Clinical trial NCT01398462: Phase I Clinical Study of CWP232291 in Acute Myeloid Leukemia Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Myelodysplastic Syndrome
Myelofibrosis
Lead sponsor: JW Pharmaceutical
Sponsor class: INDUSTRY
First posted: 2011-07-20
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Maximum Tolerated Dose
timeFrame: Up to 3 weeks after start of injection
Secondary outcomes:
measure: Cmax as a pharmacokinetic parameter of 'CWP232291'
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 8, 24 hours post-dose
measure: AUC as a pharmacokinetic parameter of 'CWP232291'
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 8, 24 hours post-dose
measure: Cmax as a pharmacokinetic parameter of metabolites of 'CWP232291'
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 8, 24 hours post-dose
measure: AUC as a pharmacokinetic parameter of metabolites of 'CWP232291'
timeFrame: 0, 0.25, 0.5, 1, 1.5, 2, 4, 8, 24 hours post-dose
Other outcomes:
Locations:
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
Study officials:
References:
citation: Lee JH, Faderl S, Pagel JM, Jung CW, Yoon SS, Pardanani AD, Becker PS, Lee H, Choi J, Lee K, Kim M, Cortes JE. Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome. Blood Adv. 2020 May 12;4(9):2032-2043. doi: 10.1182/bloodadvances.2019000757.