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

• ClinicalTrials.gov Identifier: NCT01207440
• Recruitment Status: Completed
• First Posted: September 23, 2010
• Results First Posted: January 29, 2020
• Last Update Posted: February 2, 2021
• Sponsor: Ariad Pharmaceuticals
• Information provided by (Responsible Party): Takeda ( Ariad Pharmaceuticals )

Tracking Information

• First Submitted Date: September 20, 2010
• First Posted Date: September 23, 2010
• Results First Submitted Date: December 19, 2019
• Results First Posted Date: January 29, 2020
• Last Update Posted Date: February 2, 2021
• Actual Study Start Date: September 30, 2010
• Actual Primary Completion Date: December 20, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 17, 2020)

• 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.
• 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.
• 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.

Original Primary Outcome Measures (submitted: September 22, 2010)

major cytogenetic response (MCyR) [ Time Frame: up to 24 months after first dose ]

1. For CML patients in CP at study entry: major cytogenetic response (MCyR), defined as complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). CP patients in CCyR are not eligible for this study.
2. For CML patients in AP at study entry: major hematologic response (MaHR), defined as complete hematologic response (CHR) or no evidence of leukemia (NEL). AP patients in MaHR are not eligible for this study.
3. For CML patients in BP at study entry or Ph+ ALL patients: MaHR, consisting of CHR or NEL. BP and Ph+ ALL patients in MaHR are not eligible for this study.

Current Secondary Outcome Measures (submitted: January 17, 2020)

• 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).
• 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.
• 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).
• 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.
• 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.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.

Original Secondary Outcome Measures (submitted: September 22, 2010)

Hematologic responses [ Time Frame: up to 24 months after first dose ]

1. For CML patients in CP:
   1. Hematologic responses: CHR;
   2. Cytogenetic responses: confirmed MCyR; and
   3. Molecular responses: major molecular response (MMR).
2. For CML patients in AP or BP or Ph+ ALL patients:
   1. Cytogenetic responses: CCyR, PCyR, confirmed MCyR; and
   2. Molecular responses: MMR.
3. For all patients: time to response, duration of response, progression free survival, and overall survival.
4. For all patients: safety and tolerability.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ponatinib for Chronic Myeloid Leukemia (CML) Evaluation and Ph+ Acute Lymphoblastic Leukemia (ALL)
• Official Title: A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients With Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
• 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.

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Chronic Myeloid Leukemia
• Ph+ Acute Lymphoblastic Leukemia

Intervention

Drug: Ponatinib

Ponatinib tablets.

Other Names:

• AP24534
• Iclusig

Study Arms

• 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).
  Intervention: Drug: Ponatinib
• 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).
  Intervention: Drug: Ponatinib
• 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).
  Intervention: Drug: Ponatinib
• 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).
  Intervention: Drug: Ponatinib
• 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).
  Intervention: Drug: Ponatinib
• 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).
  Intervention: Drug: Ponatinib
• 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).
  Intervention: Drug: Ponatinib

Publications *

• Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Muller MC, Gambacorti-Passerini C, Lustgarten S, Rivera VM, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes TP, Shah NP, Kantarjian HM. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018 Jul 26;132(4):393-404. doi: 10.1182/blood-2016-09-739086. Epub 2018 Mar 22.
• Januzzi JL, Garasic JM, Kasner SE, McDonald V, Petrie MC, Seltzer J, Mauro M, Croce K, Berman E, Deininger M, Hochhaus A, Pinilla-Ibarz J, Nicolini F, Kim DW, DeAngelo DJ, Kantarjian H, Xu J, Hall T, Srivastava S, Naranjo D, Cortes J. Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee. J Hematol Oncol. 2022 Jan 6;15(1):1. doi: 10.1186/s13045-021-01221-z. Erratum In: J Hematol Oncol. 2022 Mar 23;15(1):33.
• Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Muller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013 Nov 7;369(19):1783-96. doi: 10.1056/NEJMoa1306494. Epub 2013 Nov 1.
• O'Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012 Jul 24;12(8):513-26. doi: 10.1038/nrc3317. Erratum In: Nat Rev Cancer. 2012 Dec;12(12):886.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 12, 2016): 449
• Original Estimated Enrollment (submitted: September 22, 2010): 350
• Actual Study Completion Date: January 17, 2019
• Actual Primary Completion Date: December 20, 2018 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, France, Germany, Italy, Korea, Republic of, Netherlands, Singapore, Spain, Sweden, United Kingdom
• Removed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT01207440
• Other Study ID Numbers: AP24534-10-201; 2010-020414-28 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://vivli.org/ourmember/takeda/

• Current Responsible Party: Takeda ( Ariad Pharmaceuticals )
• Original Responsible Party: Frank G. Haluska, M.D., Ph.D., Chief Medical Officer, VP, Clinical Research and Development, Ariad Pharmaceuticals, Inc.
• Current Study Sponsor: Ariad Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director Clinical Science; Takeda

• PRS Account: Takeda
• Verification Date: January 2021