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Cardiovascular Assessment of Ponatinib as Third Line Treatment in Chronic Phase Chronic Myeloid Leukemia (CarPAs)

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ClinicalTrials.gov Identifier: NCT04709731
Recruitment Status : Not yet recruiting
First Posted : January 14, 2021
Last Update Posted : February 3, 2021
Sponsor:
Information provided by (Responsible Party):
Associazione Italiana Pazienti Leucemia Mieloide Cronica

Study Description
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Brief Summary:
This study will address the therapeutic activity and the safety/biological profile of Ponatinib when used as third line therapy of Chronic Myeloid Leukemia in Chronic Phase after the only two TKIs known for their cardiovascular safety, i.e. Imatinib and Bosutinib.

Condition or disease Intervention/treatment Phase
Chronic Myeloid Leukemia (CML) Drug: Ponatinib 15mg QD Drug: Ponatinib 30mg QD Phase 2

Detailed Description:
Phase 2, single-arm, multicentre, open label study which aims to investigate the therapeutic activity and the cardiovascular safety profile of Ponatinib when used as third line therapy of Chronic Myeloid Leukemia in Chronic Phase, after using the only two Tyrosine Kinase Inhibitors (TKIs) known for the safest cardiovascular profile, i.e. Imatinib and Bosutinib. Patients will be stratified according to the cause of discontinuation of the second TKI: intolerance or resistance. The safety of Ponatinib will be assessed by a combination of clinical tests such as ECG, Doppler ultrasound studies to assess arterial and venous vessels, blood pressure monitoring and lipid profiles, combined with inflammatory cytokine analysis which is a known predictor of subsequent cardiovascular adverse events.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cardiovascular Assessment of Ponatinib as Third Line Treatment Option in Chronic Phase Chronic Myeloid Leukemia After Failure of Imatinib and Bosutinib (CarPAs)
Estimated Study Start Date : February 1, 2021
Estimated Primary Completion Date : October 31, 2024
Estimated Study Completion Date : April 1, 2025

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Total Patients
Intolerant Group Ponatinib 15 mg tablet, taken orally once daily (QD) Resistant Group Ponatinib 30 mg tablet, taken orally once daily (QD) The dose will be reduced to 15mg once daily (QD) as soon as a Complete Cytogenetic Response will be obtained. In those patients showing Major Molecular Response or better, the dose could be further reduced to 15MG every other day (EOD), due to the prolonged half-life of the drug.
 Drug: Ponatinib 15mg QD
Ponatinib 15 mg tablet, taken orally once daily
Other Names:
  • ICLUSIG
  • AP24534

Drug: Ponatinib 30mg QD
Ponatinib 30 mg tablet, taken orally once daily
Other Names:
  • ICLUSIG
  • AP24534


Outcome Measures
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Primary Outcome Measures :
  1. Exposure adjusted Rate of Arterial Occlusive Events and Serious Arterial Occlusive Events at 1 year after study treatment initiation of each patient [ Time Frame: 1 year ]
    Exposure adjusted Rate of Arterial Occlusive Events (AOE) and Serious AOE (SOE) at 1 year after study treatment initiation of each patient


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed and dated Informed Consent approved by Local Ethical Committee before any protocol-specific screening procedures.
  2. CML diagnosis, Chronic Phase (CP), treated with imatinib and bosutinib. Previous treatment with dasatinib or nilotinib will not be allowed.
  3. Resistant or intolerant to imatinib and/or bosutinib.
  4. Able to take oral therapy.
  5. Female or male, 18 years of age or older.
  6. ECOG performance status 0-2.
  7. Minimum life expectancy of 3 months or more.

  8. Adequate organ function as defined by the following criteria:

    • Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) or AST and ALT ≤ 5 x ULN if liver function abnormalities are due to underlying malignancy
    • Total serum bilirubin ≤ 1.5 x ULN (except patients with documented Gilbert's syndrome)
    • Creatinine ≤ 1.5 x ULN
    • Prothrombin time (PT) < 1.5 × ULN
    • Lipase ≤ 1.5 × ULN for institution
    • Amylase ≤ 1.5 × ULN for institution
  9. Normal QTcF interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
  10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
  11. Female and male patients who are of childbearing potential must agree to use an effective form of contraception (2 forms of contraception) with their partners throughout participation in this study and for at least 90 days after the last dose of treatment.
  12. For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment.

Exclusion Criteria:

  1. Current treatment on another therapeutic clinical trial.
  2. Received TKI therapy within 7 days prior to receiving the first dose of ponatinib, or have not recovered (> grade 1 by NCI CTCAE, v. 4.0) from AEs (except alopecia) due to agents previously administered.
  3. Underwent autologous or allogeneic stem cell transplant < 60 days prior to receiving the first dose of ponatinib; any evidence of on-going graft versus-host disease (GVHD), or GVHD requiring immunosuppressive therapy.
  4. Take medications that are known to be associated with Torsades de Pointes.
  5. Require concurrent treatment with immunosuppressive agents, other than corticosteroids prescribed for a short course of therapy.
  6. Have previously been treated with ponatinib.
  7. Have active central nervous system (CNS) disease as evidenced by cytology or pathology. In the absence of clinical CNS disease, lumbar puncture is not required. History itself of CNS involvement is not exclusionary if CNS has been cleared with a documented negative lumbar puncture.

  8. Have significant or active cardiovascular disease, specifically including, but not restricted to:

    1. Myocardial infarction within 3 months prior to first dose of ponatinib,
    2. History of clinically significant atrial arrhythmia or any ventricular arrhythmia,
    3. Unstable angina within 3 months prior to first dose of ponatinib,
    4. Congestive heart failure within 3 months prior to first dose of ponatinib.
  9. Have a significant bleeding disorder unrelated to CML or Ph+ ALL.
  10. Have a history of pancreatitis or alcohol abuse.
  11. Have uncontrolled hypertriglyceridemia (triglycerides > 450 mg/dL).
  12. Have malabsorption syndrome or other gastrointestinal illness that could affect absorption of orally administered ponatinib.
  13. Have been diagnosed with another primary malignancy within the past 3 years (except for non-melanoma skin cancer or cervical cancer in situ, or controlled prostate cancer, which are allowed within 3 years).
  14. Pregnancy or breastfeeding.
  15. Underwent major surgery (with the exception of minor surgical procedures, such as catheter placement or BM biopsy) within 14 days prior to first dose of ponatinib.
  16. Have ongoing or active infection (including known history of human immunodeficiency virus [HIV], hepatitis B virus [HBV], or hepatitis C virus [HCV]). Testing for these viruses is not required in the absence of history.
  17. Other severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities that would impart, in the judgment of the investigator and/or sponsor, excess risk associated with study participation or study drug administration.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04709731


Contacts
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Contact: Michaela De Palo 0283427930 michaela.depalo@galseq.com, studiclinici@galseq.com
Contact: Nicoletta Re 0258103979 aip.info@libero.it, re.nicoletta@outlook.com

Locations
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Italy
Presidio Ospedaliero "Oncologico Businco" - Cagliari (CA)
Cagliari, Italy, 09121
Contact: Giovanni Caocci, Prof.       giovanni.caocci@unica.it   
Principal Investigator: Giovanni Caocci         
AOU "Policlinico Vittorio Emanuele" - Catania (CT)
Catania, Italy, 95124
Contact: Fabio Stagno, Dr.       fsematol@tiscali.it   
Principal Investigator: Fabio Stagno         
Ospedale San Gerardo - Monza (MB)
Milano, Italy, 20090
Contact: Carlo Gambacorti, Prof.       carlo.gambacorti@unimib.it   
Principal Investigator: Carlo Gambacorti Passerini         
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Milano (MI)
Milano, Italy, 20122
Contact: Alessandra Iurlo, Dr.ssa       alessandra.iurlo@policlinico.mi.it   
Principal Investigator: Alessandra Iurlo         
Azienda Ospedaliera Universitaria "Federico II" - Napoli (NA)
Napoli, Italy, 80131
Contact: Luigia Luciano, Dr.ssa       lulucian@unina.it   
Principal Investigator: Luigia Luciano         
Fondazione IRCCS Policlinico San Matteo - Pavia (PV)
Pavia, Italy, 27100
Contact: Chiara Elena, Dr.ssa       chiara.elena1@gmail.com   
Principal Investigator: Chiara Elena         
Grande Ospedale Metropolitano "Bianchi-Melacrino-Morelli" - Reggio Calabria (RC)
Reggio Calabria, Italy, 89133
Contact: Bruno Martino, Dr.       ematologiarc@alice.it   
Principal Investigator: Bruno Martino         
AUSL Reggio Emilia (RE)
Reggio Emilia, Italy, 42122
Contact: Isabella Capodanno, Dr.ssa       capodanno.isabella@ausl.re.it   
Principal Investigator: Isabella Capodanno         
ASL Roma 2 "Ospedale S. Eugenio" - Roma (RM)
Roma, Italy, 00144
Contact: Elisabetta Abruzzese, Dr.ssa       elisabetta.abruzzese@uniroma2.it   
Principal Investigator: Elisabetta Abruzzese         
AOU Policlinico Umberto I "Università La Sapienza" - Roma (RM)
Roma, Italy, 00161
Contact: Roberto Latagliata, Dr.       latagliata@bce.uniroma1.it   
Principal Investigator: Roberto Latagliata         
Azienda Ospedaliero-Universitaria Senese - Siena (SI)
Siena, Italy, 53100
Contact: Monica Bocchia, Prof.ssa       bocchia@unisi.it   
Principal Investigator: Monica Bocchia         
AOU Città della Salute e della Scienza - Torino (TO)
Torino, Italy, 10126
Contact: Patrizia Pregno, Dr.ssa       ppregno@cittadellasalute.to.it   
Principal Investigator: Patrizia Pregno         
AOU Integrata Verona "Ospedale Borgo Roma" - Verona (VN)
Verona, Italy, 37134
Contact: Massimiliano Bonifacio, Dr.       massimiliano.bonifacio@univr.it   
Principal Investigator: Massimiliano Bonifacio         
Sponsors and Collaborators
Associazione Italiana Pazienti Leucemia Mieloide Cronica
Investigators
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Principal Investigator: Carlo Gambacorti Ospedale San Gerardo - Monza (MI)
More Information
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Responsible Party: Associazione Italiana Pazienti Leucemia Mieloide Cronica
ClinicalTrials.gov Identifier: NCT04709731    
Other Study ID Numbers: AssociazioneIPLMC
2018-001334-18 ( EudraCT Number )
First Posted: January 14, 2021    Key Record Dates
Last Update Posted: February 3, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Associazione Italiana Pazienti Leucemia Mieloide Cronica:
Chronic Myeloid Leukemia
Chronic Phase
Ponatinib
BCR-ABL Positive (BCR-ABL+)
 Philadelphia Chromosome Positive (Ph+)
Imatinib and/or Bosutinib Intolerance
Imatinib and/or Bosutinib Resistance
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid, Chronic-Phase
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
 Bone Marrow Diseases
Hematologic Diseases
Ponatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action