.
Assessing the incidence of adverse events (AEs) using the Common Terminology Criteria for Adverse Events (CTCAE Version 5)
Secondary Outcomes
- Assessment of the AUC of STI-8591 and its major metabolites (if any).(At the end of Cycle 1 and the first day of Cycle 2 (each cycle is 30 days) .)
- Assessment of the Tmax of STI-8591 and its major metabolites (if any).(At the end of Cycle 1 and the first day of Cycle 2 (each cycle is 30 days) .)
- Assessment of the Cmax of STI-8591 and its major metabolites (if any).(At the end of Cycle 1 and the first day of Cycle 2 (each cycle is 30 days) .)
- Percentage change in FLT3 plasma inhibitory activity (PIA) relative to baseline(At the end of Cycle 1 and the first day of Cycle 2 (each cycle is 30 days) .)
- Assessing the CRc of STI-8591 in advanced AML.(Through study completion, an average of 2 years.)
- Assessing the objective remission rate ORR (CRc + PR + morphologic leukemia-free status [MLFS]) of STI-8591 in advanced AML.(Through study completion, an average of 2 years.)
- Assessing the duration of remission (DOR) of STI-8591 in advanced AML.(Through study completion, an average of 2 years.)
- Assessing the event-free survival (EFS) of STI-8591 in advanced AML.(Through study completion, an average of 2 years.)
- Assessing the progression-free survival (PFS) of STI-8591 in advanced AML.(Through study completion, an average of 2 years.)
- Assessing the leukemia-free survival (LFS) of STI-8591 in advanced AML.(Through study completion, an average of 2 years.)
- Assessing the overall survival (OS) of STI-8591 in advanced AML.(Through study completion, an average of 2 years.)
- Assessing the CR rate of STI-8591 in advanced AML.(Through study completion, an average of 2 years.)