Clinical trial NCT01207440: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia
Ph+ Acute Lymphoblastic Leukemia
Keywords: CML
ALL
PH
ponatinib
Ph+ALL
T315I mutation
Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2010-09-23
Enrollment: 449
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage of CP-CML Participants With Major Cytogenetic Response (MCyR)
timeFrame: Up to 12 months after initiation of study treatment
measure: Percentage of AP-CML Participants With Major Hematologic Response (MaHR)
timeFrame: Up to 6 months after initiation of study treatment
measure: Percentage of BP-CML/Ph+ ALL Participants With MaHR
timeFrame: Up to 6 months after initiation of study treatment
Secondary outcomes:
measure: Percentage of CP-CML Participants With CHR
timeFrame: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)
measure: Percentage of CP-CML Participants With Confirmed MCyR
timeFrame: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)
measure: Percentage of CP-CML Participants With Major Molecular Response (MMR)
timeFrame: Every 3 cycles up to 39 cycles, followed by every subsequent sixth cycle (Up to approximately 48 months after first dose)
measure: Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MCyR
timeFrame: 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)
measure: Percentage of AP-CML or BP-CML/Ph+ ALL Participants With Confirmed MCyR
timeFrame: 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)
measure: Percentage of AP-CML or BP-CML/Ph+ ALL Participants With MMR
timeFrame: 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)
measure: Time to Response
timeFrame: Up to approximately 48 months after first dose
measure: Duration of Response
timeFrame: Up to approximately 48 months after first dose
measure: Progression-free Survival (PFS)
timeFrame: 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)
measure: Overall Survival (OS)
timeFrame: From the first dose of study treatment until death (Up to 96 months post last dose)
measure: Number of Participants With Treatment-Emergent Adverse Event (TEAE) and Serious AE (SAE)
timeFrame: From first dose up to 30 days after last dose of the study drug (Up to approximately 49 months)
Other outcomes:
Locations:
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Box Hill
country: Australia
facility: Alfred Hospital
state: Victoria
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Bruxelles
country: Belgium
facility: UCL Bruxelles
city: Leuven
country: Belgium
facility: UZ Leuven
city: Bordeaux
country: France
facility: Institut Bergonie
city: Le Chesnay
country: France
facility: Hopital Andre Mignot
city: Lille
country: France
facility: Hopital Claude Huriez CHRU
city: Nancy
country: France
facility: Chu Brabois
city: Nice
country: France
facility: Hopital Archet
city: Paris
country: France
facility: Hopital St. Louis
city: Pierre-Benite
country: France
facility: Hopital Edouard Herriot
city: Poitiers
country: France
facility: Entre Hospitalier Universitaire
city: Toulouse
country: France
facility: Hopital de Purpan
city: Berlin
country: Germany
facility: Charite - Universitatsmedizin Berlin,
city: Frankfurt
country: Germany
facility: Klinikum der Goethe Universitat,
city: Jena
country: Germany
facility: Universitatsklinikum Jena
city: Mannheim
country: Germany
facility: University of Heidelberg
city: Munchen
country: Germany
facility: III. Med. Klinik und Poliklinik
city: Bologna
country: Italy
facility: Universita di Bologna
city: Modena
country: Italy
facility: University of Modena
city: Monza
country: Italy
facility: University of Milano Bicocca
city: Orbassano (TO)
country: Italy
facility: University of Turin
city: Roma
country: Italy
facility: University Tor Vergata
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St.Mary's Hospital
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
city: Groningen
country: Netherlands
facility: University Medical Center Groeningen
city: Singapore
country: Singapore
facility: Singapore General Hospital
city: Barcelona
country: Spain
facility: Hospital Clinic
city: Madrid
country: Spain
facility: La Paz
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Hospital Clinico of Valencia
city: Lund
country: Sweden
facility: Lund University
city: Stockholm
country: Sweden
facility: Karolinska Hospital
city: Uppsala
country: Sweden
facility: University Hospital Uppsala
city: Glasgow
country: United Kingdom
facility: Gartnavel General Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: Newcastle
country: United Kingdom
facility: Royal Victoria Infirmary
city: Nottingham
country: United Kingdom
facility: University of Nottingham
Study officials:
affiliation: Takeda
name: Medical Director Clinical Science
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.