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.
Refractory to at least 1 cycle of prior therapy
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 was diagnosed with acute promyelocytic leukemia (APL).
Study participant has known BCR-ABL-positive leukemia.
Study participant has an active malignancy other than AML, MDS-IB2, or CMML.
Study participant has persistent non-hematological toxicities of ≥ Grade 2 (CTCAE v4.03), with symptoms and objective findings, from prior AML, MDS-IB2, or CMML treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery)
Sequential
Tuspetinib
DrugDaily (QD), continuous dosing
Venetoclax Oral Tablet
DrugVenetoclax will be given to study participants in the Part C tuspetinib plus venetoclax combination treatment group either in 50 mg or 100 mg tablets
Azacitidine for Intravenous Infusion
DrugAzacitidine will be given to study participants in Part D as intravenous infusion at a dose of 75 mg/m\^2
Frequency and severity of drug-related adverse events
Maximum tolerated dose (MTD) of tuspetinib
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)
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)
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.
Complete remission (CR)
Complete remission (CR) will be summarized using descriptive statistics.
Complete remission with partial hematologic recovery (CRh)
Complete remission with partial hematologic recovery (CRh) will be summarized using descriptive statistics.
Complete remission with incomplete platelet recovery (CRp)
Complete remission with incomplete platelet recovery (CRp) will be summarized using descriptive statistics.
Complete remission with incomplete hematologic recovery (CRi)
Complete remission with incomplete hematologic recovery (CRi) will be summarized using descriptive statistics.
Percent inhibition of phosphorylation of targeted proteins
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
Mutation status of genes including, but limited to, FLT3, NRAS, and TP53
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