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

NCT ID: NCT01207440

Last Updated: 2021-02-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 449 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-09-30
• Study Completion Date: 2019-01-17

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.

Conditions

Chronic Myeloid Leukemia; Ph+ Acute Lymphoblastic Leukemia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

Ponatinib tablets.

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).

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

Ponatinib tablets.

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).

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

Ponatinib tablets.

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).

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

Ponatinib tablets.

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).

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

Ponatinib tablets.

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).

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

Ponatinib tablets.

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).

Group Type: EXPERIMENTAL

Ponatinib

Intervention Type: DRUG

Ponatinib tablets.

Interventions

Ponatinib

Ponatinib tablets.

Intervention Type: DRUG

Other Intervention Names

AP24534; Iclusig

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ariad Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director Clinical Science

Role: STUDY_DIRECTOR

Takeda

Locations

Royal North Shore Hospital

St Leonards, New South Wales, Australia

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Alfred Hospital

Box Hill, Victoria, Australia

Peter MacCallum Cancer Centre

East Melbourne, Victoria, Australia

UCL Bruxelles

Brussels, , Belgium

UZ Leuven

Leuven, , Belgium

Institut Bergonie

Bordeaux, , France

Hopital Andre Mignot

Le Chesnay, , France

Hopital Claude Huriez CHRU

Lille, , France

Chu Brabois

Nancy, , France

Hopital Archet

Nice, , France

Hopital St. Louis

Paris, , France

Hopital Edouard Herriot

Pierre-Bénite, , France

Entre Hospitalier Universitaire

Poitiers, , France

Hopital de Purpan

Toulouse, , France

Charite - Universitatsmedizin Berlin,

Berlin, , Germany

Klinikum der Goethe Universitat,

Frankfurt, , Germany

Universitatsklinikum Jena

Jena, , Germany

University of Heidelberg

Mannheim, , Germany

III. Med. Klinik und Poliklinik

München, , Germany

Universita di Bologna

Bologna, , Italy

University of Modena

Modena, , Italy

University of Milano Bicocca

Monza, , Italy

University of Turin

Orbassano (TO), , Italy

University Tor Vergata

Roma, , Italy

VU University Medical Center

Amsterdam, , Netherlands

University Medical Center Groeningen

Groningen, , Netherlands

Singapore General Hospital

Singapore, , Singapore

The Catholic University of Korea, Seoul St.Mary's Hospital

Seoul, , South Korea

Hospital Clinic

Barcelona, , Spain

La Paz

Madrid, , Spain

Hospital Universitario de Salamanca

Salamanca, , Spain

Hospital Clinico of Valencia

Valencia, , Spain

Lund University

Lund, , Sweden

Karolinska Hospital

Stockholm, , Sweden

University Hospital Uppsala

Uppsala, , Sweden

Gartnavel General Hospital

Glasgow, , United Kingdom

Royal Liverpool University Hospital

Liverpool, , United Kingdom

Hammersmith Hospital

London, , United Kingdom

Royal Victoria Infirmary

Newcastle, , United Kingdom

University of Nottingham

Nottingham, , United Kingdom

Countries

Australia; Belgium; France; Germany; Italy; Netherlands; Singapore; South Korea; Spain; Sweden; United Kingdom

References

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.

Reference Type: RESULT

PMID: 29567798 (View on PubMed)

Kantarjian 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.

Reference Type: DERIVED

PMID: 36054756 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34991679 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24180494 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 22825216 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Other Identifiers

2010-020414-28

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

AP24534-10-201

Identifier Type: -

Identifier Source: org_study_id