Chronic Myelomonocytic Leukemia, Leukemia, Myeloid, Acute, Myelodysplastic Syndrome With Excess Blasts-2, Refractory AML, Relapsed Adult AML
Conditions
Keywords
Tuspetinib, Acute Myeloid Leukemia, AML, Relapsed, Refractory, Myelodysplastic Syndromes with Increased Blasts Grade 2, MDS-IB2, Chronic Myelomonocytic Leukemia, CMML, Venetoclax, Azacitidine, Newly Diagnosed
Brief summary
The main purpose of this study is to identify a safe and potentially effective dose of tuspetinib to be used in future studies in study participants diagnosed with acute myeloid leukemia (AML), myelodysplastic syndromes with increased blasts grade 2 (MDS-IB2), or chronic myelomonocytic leukemia (CMML) that is relapsed or refractory after at least one line of prior therapy, or in study participants with newly diagnosed AML. Tuspetinib will be administered as a single agent or in combination with other drugs (venetoclax or venetoclax plus azacitidine), as specified for each part of the study.
Detailed description
This is a Phase 1/2, open-label, multi-center study designed to assess the efficacy, safety, tolerability, and pharmacokinetics, including determining the recommended Phase 2 dose (RP2D) of tuspetinib (HM43239) in subjects with relapsed or treatment-refractory acute myeloid leukemia (AML). Part C: This portion of the study will evaluate tuspetinib (HM43239) as monotherapy in patients with relapsed or refractory (R/R) AML, focusing on safety, tolerability, pharmacokinetics, and preliminary efficacy (Aptivate). Part D: This portion of the study will evaluate the safety, tolerability, and PK parameters of tuspetinib (HM43239) in combination with venetoclax and azacitidine when administered to newly diagnosed AML patients who are ineligible for induction chemotherapy (Tuscany).
Interventions
DRUGTuspetinib
Daily (QD), continuous dosing
Venetoclax will be given to study participants in the Part C tuspetinib plus venetoclax combination treatment group either in 50 mg or 100 mg tablets
DRUGAzacitidine for Intravenous Infusion
Azacitidine will be given to study participants in Part D as intravenous infusion at a dose of 75 mg/m\^2
Sponsors
Aptose Biosciences Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
1. Part A: Tuspetinib dose escalation 2. Part B: Tuspetinib dose exploration 3. Part C: Tuspetinib monotherapy dose expansion 4. Part C: Tuspetinib in combination with venetoclax (doublet therapy) dose expansion 5. Part D: Tuspetinib in combination with venetoclax and azacitidine (triplet therapy) dose exploration
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for Parts A/B/C: * Study participant is defined as having morphologically documented primary or secondary AML, MDS-IB2 (≥ 10% bone marrow blasts), or CMML by the World Health Organization (WHO) criteria (2016), and fulfills one of the following: 1. Refractory to at least 1 cycle of prior therapy 2. Relapsed after achieving remission with a prior therapy * Study participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. * Study participant's interval from prior treatment to time of study drug administration is at least 2 weeks for cytotoxic agents (except hydroxyurea given for controlling blast cells), at 4 weeks for biologic or cellular immunotherapies, or least 5 half-lives for prior experimental agents or noncytotoxic agents, including immunosuppressive therapy post hematopoietic stem cell transplantation (HSCT). Upon discussion with the Medical Monitor, a shorter than stated washout period may be considered provided that the study participant has recovered from any clinically relevant safety issue and recovered to Grade ≤ 1 toxicity from prior therapies. * Study participant must meet the following criteria as indicated on the clinical laboratory tests. 1. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3× institutional upper limit normal (ULN) 2. Total serum bilirubin ≤ 1.5× institutional ULN 3. Creatinine clearance as calculated by the Cockcroft-Gault formula or measured by 24-h urine collection of \> 45 mL/min. * Study participant is suitable for oral administration of study drug and has minimum life expectancy (≥ 3 months) * Female study participants must be either: * Of non-childbearing potential 1. Post-menopausal (defined as at least 1 year without any menses) prior to screening, or 2. Documented surgically sterile or status post hysterectomy (at least 1 month prior to screening) * Or, if of childbearing potential, 1. Must have a negative serum or urine pregnancy test at screening (within 72 hours prior to start of treatment), and 2. Must use an acceptable highly effective method of birth control starting at screening and throughout the study period and for 90 days after the final study drug administration. * Female study participants must not be breastfeeding at screening and during the study period, and for 90 days after the final study drug administration * Female study participants must not donate ova starting at screening and throughout the study period, and for 90 days after the final study drug administration. * Male study participants and their female spouse/partners who are of childbearing potential must be using highly effective contraception starting at screening and continue throughout the study period and for 90 days after the final study drug administration. * Male study participants must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration. * Study participant agrees not to participate in another interventional study while on treatment.
Exclusion criteria
for Parts A/B/C: Study participants must not enter the study if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase 2 dose (RP2D) of tuspetinib | 4 years | The RP2D will be based on safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) considerations. |
| Plasma clearance (CL) | Cycle 1 (at least 28 days) | Plasma clearance (CL) will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate. |
| Frequency and severity of drug-related adverse events | 4 years | — |
| Maximum tolerated dose (MTD) of tuspetinib | 4 years | The MTD will be determined as the dose at which no more than 1 out of 6 study participants experiences a dose-limiting toxicity (DLT). Alternatively, the safety of a clinically effective dose below the MTD will be established if the MTD is not reached in study participants. |
| Maximum plasma concentration (Cmax) | Cycle 1 (at least 28 days) | Maximum plasma concentration (Cmax) will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate. |
| Minimum plasma concentration (Cmin) | Cycle 1 (at least 28 days) | Minimum plasma concentration (Cmin) will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate. |
| Area under the plasma concentration-time curve (AUC) | Cycle 1 (at least 28 days) | Area under the plasma concentration-time curve (AUC) for various timepoints will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate. |
| Time to maximum concentration (Tmax) | Cycle 1 (at least 28 days) | Time to maximum concentration (Tmax) will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate. |
| Terminal half-life (t1/2) | Cycle 1 (at least 28 days) | Terminal half-life (t1/2) will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate. |
| Volume of distribution | Cycle 1 (at least 28 days) | Volume of distribution at various timepoints will be summarized by cohort using descriptive statistics including number of study participants, mean, standard deviation, minimum, median, maximum, geometric mean, and coefficient of variation (CV) of the mean and geometric mean. Time-course of drug concentrations will be plotted as appropriate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free survival (EFS) | 4 years | Survival curves and median for time-to-event variables will be estimated using the Kaplan-Meier method and will be reported along with corresponding 95% confidence intervals. |
| Complete remission (CR) | 4 years | Complete remission (CR) will be summarized using descriptive statistics. |
| Complete remission with partial hematologic recovery (CRh) | 4 years | Complete remission with partial hematologic recovery (CRh) will be summarized using descriptive statistics. |
| Complete remission with incomplete platelet recovery (CRp) | 4 years | Complete remission with incomplete platelet recovery (CRp) will be summarized using descriptive statistics. |
| Complete remission with incomplete hematologic recovery (CRi) | 4 years | Complete remission with incomplete hematologic recovery (CRi) will be summarized using descriptive statistics. |
| Partial remission (PR) | 4 years | Partial remission (PR) will be summarized using descriptive statistics. |
| Overall response rate | 4 years | Overall response rate will be summarized using descriptive statistics. |
| Duration of response | 4 years | Survival curves and median for time-to-event variables will be estimated using the Kaplan-Meier method and will be reported along with corresponding 95% confidence intervals. |
| Disease-free survival (DFS) | 4 years | Survival curves and median for time-to-event variables will be estimated using the Kaplan-Meier method and will be reported along with corresponding 95% confidence intervals. |
| Overall survival (OS) | 4 years | Survival curves and median for time-to-event variables will be estimated using the Kaplan-Meier method and will be reported along with corresponding 95% confidence intervals. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percent inhibition of phosphorylation of targeted proteins | 4 years | Flow cytometry will be used to identify leukemic blasts and quantify levels of phosphorylated targeted proteins including FLT3 and STAT5, among others, using a plasma inhibitory activity (PIA) assay that exposes cell lines to plasma from study participants treated in the study. |
| Mutation status of genes after treatment with tuspetinib | 4 years | Mutation status of genes including, but limited to, FLT3, NRAS, and TP53 |
Countries
Australia, Germany, New Zealand, South Korea, Spain, United States
Contacts
Primary ContactRafael Bejar, MD, PhD
Outcome results
None listed