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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01207440
Recruitment Status : Completed
First Posted : September 23, 2010
Results First Posted : January 29, 2020
Last Update Posted : January 29, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda ( Ariad Pharmaceuticals )

Brief Summary:
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 philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who either are resistant or intolerant to either dasatinib or nilotinib, or have the (T)hreonine-315-(I)soleucine (T315I) mutation.

Condition or disease Intervention/treatment Phase
Chronic Myeloid Leukemia Ph+ Acute Lymphoblastic Leukemia Drug: Ponatinib Phase 2

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. The study enrolled 449 patients. Participants assigned to 1 of 6 cohorts in accordance with disease group and received:

  • Ponatinib 45 mg

This multi-center trial is conducted worldwide. The overall time to participate in this study is 96 months after last dose of study drug treatment.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 449 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (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
Actual Study Start Date : September 30, 2010
Actual Primary Completion Date : December 20, 2018
Actual Study Completion Date : January 17, 2019


Arm Intervention/treatment
Experimental: Cohort A: CP-CML R-I
CP-CML participants R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Drug: Ponatinib
Ponatinib tablets.
Other Names:
  • AP24534
  • Iclusig

Experimental: Cohort B: CP-CML with T315I Mutation
CP-CML participants who had T315I mutation of breakpoint cluster region-Abelson complex (BCR-ABL) were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Drug: Ponatinib
Ponatinib tablets.
Other Names:
  • AP24534
  • Iclusig

Experimental: Cohort C: Accelerated Phase (AP)-CML R-I
AP-CML R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Drug: Ponatinib
Ponatinib tablets.
Other Names:
  • AP24534
  • Iclusig

Experimental: Cohort D: AP-CML with T315I Mutation
AP-CML participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Drug: Ponatinib
Ponatinib tablets.
Other Names:
  • AP24534
  • Iclusig

Experimental: Cohort E: Blast Phase (BP)-CML/Ph+ ALL R-I
BP-CML or Ph+ ALL R-I to dasatinib or nilotinib or Ph+ ALL R-I to dasatinib or nilotinib were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Drug: Ponatinib
Ponatinib tablets.
Other Names:
  • AP24534
  • Iclusig

Experimental: Cohort F: BP-CML or Ph+ ALL with T315I Mutation
BP-CML or Ph+ ALL participants who had T315I mutation of BCR-ABL were administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Drug: Ponatinib
Ponatinib tablets.
Other Names:
  • AP24534
  • Iclusig

Experimental: Unassigned to Cohorts A-F
Participants who were not assigned to any of the cohorts and have no T315I mutation at study entry and were not R-I to dasatinib or nilotinib, administered ponatinib 45 mg, tablet, orally, once daily until disease progression or development of intolerance or if they met one or more of the protocol defined criteria for discontinuation (Up to approximately 48 months).
Drug: Ponatinib
Ponatinib tablets.
Other Names:
  • AP24534
  • Iclusig




Primary Outcome Measures :
  1. Percentage of CP-CML Participants With Major Cytogenetic Response (MCyR) [ Time Frame: Up to 12 months after initiation of study treatment ]
    MCyR is defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells.

  2. Percentage of AP-CML Participants With Major Hematologic Response (MaHR) [ Time Frame: Up to 6 months after initiation of study treatment ]
    MaHR is defined as percentage of participants with complete hematologic response (CHR) or no evidence of leukemia (NEL). Response criteria for CHR is reported as white blood cells (WBC)≤institutional upper limit of normal, absolute neutrophil count (ANC)≥1000/mm^3, platelets≥100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3≤platelets<100,000/mm^3; (ii) 500/mm^3≤ANC<1000/mm^3.

  3. Percentage of BP-CML/Ph+ ALL Participants With MaHR [ Time Frame: Up to 6 months after initiation of study treatment ]
    MaHR is defined as percentage of participants with CHR or NEL. Response criteria for CHR is reported as WBC≤institutional upper limit of normal, ANC≥1000/mm^3, platelets ≥100,000/mm^3, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement; Response criteria for NEL is reported as WBC≤ institutional upper limit of normal, no blasts or promyelocytes in peripheral blood, BM blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement, at least 1 of the following: (i) 20,000/mm^3 ≤platelets<100,000/mm^3; (ii) 500/mm^3≤ANC<1000/mm^3.


Secondary Outcome Measures :
  1. Percentage of CP-CML Participants With CHR [ Time Frame: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
    Response criteria for CHR is reported as WBC≤institutional upper limit of normal, platelets<450,000/mm^3, no blasts or promyelocytes in peripheral blood, <5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood <5%, no extramedullary involvement (including no hepatomegaly or splenomegaly).

  2. Percentage of CP-CML Participants With Confirmed MCyR [ Time Frame: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
    Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart. For CP participants entering the trial in PCyR, confirmed MCyR is defined as 2 assessments of CCyR at least 28 days apart.

  3. Percentage of CP-CML Participants With Major Molecular Response (MMR) [ Time Frame: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
    MMR is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).

  4. Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MCyR [ Time Frame: Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
    MCyR is defined as percentage of participants with CCyR or PCyR. Cytogenetic response is the percentage of Ph+ metaphases in BM. Response is further defined as MCyR: CCyR or PCyR, where CCyR: no Ph+ cells; PCyR: 1 to 35% Ph+ cells.

  5. Percentage of AP-CML or BP-CML/Ph+ ALL Participants With Confirmed MCyR [ Time Frame: Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
    Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart.

  6. Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MMR [ Time Frame: Every 2 cycles up to 26 cycles, followed by every 3 cycles from cycles 27 through 39, and then every subsequent sixth cycle (Up to approximately 48 months after first dose) ]
    MMR is defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).

  7. Time to Response [ Time Frame: Up to approximately 48 months after first dose ]
    Time to response is defined as the interval from the first dose of study treatment until the criteria for response are first met, censored at the last assessment of response. Median time to response was estimated using the Kaplan-Meier method.

  8. Duration of Response [ Time Frame: Up to approximately 48 months after first dose ]
    Duration of Response is defined as the interval between the first assessment at which the criteria for response are met until the criteria for progression are met, censored at the last date at which the criteria for response are met. Duration of response was estimated by the Kaplan-Meier method as the probability of remaining in response.

  9. Progression-free Survival (PFS) [ Time Frame: Every 12 weeks ± 2 weeks from last dose of study drug or the investigator/participant decision to discontinue treatment, whichever occurred later (Up to approximately 96 months after last dose) ]
    PFS is defined as the interval from the first dose of study treatment until the criteria for progression or death are met, censored at the last response assessment. Progression from CP is reported as death, development of AP or BP, loss of CHR (in the absence of cytogenetic response), confirmed by development in complete blood counts (CBCs) at least 4 weeks apart, loss of MCyR, increasing WBC in participant without CHR defined by doubling of WBC to >20K on 2 occasions at least 4 weeks apart; Progression from AP is reported as death, development of confirmed BP, loss of previous major or minor hematologic response over a 2-week period, no decrease from baseline levels in percentage blasts in peripheral blood or BM on all assessments over a 4-week period; Progression from BP or Ph+ ALL is reported as death, increasing blasts in peripheral blood or BM over a 4 week period.

  10. Overall Survival (OS) [ Time Frame: From the first dose of study treatment until death (Up to 96 months post last dose) ]
    OS is defined as the interval from the first dose of study treatment until death, censored at the last date at which participant was known to be alive.

  11. Number of Participants With Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE) [ Time Frame: From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months) ]
    An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants 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) participants, 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) participants, received chemotherapy within 14 days prior to the first dose of ponatinib.
    3. For Ph+ ALL participants, 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 participants are excluded if they are in Complete cytogenetic response (CCyR)
  • Participants 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01207440


Locations
Show Show 42 study locations
Sponsors and Collaborators
Ariad Pharmaceuticals
Investigators
Layout table for investigator information
Study Director: Medical Director Clinical Science Takeda
  Study Documents (Full-Text)

Documents provided by Takeda ( Ariad Pharmaceuticals ):
Statistical Analysis Plan  [PDF] December 14, 2010
Study Protocol  [PDF] April 3, 2015

Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Ariad Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01207440    
Other Study ID Numbers: AP24534-10-201
2010-020414-28 ( EudraCT Number )
First Posted: September 23, 2010    Key Record Dates
Results First Posted: January 29, 2020
Last Update Posted: January 29, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
Keywords provided by Takeda ( Ariad Pharmaceuticals ):
CML
ALL
PH
ponatinib
Ph+ALL
T315I mutation
Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Additional relevant MeSH terms:
Layout table for 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