Safety Study of AP24534 to Treat Chronic Myelogenous Leukemia (CML) and Other Hematological Malignancies

Study Overview
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Brief Summary
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The purpose of this study is to determine the maximum tolerated dose or a recommended dose of oral AP24534 in a defined schedule in patients with refractory or advanced chronic myelogenous leukemia and other refractory hematologic malignancies.

Official Title
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A Phase 1 Dose Escalation Trial to Determine the Safety, Tolerability and Maximum Tolerated Dose of Oral AP24534 in Patients With Refractory or Advanced Chronic Myelogenous Leukemia and Other Hematologic Malignancies

Conditions
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Chronic Myelogenous Leukemia, Hematologic Malignancies

Intervention / Treatment
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* Drug: Ponatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female ≥ 18 years old Diagnosed hematologic malignancy (other than lymphoma) that has relapsed or is refractory to standard care or for which no standard care is available or acceptable Able to give written informed consent ECOG performance status ≤ 2 BSA ≥ 1.5 m² (first cohort only) Minimum life expectancy of 3 months or more Adequate renal function defined as serum creatinine <1.5× upper limit of normal (ULN) for institution Adequate hepatic function (defined as: Total bilirubin <1.5 × ULN for institution; ALT and AST <2.5 × ULN for institution [<5 X ULN if liver involvement with leukemia]; Prothrombin time <1.5 × ULN) Ability to comply with study procedures in the Investigator's opinion Adequate cardiac function defined as ejection fraction (EF) >40% by any method of the investigator's choice Normal QTcF interval on screening ECG evaluation, defined as QTcF of <450 ms. For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment Female patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners throughout participation in this study Exclusion Criteria: Have had cytotoxic chemotherapy or radiotherapy within 21 days prior to entering the study, or those who have not recovered from adverse events due to agents administered more than 28 days earlier with the exception of alopecia Received any other investigational agents or have received an investigational agent within 14 days of starting ponatinib Malabsorption syndrome or other illness which could affect oral absorption Significant uncontrolled cardiac disease Patients taking medicinal products that are known to be associated with prolongation of the QT interval on the electrocardiogram. Uncontrolled hypertension (Diastolic BP >100 mmHg; Systolic >150 mmHg) Uncontrolled intercurrent illness Pregnant Known infection with HIV Autologous or allogeneic stem cell transplant < 3 months prior to enrollment; any evidence of ongoing graft versus host disease (GVHD), or GVHD requiring immunosuppressive therapy Another primary malignancy within the past 3 years Any condition or illness which, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the safety of the drug Patients taking medicinal products that are known to be associated with prolongation of the QT interval on the electrocardiogram Major surgery (with the exception of intravenous catheter placement or bone marrow biopsy) within 14 days prior to initiating ponatinib therapy

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: ponatnib<br>Comparison of different dosages of ponatinib given orally once per day. | Drug: Ponatinib<br>* Comparison of different dosages of drug given orally once per day.<br>* Other names: Iclusig;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine Maximum Tolerated Dose (MTD) or Recommended dose | Determine MTD dose or a recommended dose of oral ponatinib in a defined schedule (QD) in patients with refractory or advanced chronic myelogenous leukemia and other refractory hematologic malignancies. | Up to | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To examine the safety of AP24534 in patients with resistant/refractory hematologic malignancies |  | Up to 7 years | 
| To describe the anti-tumor activity of AP24534 in patients with refractory hematologic malignancies |  | Up to 7 years | 
| To examine the pharmacokinetics of AP24534 |  | Up to 2 cycles (1 cycle = 28 days) | 
| To examine pharmacodynamic activity of AP24534 in CML and Ph + ALL patients |  | Up to 7 years | 
| To describe potential pharmacogenomic markers of AP24534 anti-tumor activity |  | Up to 7 years |