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

NCT01207440 | Completed Phase 2 Results DMC

• 2 other identifiers: AP24534-10-2012010-020414-28
• Study Type: interventional
• Target: 449
• Locations: 11 countries
• Sites: 42

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.

Conditions

Chronic Myeloid Leukemia; Ph+ Acute Lymphoblastic Leukemia

Keywords

CML; ALL; PH; ponatinib; Ph+ALL; T315I mutation; Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  Up to 6 months after initiation of study treatment

Secondary Outcomes (11)

• Percentage of CP-CML Participants With CHR

  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

  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)

  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

  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

  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)

Study Arms (7)

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).

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).

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).

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).

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).

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).

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).

Drug: Ponatinib

Interventions

Ponatinib DRUG

Ponatinib tablets.

Also known as: AP24534, Iclusig

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

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Ariad Pharmaceuticals: lead

Study Sites (42)

Royal North Shore Hospital

St Leonards, New South Wales, 2065, Australia

Location

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Alfred Hospital

Box Hill, Victoria, 3128, Australia

Location

Peter MacCallum Cancer Centre

East Melbourne, Victoria, 3002, Australia

Location

UCL Bruxelles

Brussels, 1200, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

Institut Bergonie

Bordeaux, 33076, France

Location

Hopital Andre Mignot

Le Chesnay, 78157, France

Location

Hopital Claude Huriez CHRU

Lille, 59307, France

Location

Chu Brabois

Nancy, 54551, France

Location

Hopital Archet

Nice, 6202, France

Location

Hopital St. Louis

Paris, 75010, France

Location

Hopital Edouard Herriot

Pierre-Bénite, 69495, France

Location

Entre Hospitalier Universitaire

Poitiers, 86021, France

Location

Hopital de Purpan

Toulouse, 31059, France

Location

Charite - Universitatsmedizin Berlin,

Berlin, 13353, Germany

Location

Klinikum der Goethe Universitat,

Frankfurt, 60590, Germany

Location

Universitatsklinikum Jena

Jena, 07747, Germany

Location

University of Heidelberg

Mannheim, 68169, Germany

Location

III. Med. Klinik und Poliklinik

München, 81675, Germany

Location

Universita di Bologna

Bologna, 40138, Italy

Location

University of Modena

Modena, 41124, Italy

Location

University of Milano Bicocca

Monza, 20052, Italy

Location

University of Turin

Orbassano (TO), 10043, Italy

Location

University Tor Vergata

Roma, 144, Italy

Location

VU University Medical Center

Amsterdam, 1081 HV, Netherlands

Location

University Medical Center Groeningen

Groningen, 9713 GZ, Netherlands

Location

Singapore General Hospital

Singapore, 169608, Singapore

Location

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

Seoul, 137-701, South Korea

Location

Hospital Clinic

Barcelona, 8036, Spain

Location

La Paz

Madrid, 28046, Spain

Location

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

Location

Hospital Clinico of Valencia

Valencia, 46010, Spain

Location

Lund University

Lund, 22185, Sweden

Location

Karolinska Hospital

Stockholm, 17176, Sweden

Location

University Hospital Uppsala

Uppsala, 75185, Sweden

Location

Gartnavel General Hospital

Glasgow, G12 0XB, United Kingdom

Location

Royal Liverpool University Hospital

Liverpool, L7 8XP, United Kingdom

Location

Hammersmith Hospital

London, W12 0NN, United Kingdom

Location

Royal Victoria Infirmary

Newcastle, NE2 4HH, United Kingdom

Location

University of Nottingham

Nottingham, NG5 1PB, United Kingdom

Location

Related Publications (5)

• 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.

  PMID: 29567798 RESULT

• 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.

  PMID: 36054756 DERIVED

• 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.

  PMID: 34991679 DERIVED

• 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.

  PMID: 24180494 DERIVED

• 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.

  PMID: 22825216 DERIVED

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Interventions

ponatinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director Clinical Science

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 20, 2010
• First Posted: September 23, 2010
• Study Start: September 30, 2010
• Primary Completion: December 20, 2018
• Study Completion: January 17, 2019
• Last Updated: February 2, 2021
• Results First Posted: January 29, 2020

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, 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.

Locations

DE (5); BE (2); SE (3); FR (9); KR (1); GB (5); AU (5); NL (2); IT (5); ES (4); SG (1)