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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Myelogenous Leukemia; Hematologic Malignancies
• Intervention / Treatment: Drug: Ponatinib

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Phase 1

Expanded Access

Approved for sale to the public. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • ARIAD Investigational Site #075
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • ARIAD Investigational Site #011
  • Oregon
    • Portland, Oregon, United States, 97239
      • ARIAD Investigational Site #048
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • ARIAD Investigational Site #076
  • Texas
    • Houston, Texas, United States, 70030
      • ARIAD Investigational Site #005

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ponatnib; Comparison of different dosages of ponatinib given orally once per day.	Drug: Ponatinib; Comparison of different dosages of drug given orally once per day.; Other Names: Iclusig; AP24534

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Ariad Pharmaceuticals

Publications and helpful links

General Publications

• Hanley MJ, Diderichsen PM, Narasimhan N, Srivastava S, Gupta N, Venkatakrishnan K. Population Pharmacokinetics of Ponatinib in Healthy Adult Volunteers and Patients With Hematologic Malignancies and Model-Informed Dose Selection for Pediatric Development. J Clin Pharmacol. 2022 Apr;62(4):555-567. doi: 10.1002/jcph.1990. Epub 2021 Dec 16.
• Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O'Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88. doi: 10.1056/NEJMoa1205127.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2008
• Primary Completion (Actual): May 1, 2016
• Study Completion (Actual): May 1, 2016

Study Registration Dates

• First Submitted: April 15, 2008
• First Submitted That Met QC Criteria: April 16, 2008
• First Posted (Estimate): April 17, 2008

Study Record Updates

• Last Update Posted (Actual): May 16, 2018
• Last Update Submitted That Met QC Criteria: May 15, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Neoplasms; Hematologic Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Ponatinib
• Other Study ID Numbers: AP24534-07-101