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Ponatinib for Chronic Myeloid Leukemia (CML) Evaluation and Ph+ Acute Lymphoblastic Leukemia (ALL) (PACE)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Ariad Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01207440
First received: September 20, 2010
Last updated: October 28, 2016
Last verified: March 2016
  Purpose
The purpose of this study is to determine the efficacy of ponatinib in patients with chronic myeloid leukemia (CML) in chronic phase (CP), accelerated phase (AP) or blast phase (BP) or with Ph positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the T315I mutation.

Condition Intervention Phase
Chronic Myeloid Leukemia
Ph+ Acute Lymphoblastic Leukemia
Drug: Ponatinib
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients With Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia

Resource links provided by NLM:


Further study details as provided by Ariad Pharmaceuticals:

Primary Outcome Measures:
  • Major cytogenetic response (MCyR) in CP-CML patients [ Time Frame: up to 48 months after first dose ] [ Designated as safety issue: No ]
    Defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR).

  • Major hematologic response (MaHR) in AP-CML patients [ Time Frame: up to 48 months after first dose ] [ Designated as safety issue: No ]
    Consists of complete hematologic response (CHR) or no evidence of leukemia (NEL)

  • MaHR in BP-CML/Ph+ALL patients [ Time Frame: up to 48 months after first dose ] [ Designated as safety issue: No ]
    Consists of CHR or NEL


Secondary Outcome Measures:
  • Responses in CP-CML patients [ Time Frame: up to 48 months after first dose ] [ Designated as safety issue: No ]

    The composite of:

    • Hematologic responses: CHR;
    • Cytogenetic responses: confirmed MCyR; and
    • Molecular response: major molecular response (MMR).

  • Responses in AP-CML or BP-CML/Ph+ ALL patients [ Time Frame: up to 48 months after first dose ] [ Designated as safety issue: No ]

    The composite of:

    • Cytogenetic responses: CCyR, PCyR, confirmed MCyR; and
    • Molecular response: MMR.

  • Responses in all patients [ Time Frame: up to 48 months after first dose ] [ Designated as safety issue: No ]
    The composite of time to response, duration of response, progression free survival, and overall survival.

  • Safety and tolerability for all patients [ Time Frame: up to 48 months after first dose ] [ Designated as safety issue: Yes ]
    The Adverse Event (AE) incidence rates as well as the frequency of occurrence of overall toxicity, categorized by toxicity grades (severity) will be described for each cohort of the trial. Listings of laboratory test results will also be generated, and descriptive statistics summarizing the changes in laboratory tests over time will be presented.


Enrollment: 449
Study Start Date: September 2010
Estimated Study Completion Date: March 2017
Estimated Primary Completion Date: March 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: CP-CML R/I
Chronic Phase (CP) CML resistant or intolerant (R/I) to dasatinib or nilotinib
Drug: Ponatinib
45 mg dose taken orally once daily
Other Names:
  • AP24534
  • Iclusig
Experimental: AP-CML R/I
Accelerated Phase (AP) CML resistant or intolerant (R/I) to dasatinib or nilotinib
Drug: Ponatinib
45 mg dose taken orally once daily
Other Names:
  • AP24534
  • Iclusig
Experimental: Blast Phase (BP) CML / Ph+ ALL
Blast Phase (BP) CML or Ph+ ALL resistant or intolerant (R/I) to dasatinib or nilotinib or Ph+ ALL resistant or intolerant (R/I) to dasatinib or nilotinib
Drug: Ponatinib
45 mg dose taken orally once daily
Other Names:
  • AP24534
  • Iclusig
Experimental: CP-CML with T315I mutation
CP-CML patients who have the T315I mutation of BCR-ABL
Drug: Ponatinib
45 mg dose taken orally once daily
Other Names:
  • AP24534
  • Iclusig
Experimental: AP-CML with T315I mutation
AP-CML patients who have the T315I mutation of BCR-ABL
Drug: Ponatinib
45 mg dose taken orally once daily
Other Names:
  • AP24534
  • Iclusig
Experimental: BP-CML / Ph+ ALL with T315I mutation
BP-CML or Ph+ ALL patients who have the T315I mutation of BCR-ABL
Drug: Ponatinib
45 mg dose taken orally once daily
Other Names:
  • AP24534
  • Iclusig

Detailed Description:

The preliminary analysis of the phase 1 clinical trial revealed evidence of clinical antitumor activity in patients with resistance to approved second-generation tyrosine kinase inhibitors (TKI), dasatinib and nilotinib, including patients with the T315I mutation of the BCR-ABL gene (BCR-ABL). This Phase 1 study, taken together with the strong preclinical data that characterize ponatinib, provides the rationale for moving to a pivotal phase 2 trial of this agent in a population of patients with chronic myeloid leukemia (CML) and Ph+ Acute Lymphoblastic Leukemia (ALL) who are resistant or intolerant to prior TKI therapy and in those patients with the T315I mutation.

PACE is a multi-center, international, phase 2, uncontrolled, open-label trial of oral ponatinib in patients with Philadelphia chromosome-positive (Ph+) disease.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL
  • Previously treated with and developed resistance or intolerance to dasatinib or nilotinib OR developed the T3151 mutation after any tyrosine kinase inhibitor (TKI) therapy
  • ≥18 years old
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • Minimum life expectancy of ≥3 months
  • Adequate kidney function
  • Adequate liver function
  • Normal pancreatic function
  • Normal QT Fridericia-corrected interval (QTcF) ≤450 ms for males and ≤470 ms for females
  • Negative pregnancy test (if woman of childbearing potential)
  • Agree to use effective form of contraception (as applicable)
  • Ability to comply with study procedures, in the Investigator's opinion

Exclusion Criteria:

  • Received prior TKI treatment within 7 days prior to receiving the first dose of ponatinib, or have not recovered from adverse events (except alopecia) due to agents previously administered.
  • Received other therapies as follows:

    1. For CML chronic phase (CP) and accelerated phase (AP) patients, received hydroxyurea or anagrelide within 24 hours prior to receiving the first dose of ponatinib; interferon, cytarabine, or immunotherapy within 14 days prior to first dose of ponatinib; or any other cytotoxic chemotherapy, radiotherapy, or investigational therapy within 28 days prior to receiving the first dose of ponatinib.
    2. For CML blast phase (BP) patients, received chemotherapy within 14 days prior to the first dose of ponatinib.
    3. For Ph+ ALL patients, received corticosteroids within 24 hours before the first dose of ponatinib; or vincristine within 7 days prior to the first dose of ponatinib; or received other chemotherapy within 14 days prior to the first dose of ponatinib.
  • Underwent stem cell transplant <60 days prior to receiving first dose of ponatinib
  • Evidence of on-going graft versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy
  • Taking medications that are known to be associated with Torsades de Pointes
  • Require concurrent treatment with immunosuppressive agents (other than corticosteroids prescribed for a short course of therapy)
  • Previously treated with ponatinib
  • CML CP patients are excluded if they are in Complete cytogenetic response (CCyR)
  • Patients with CML AP, CML BP, or Ph+ ALL are excluded if they are in Major Hematologic Response (MaHR).
  • Have active Central Nervous System (CNS) disease
  • Have significant or active cardiovascular disease
  • Have a significant bleeding disorder unrelated to CML or Ph+ALL
  • Have a history of pancreatitis or alcohol abuse
  • Have uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL)
  • Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of ponatinib
  • Diagnosed with another primary malignancy in the past 3 years
  • Pregnant or lactating
  • Underwent major surgery within 14 days prior to first dose of ponatinib
  • Have ongoing or active infection
  • Suffer from any other condition or illness that would compromise safety or interfere with evaluation of the drug
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01207440

  Show 60 Study Locations
Sponsors and Collaborators
Ariad Pharmaceuticals
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Ariad Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01207440     History of Changes
Other Study ID Numbers: AP24534-10-201  2010-020414-28 
Study First Received: September 20, 2010
Last Updated: October 28, 2016
Health Authority: United States: Food and Drug Administration
Australia: Department of Health and Ageing Therapeutic Goods Administration
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Canada: Health Canada
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Ministry of Health
Italy: The Italian Medicines Agency
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Singapore: Health Sciences Authority
South Korea: Ministry of Food and Drug Safety
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Sweden: Medical Products Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Ariad Pharmaceuticals:
CML
ALL
PH
ponatinib
Ph+ALL
T315I mutation
Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Ponatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on December 09, 2016