Phase I Clinical Study of CWP232291 in Acute Myeloid Leukemia Patients

Study Overview
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Brief Summary
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CWP232291 blocks proliferation of cancer cells via activation of caspases. Active caspase have been shown to target beta-catenin, the hallmark of canonical Wnt signaling, for degradation through caspase-directed cleavage. CWP232291 targets beta-catenin for degradation and thereby inhibits the expression of cell cycle and anti-apoptotic genes such as cyclin D1 and survivin.

Official Title
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A Phase I Clinical Study of CWP232291 in Patients With Relapsed or Refractory Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia-2, Myelodysplastic Syndrome Having Failed Hypomethylating Treatment, and High-Risk Myelofibrosis

Conditions
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Acute Myeloid Leukemia, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndrome, Myelofibrosis

Intervention / Treatment
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* Drug: CWP232291


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to understand and willing to sign an informed consent form (ICF) prior to initiation of any study-specific procedure and treatment 18 years of age 3. A pathologically confirmed diagnosis of AML or CMML-2 by World Health Organization (WHO) classification that is relapsed or refractory or for which no current therapies are anticipated to result in a durable remission, or MDS by WHO classification are RAEB-1 or RAEB-2 and that have failed at least three cycles of hypomethylating therapy, or primary (PMF), post-polycythemia vera (PPMF) or post-essential thrombocythemia (PTMF) MF by WHO classification, are high-risk category by the Dynamic International Prognostic Scoring System (DIPSS Plus), have ≥1% circulating blasts, and have failed treatment with ruxolitinib Eastern Cooperative Oncology Group (ECOG) performance score 0-2 In the absence of rapidly progressing disease, the interval from prior treatment to time of study drug administration should be at least 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents. If a patient is on hydroxyurea to control peripheral blood leukemic cell counts, the patient must have discontinued hydroxyurea for at least 24 hours before initiation of treatment with study drug. Persistent clinically significant toxicities from prior chemotherapy must not be greater than grade 1 Adequate renal function: Serum creatinine =/< 2.0mg/dL Adequate hepatic function: Total bilirubin <1.5 x upper limit of normal (ULN), unless considered due to Gilbert's syndrome Alkaline phosphatase (AP) =/< 2.5 x ULN Aspartate transaminase (AST) or alanine transaminase (ALT) ≤3 x ULN, unless considered due to organ leukemic involvement Women of child-bearing potential (i.e., women who are pre menopausal or not surgically sterile) must use acceptable contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive, or double barrier device), and must have a negative serum or urine pregnancy test within 2 weeks prior to beginning treatment on this trial. Sexually active men must also use acceptable contraceptive methods for the duration of time on study Able to adhere to the study visit schedule and other protocol requirements Exclusion Criteria: Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure (CHF), cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements Active heart disease including myocardial infarction (MI) within previous 3 months, symptomatic coronary artery disease (CAD), arrhythmias not controlled by medication, or uncontrolled CHF Active central nervous system (CNS) disease Therapy with any other standard or investigational treatment for hematologic malignancy (except hydroxyurea, as mentioned in the inclusion criteria) Therapy with anticoagulant or antithrombotic agents (including aspirin) within 7 days prior to study drug administration History of gastrointestinal (GI) hemorrhage Known positive status for human immunodeficiency virus (HIV) and/or active hepatitis B or C Pregnant or nursing women. Pregnant and nursing patients are excluded because the effects of CWP232291 on a fetus or nursing child are unknown. Patients eligible for bone marrow transplant, regardless of age Patients with FLT3 ITD positive AML or AML patients with other cytogenetic abnormalities who are eligible for trials of other targeted investigational agents from which the investigator feels there is greater benefit.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CWP232291<br> | Drug: CWP232291<br>* IV Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | If myelosuppression is DLT (Dose-Limiting Toxicity), it will be monitored up to 42 days after start of injection. | Up to 3 weeks after start of injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax as a pharmacokinetic parameter of 'CWP232291' | Peak Plasma Concentration (Cmax) of 'CWP232291' | 0, 0.25, 0.5, 1, 1.5, 2, 4, 8, 24 hours post-dose | 
| AUC as a pharmacokinetic parameter of 'CWP232291' | Area under the plasma concentration versus time curve (AUC) of 'CWP232291' | 0, 0.25, 0.5, 1, 1.5, 2, 4, 8, 24 hours post-dose | 
| Cmax as a pharmacokinetic parameter of metabolites of 'CWP232291' | Peak Plasma Concentration (Cmax) of metabolites of 'CWP232291' | 0, 0.25, 0.5, 1, 1.5, 2, 4, 8, 24 hours post-dose | 
| AUC as a pharmacokinetic parameter of metabolites of 'CWP232291' | Area under the plasma concentration versus time curve (AUC) of metabolites of 'CWP232291' | 0, 0.25, 0.5, 1, 1.5, 2, 4, 8, 24 hours post-dose |