Chronic Myeloid LeukemiaPhase 2PACENCT01207440
Ponatinib for Chronic Myeloid Leukemia (CML) Evaluation and Ph+ Acute Lymphoblastic Leukemia (ALL)
A Phase 2 study testing Ponatinib in people with Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia, run by Ariad Pharmaceuticals at 42 sites in 11 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Myeloid Leukemia, Ph+ Acute Lymphoblastic Leukemia
- What is being tested?
- Ponatinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 449 participants
- Where
- 42 sitesin 11 countries
- Study dates
- 30 Sep 2010to 17 Jan 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 12Show fewer
- 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
Who cannot join
- 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:
- 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.
- For CML blast phase (BP) participants, received chemotherapy within 14 days prior to the first dose of ponatinib.
- 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
Show all 23Show fewer
- 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
Trial locations and contacts
42 sites in 11 countries.
42 sites in 11 countries
France9 sites
Institut Bergonie
Bordeaux, 33076
Hopital Andre Mignot
Le Chesnay, 78157
Hopital Claude Huriez CHRU
Lille, 59307
Chu Brabois
Nancy, 54551
Hopital Archet
Nice, 6202
Hopital St. Louis
Paris, 75010
Hopital Edouard Herriot
Pierre-Bénite, 69495
Entre Hospitalier Universitaire
Poitiers, 86021
Hopital de Purpan
Toulouse, 31059
Australia5 sites
Royal Adelaide Hospital
Adelaide, South Australia, 5000
Alfred Hospital
Box Hill, Victoria, 3128
Peter MacCallum Cancer Centre
East Melbourne, Victoria, 3002
Royal North Shore Hospital
St Leonards, New South Wales, 2065
Princess Alexandra Hospital
Woolloongabba, Queensland, 4102
Germany5 sites
Charite - Universitatsmedizin Berlin,
Berlin, 13353
Klinikum der Goethe Universitat,
Frankfurt, 60590
Universitatsklinikum Jena
Jena, 07747
University of Heidelberg
Mannheim, 68169
III. Med. Klinik und Poliklinik
München, 81675
Italy5 sites
Universita di Bologna
Bologna, 40138
University of Modena
Modena, 41124
University of Milano Bicocca
Monza, 20052
University of Turin
Orbassano (TO), 10043
University Tor Vergata
Roma, 144
United Kingdom5 sites
Gartnavel General Hospital
Glasgow, G12 0XB
Royal Liverpool University Hospital
Liverpool, L7 8XP
Hammersmith Hospital
London, W12 0NN
Royal Victoria Infirmary
Newcastle, NE2 4HH
University of Nottingham
Nottingham, NG5 1PB
Spain4 sites
Hospital Clinic
Barcelona, 8036
La Paz
Madrid, 28046
Hospital Universitario de Salamanca
Salamanca, 37007
Hospital Clinico of Valencia
Valencia, 46010
Sweden3 sites
Lund University
Lund, 22185
Karolinska Hospital
Stockholm, 17176
University Hospital Uppsala
Uppsala, 75185
Netherlands2 sites
VU University Medical Center
Amsterdam, 1081 HV
University Medical Center Groeningen
Groningen, 9713 GZ
South Korea1 site
The Catholic University of Korea, Seoul St.Mary's Hospital
Seoul, 137-701
About this study
Official title: A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients With Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
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.
Read the 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.
- Being tested
- Ponatinib
- Keywords
- CML, ALL, PH, ponatinib, Ph+ALL, T315I mutation, Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
- Medical subject headings
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PonatinibDrug
Also called AP24534, Iclusig
Ponatinib tablets.
| Study group | Role | What they receive |
|---|---|---|
| Cohort A: CP-CML R-I | Experimental | 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). Receives: Drug: Ponatinib |
| Cohort B: CP-CML with T315I Mutation | Experimental | 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). Receives: Drug: Ponatinib |
| Cohort C: Accelerated Phase (AP)-CML R-I | Experimental | 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). Receives: Drug: Ponatinib |
| Cohort D: AP-CML with T315I Mutation | Experimental | 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). Receives: Drug: Ponatinib |
| Cohort E: Blast Phase (BP)-CML/Ph+ ALL R-I | Experimental | 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). Receives: Drug: Ponatinib |
| Cohort F: BP-CML or Ph+ ALL with T315I Mutation | Experimental | 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). Receives: Drug: Ponatinib |
| Unassigned to Cohorts A-F | Experimental | 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). Receives: Drug: Ponatinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of CP-CML Participants With Major Cytogenetic Response (MCyR)
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.
Measured: Up to 12 months after initiation of study treatment
Percentage of AP-CML Participants With Major Hematologic Response (MaHR)
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.
Measured: Up to 6 months after initiation of study treatment
Percentage of BP-CML/Ph+ ALL Participants With MaHR
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.
Measured: Up to 6 months after initiation of study treatment
Secondary outcomes (11)
Percentage of CP-CML Participants With CHR
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).
Measured: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)
Percentage of CP-CML Participants With Confirmed MCyR
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.
Measured: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)
Percentage of CP-CML Participants With Major Molecular Response (MMR)
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).
Measured: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)
Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MCyR
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.
Measured: 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)
Percentage of AP-CML or BP-CML/Ph+ ALL Participants With Confirmed MCyR
Confirmed MCyR is defined as 2 assessments of CCyR or PCyR at least 28 days apart.
Measured: 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)
Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MMR
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).
Measured: 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)
Time to Response
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.
Measured: Up to approximately 48 months after first dose
Duration of Response
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.
Measured: Up to approximately 48 months after first dose
Progression-free Survival (PFS)
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.
Measured: 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)
Overall Survival (OS)
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.
Measured: From the first dose of study treatment until death (Up to 96 months post last dose)
Number of Participants With Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE)
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.
Measured: From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Sep 2010 (estimated)
- Study start30 Sep 2010
- Primary completion20 Dec 2018
- Study completion17 Jan 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Chronic Myeloid LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 449 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ariad Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Director Clinical Science, Study director, Takeda
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01207440
- Sponsor's protocol ID
- AP24534-10-201
- Other IDs
- 2010-020414-28
- Acronym
- PACE
- Status last verified
- Jan 2021
- First submitted
- 20 Sep 2010
- Last updated
- 2 Feb 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Yes: 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.
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.
PubMed 29567798Kantarjian HM, Jabbour E, Deininger M, Abruzzese E, Apperley J, Cortes J, Chuah C, DeAngelo DJ, DiPersio J, Hochhaus A, Lipton J, Nicolini FE, Pinilla-Ibarz J, Rea D, Rosti G, Rousselot P, Shah NP, Talpaz M, Srivastava S, Ren X, Mauro M. Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia. Am J Hematol. 2022 Nov;97(11):1419-1426. doi: 10.1002/ajh.26686. Epub 2022 Aug 30.
PubMed 36054756Januzzi 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.
PubMed 34991679Cortes 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.
PubMed 24180494O'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.
PubMed 22825216
Study at a glance
From the registry record, last updated by the sponsor on 2 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pivotal Phase 2 Trial of Ponatinib (AP24534) in Patients With Refractory Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia
- ClinicalTrials.gov ID
- NCT01207440
- Acronym / sponsor ID
- PACE / AP24534-10-201
- Keywords
- CML, ALL, PH, ponatinib, Ph+ALL, T315I mutation, Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 449 participants (actual)
- Lead sponsor
- Ariad PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 30 Sep 2010 (actual)
- Primary completion
- 20 Dec 2018 (actual)
- Study completion
- 17 Jan 2019 (actual)
- First posted
- 23 Sep 2010 (estimated)
- Results
- Posted 29 Jan 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| Cohort A: CP-CML R-I | Experimental | Drug: PonatinibCP-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). |
| Cohort B: CP-CML with T315I Mutation | Experimental | Drug: PonatinibCP-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). |
| Cohort C: Accelerated Phase (AP)-CML R-I | Experimental | Drug: PonatinibAP-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). |
| Cohort D: AP-CML with T315I Mutation | Experimental | Drug: PonatinibAP-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). |
| Cohort E: Blast Phase (BP)-CML/Ph+ ALL R-I | Experimental | Drug: PonatinibBP-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). |
| Cohort F: BP-CML or Ph+ ALL with T315I Mutation | Experimental | Drug: PonatinibBP-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). |
| Unassigned to Cohorts A-F | Experimental | Drug: PonatinibParticipants 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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
Key exclusion criteria (23 listed)
- 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:
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PonatinibAlso: AP24534, IclusigPonatinib tablets. | Drug | Cohort A: CP-CML R-I, Cohort B: CP-CML with T315I Mutation, Cohort C: Accelerated Phase (AP)-CML R-I, Cohort D: AP-CML with T315I Mutation, Cohort E: Blast Phase (BP)-CML/Ph+ ALL R-I, Cohort F: BP-CML or Ph+ ALL with T315I Mutation, Unassigned to Cohorts A-F |
Primary outcome
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.
11 secondary outcomes
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)
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)
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)
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)
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)
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)
Time to Response
Time frame: Up to approximately 48 months after first dose
Duration of Response
Time frame: Up to approximately 48 months after first dose
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)
Overall Survival (OS)
Time frame: From the first dose of study treatment until death (Up to 96 months post last dose)
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)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Feb 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 29567798Cortes 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.
- Derived from this study: PubMed 36054756Kantarjian HM, Jabbour E, Deininger M, Abruzzese E, Apperley J, Cortes J, Chuah C, DeAngelo DJ, DiPersio J, Hochhaus A, Lipton J, Nicolini FE, Pinilla-Ibarz J, Rea D, Rosti G, Rousselot P, Shah NP, Talpaz M, Srivastava S, Ren X, Mauro M. Ponatinib after failure of second-generation tyrosine kinase inhibitor in resistant chronic-phase chronic myeloid leukemia. Am J Hematol. 2022 Nov;97(11):1419-1426. doi: 10.1002/ajh.26686. Epub 2022 Aug 30.
- Derived from this study: PubMed 34991679Januzzi 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.
- Derived from this study: PubMed 24180494Cortes 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.
- Derived from this study: PubMed 22825216O'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.
- Individual participant dataSharing planned: Yes. 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.
Related trials for Chronic Myeloid Leukemia
RecruitingPhase 1
Vididencel in CML-CP Patients With MRD
CML (Chronic Myelogenous Leukemia)
Active, not recruitingPhase 2
Clofarabine and Melphalan Before Donor Stem Cell Transplant in Treating Patients With Myelodysplasia, Acute Leukemia in Remission, or Chronic Myelomonocytic Leukemia
Adult Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
RecruitingObservational study
HPC Offered for PRESERVE Expansion
Bone Marrow Transplant (BMT)
Not yet recruitingPhase 2
Ropeginterferon Alfa-2b for the Treatment of Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap Syndromes and Chronic Myelomonocytic Leukemia
Atypical Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia
RecruitingObservational study
Collecting Blood Samples From Patients With and Without Cancer to Evaluate Tests for Early Cancer Detection
Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Director Clinical Science study director
Takeda
42 sites in 11 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ponatinib in people with Chronic Myeloid Leukemia and Ph+ Acute Lymphoblastic Leukemia, run by Ariad Pharmaceuticals at 42 sites in 11 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 42 sites in France, Australia, Germany, Italy, United Kingdom and 6 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Jan 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of CP-CML Participants With Major Cytogenetic Response (MCyR) (time frame: Up to 12 months after initiation of study treatment). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01207440, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Feb 2021.