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Activity and Risk Profile of Ponatinib in Chronic Phase Patients With Chronic Myeloid Leukemia Resistant to Imatinib

Primary Purpose

Chronic Myeloid Leukemia, Chronic Phase, Adults

Status
Unknown status
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Ponatinib
Sponsored by
Gruppo Italiano Malattie EMatologiche dell'Adulto
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Myeloid Leukemia focused on measuring Chronic myeloid leukemia, Chronic phase, Adults, Ponatinib, Imatinib resistant

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Cytogenetic and/or molecular confirmed diagnosis of Ph+ and/or BCR-ABL1+ CML
  2. Age ≥ 18 years
  3. Chronic phase CML
  4. Prior treatment with imatinib, any dose

  5. Resistance to imatinib, as defined by any one of the ELN 2013 failure criteria, as follows:

    • no complete hematologic response (CHR) at 3 months
    • no cytogenetic response (CyR) (Ph+ > 95%) at 3 months
    • Less than partial CyR (PCyR, Ph+ > 35%) at 6 months
    • BCR-ABL1 > 10% at 6 months
    • Non complete CyR (CCyR) (Ph+ > 0%) at 12 months
    • BCR-ABL1 > 1% at 12 months
    • Loss of CHR, at any time
    • Loss of CCyR, at any time
    • Confirmed loss of major molecular response (MMR) (BCR-ABL1 bigger or equal to 0.1% in two consecutive tests, of which one bigger or equal to 1%), at any time
    • Any new BCR-ABL1 mutation, at any time
  6. For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment
  7. An effective form of contraception with their sexual partners from enrolment through 4 months after the end of treatment
  8. Signed written informed consent according to ICH/EU/GCP and national local laws prior to any study procedures
  9. Willingness and ability to comply with scheduled visits and study procedures.

Exclusion Criteria:

  1. Accelerated or blastic phase CML
  2. Patients previously treated with nilotinib or dasatinib
  3. Patients with the T315I mutation
  4. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis or of alcohol abuse
  5. Patients with history of acute myocardial infarction (AMI), unstable angina or coronary heart disease (CHD), congestive heart failure, cerebrovascular events (CVE) (stroke or transitory ischemic attack), or peripheral artery occlusive disease (PAOD)
  6. Compelled to take medications that are known to be associated with Torsades de Pointes and/or with significant QTc prolongation
  7. Pregnant or breastfeeding
  8. Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug
  9. Lack of informed consent

Sites / Locations

  • Aos Ss. Antonio E Biagio E C. Arrigo - Soc Ematologia
  • Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi
  • Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi
  • Asst Degli Spedali Civili Di Brescia - Uo Ematologia
  • Ao Brotzu, Presidio Ospedaliero A. Businco - Sc Ematologia E Ctmo
  • Ctc U.O Di Ematologia Con Trapianto Di Midollo Osseo
  • Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
  • Ao Di Catanzaro "Pugliese-Ciaccio", Presidio Ospedaliero "Ciaccio - de Lellis" - Ematologia
  • Aou Arcispedale Sant'Anna - Cona (Fe) - Uoc Ematologia E Fisiopatologia Della Coagulazione
  • Aso S. Croce E Carle - Cuneo - Sc Ematologia
  • Irccs Aou San Martino - Genova - Uo Clinica Ematologica
  • Asl Lecce, Ospedale 'V. Fazzi' - Uo Ematologia
  • .R.S.T. Srl Irccs - Meldola - Sc Oncologia Medica
  • Aou Policlinico "G. Martino" - Messina - Uoc Ematologia
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia- Padiglione Marcora 2° piano
  • Irccs Ospedale S. Raffaele - Milano - Uo Oncoematologia
  • Milano Unità Trapianto di Midollo Ist. Nazionale Tumori
  • Ao Di Rilievo Nazionale Antonio Cardarelli - Napoli - Uoc Ematologia Con Trapianto Di Midollo
  • Aou Federico Ii - Napoli - Uoc Ematologia
  • Aou San Luigi Gonzaga - Orbassano - Scdu Ematologia Generale E Oncoematologia
  • Ao Ospedali Riuniti Villa Sofia Cervello - Palermo - Uo Ematologia Con Utmo
  • Aou Policlinico P. Giaccone - Palermo - Uo Ematologia
  • Fondazione Ircss Policlinico San Matteo - Pavia - Uo Ematologia
  • Asl Pescara, Presidio Ospedaliero 'Spirito Santo' - Uoc Ematologia Clinica
  • Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto
  • Aou Pisana - Uo Ematologia Universitaria
  • Ausl Della Romagna, Ospedale "Santa Maria Delle Croci" - Ravenna - Ematologia
  • Ausl Della Romagna, Ospedale "Infermi" - Rimini - Uo Ematologia
  • Ao San Camillo Forlanini - Roma - Uoc Ematologia E Trapianto Cellule Staminali
  • Asl Roma 2, Ospedale S. Eugenio- Ospedale S.Eugenio - Uoc Ematologia
  • Roma Uoc Pronto Soccorso E Accettazione Ematologica - Dipartimento Biotecnologie Cellulari Ed Ematologia - Università Degli Studi Di Roma "Sapienza"
  • Ente Ecclesiastico Casa Sollievo Della Sofferenza - San Giovanni Rotondo - Ematologia
  • Aou Senese - Uoc Ematologia E Trapianti
  • Ao S. Maria - Terni - Sc Onco Ematologia
  • Unità Operativa Di Ematologia - Presidio Ospedaliero Di Treviso - Azienda Ulss N.2 Marca Trevigiana
  • Aou Integrata Di Verona, Policlinico G.B. Rossi - Uoc Ematologia
  • Aulss 8 Berica - Ospedale Di Vicenza - Uoc Ematologia

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ponatinib

Arm Description

Outcomes

Primary Outcome Measures

Number of patients with major cytogenetic response
Cytogenetic response (CyR) is defined based on the percentage of Ph pos metaphases, as evaluated by chromosome banding analysis (CBA) of at least 20 marrow cell metaphases: Major Cytogenetic Response if Ph pos metaphases < 35% Complete (CCyR) if Ph pos metaphases 0 or FISH BCR-ABL1 nuclei minor or equal to 1% Partial (PCyR) if Ph pos metaphases 1-34% Minor (mCyR) if Ph pos metaphases 35-65% Minimal or none (min/none CyR) if Ph pos metaphases > 65% If marrow cell metaphases cannot be obtained or analysed, interphase fluorescence-in-situ-hybridization (FISH) can be used, but only to distinguish a CCyR (minor or equal to 1% positive nuclei out of at least 200 nuclei) from a non CCyR. FISH data cannot be used to classify a response as minimal, minor, or partial.

Secondary Outcome Measures

Number of Cardiovascular Adverse Events (AEs)
Number of blood hypertension AEs
Number of pancreatitis AEs
Number of patients achieving Complete Cytogenetic Response (CCyR)
Number of patients achieving major molecular response
Number of patients with failure-free survival
Number of patients with progression-free survival
Number of patients in overal survival
Number of patients in event-free survival
Quality of Life patterns over time with the EORTC QLQ-C30 and the EORTC QLQ-CML24 questionnaires

Full Information

First Posted
March 15, 2015
Last Updated
January 4, 2022
Sponsor
Gruppo Italiano Malattie EMatologiche dell'Adulto
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1. Study Identification

Unique Protocol Identification Number
NCT02398825
Brief Title
Activity and Risk Profile of Ponatinib in Chronic Phase Patients With Chronic Myeloid Leukemia Resistant to Imatinib
Official Title
Optimizing Ponatinib USe (OPUS). A GIMEMA Phase 2 Study of the Activity and Risk Profile of Ponatinib, 30 mg Once Daily, in Chronic Myeloid Leukemia (CML) Chronic Phase (CP) Patients Resistant to Imatinib
Study Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Unknown status
Study Start Date
June 23, 2016 (Actual)
Primary Completion Date
February 23, 2021 (Actual)
Study Completion Date
February 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gruppo Italiano Malattie EMatologiche dell'Adulto

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study aims at evaluating the efficacy of treatment with ponatinib in patients with chronic myeloid leukemia who are in a chronic phase and who previously received treatment with imatinib but resulted to be resistant to it.
Detailed Description
Phase 2, single-arm, multicentre, open label. No interim analysis is planned, but a monitoring committee will evaluate the data every 6 months. Ponatinib is given orally 30 mg daily, with dose adjustment to 15 mg daily once a BCR-ABL1 level smaller or equal to 0.1% (MMR) has been achieved and confirmed in the next test, 4 weeks apart. A return to prior, 30 mg, dose is due in case of return of BCR-ABL1 transcripts level to > 1%. Dose adjustments for toxicity are detailed in the protocol. Treatment time will be 52 weeks, during which study drug will be provided free-of-charge by ARIAD Pharmaceuticals, upon approval of the protocol. Treatment is discontinued at any time in case of failure or treatment-related SAEs. After one year of treatment, upon request of the local investigator and upon confirmation of the Treatment Advisory Committee (TAC, see section 23), ARIAD Pharmaceutics, Inc. will continue to provide ponatinib for the study patients who will benefit from treatment continuation, for at least 2 years, until the drug will be approved with that indication.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Myeloid Leukemia, Chronic Phase, Adults
Keywords
Chronic myeloid leukemia, Chronic phase, Adults, Ponatinib, Imatinib resistant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
16 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ponatinib
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Ponatinib
Intervention Description
Ponatinib is given orally 30 mg daily, with dose adjustment to 15 mg daily once a BCR-ABL1 level minor or equal to 0.1% (MMR) has been achieved and confirmed in the next test, 4 weeks apart. A return to prior, 30 mg, dose is due in case of return of BCR-ABL1 transcripts level to > 1%. Dose adjustments for toxicity are detailed in the protocol.
Primary Outcome Measure Information:
Title
Number of patients with major cytogenetic response
Description
Cytogenetic response (CyR) is defined based on the percentage of Ph pos metaphases, as evaluated by chromosome banding analysis (CBA) of at least 20 marrow cell metaphases: Major Cytogenetic Response if Ph pos metaphases < 35% Complete (CCyR) if Ph pos metaphases 0 or FISH BCR-ABL1 nuclei minor or equal to 1% Partial (PCyR) if Ph pos metaphases 1-34% Minor (mCyR) if Ph pos metaphases 35-65% Minimal or none (min/none CyR) if Ph pos metaphases > 65% If marrow cell metaphases cannot be obtained or analysed, interphase fluorescence-in-situ-hybridization (FISH) can be used, but only to distinguish a CCyR (minor or equal to 1% positive nuclei out of at least 200 nuclei) from a non CCyR. FISH data cannot be used to classify a response as minimal, minor, or partial.
Time Frame
After 52 weeks of ponatinib treatment start
Secondary Outcome Measure Information:
Title
Number of Cardiovascular Adverse Events (AEs)
Time Frame
After three years from ponatinib treatment start
Title
Number of blood hypertension AEs
Time Frame
After three years from ponatinib treatment start
Title
Number of pancreatitis AEs
Time Frame
After three years from ponatinib treatment start
Title
Number of patients achieving Complete Cytogenetic Response (CCyR)
Time Frame
After 52 weeks of ponatinib treatment start
Title
Number of patients achieving major molecular response
Time Frame
After 52 weeks of ponatinib treatment start
Title
Number of patients with failure-free survival
Time Frame
At 36 months from ponatinib treatment start
Title
Number of patients with progression-free survival
Time Frame
At 36 months from ponatinib treatment start
Title
Number of patients in overal survival
Time Frame
At 36 months from ponatinib treatment start
Title
Number of patients in event-free survival
Time Frame
At 36 months from ponatinib treatment start
Title
Quality of Life patterns over time with the EORTC QLQ-C30 and the EORTC QLQ-CML24 questionnaires
Time Frame
At baseline and at at weeks 4, 12, 24, 36 and 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Cytogenetic and/or molecular confirmed diagnosis of Ph+ and/or BCR-ABL1+ CML Age ≥ 18 years Chronic phase CML Prior treatment with imatinib, any dose Resistance to imatinib, as defined by any one of the ELN 2013 failure criteria, as follows: no complete hematologic response (CHR) at 3 months no cytogenetic response (CyR) (Ph+ > 95%) at 3 months Less than partial CyR (PCyR, Ph+ > 35%) at 6 months BCR-ABL1 > 10% at 6 months Non complete CyR (CCyR) (Ph+ > 0%) at 12 months BCR-ABL1 > 1% at 12 months Loss of CHR, at any time Loss of CCyR, at any time Confirmed loss of major molecular response (MMR) (BCR-ABL1 bigger or equal to 0.1% in two consecutive tests, of which one bigger or equal to 1%), at any time Any new BCR-ABL1 mutation, at any time For females of childbearing potential, a negative pregnancy test must be documented prior to enrolment An effective form of contraception with their sexual partners from enrolment through 4 months after the end of treatment Signed written informed consent according to ICH/EU/GCP and national local laws prior to any study procedures Willingness and ability to comply with scheduled visits and study procedures. Exclusion Criteria: Accelerated or blastic phase CML Patients previously treated with nilotinib or dasatinib Patients with the T315I mutation History of acute pancreatitis within 1 year of study or history of chronic pancreatitis or of alcohol abuse Patients with history of acute myocardial infarction (AMI), unstable angina or coronary heart disease (CHD), congestive heart failure, cerebrovascular events (CVE) (stroke or transitory ischemic attack), or peripheral artery occlusive disease (PAOD) Compelled to take medications that are known to be associated with Torsades de Pointes and/or with significant QTc prolongation Pregnant or breastfeeding Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the drug Lack of informed consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fausto Castagnetti
Organizational Affiliation
Department of Hematology, S. Orsola-Malpighi University of Bologna
Official's Role
Study Chair
Facility Information:
Facility Name
Aos Ss. Antonio E Biagio E C. Arrigo - Soc Ematologia
City
Alessandria
Country
Italy
Facility Name
Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi
City
Ancona
Country
Italy
Facility Name
Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Facility Name
Asst Degli Spedali Civili Di Brescia - Uo Ematologia
City
Brescia
Country
Italy
Facility Name
Ao Brotzu, Presidio Ospedaliero A. Businco - Sc Ematologia E Ctmo
City
Cagliari
Country
Italy
Facility Name
Ctc U.O Di Ematologia Con Trapianto Di Midollo Osseo
City
Catania
Country
Italy
Facility Name
Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
City
Catania
Country
Italy
Facility Name
Ao Di Catanzaro "Pugliese-Ciaccio", Presidio Ospedaliero "Ciaccio - de Lellis" - Ematologia
City
Catanzaro
Country
Italy
Facility Name
Aou Arcispedale Sant'Anna - Cona (Fe) - Uoc Ematologia E Fisiopatologia Della Coagulazione
City
Cona
Country
Italy
Facility Name
Aso S. Croce E Carle - Cuneo - Sc Ematologia
City
Cuneo
Country
Italy
Facility Name
Irccs Aou San Martino - Genova - Uo Clinica Ematologica
City
Genova
Country
Italy
Facility Name
Asl Lecce, Ospedale 'V. Fazzi' - Uo Ematologia
City
Lecce
Country
Italy
Facility Name
.R.S.T. Srl Irccs - Meldola - Sc Oncologia Medica
City
Meldola
Country
Italy
Facility Name
Aou Policlinico "G. Martino" - Messina - Uoc Ematologia
City
Messina
Country
Italy
Facility Name
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia- Padiglione Marcora 2° piano
City
Milano
Country
Italy
Facility Name
Irccs Ospedale S. Raffaele - Milano - Uo Oncoematologia
City
Milano
Country
Italy
Facility Name
Milano Unità Trapianto di Midollo Ist. Nazionale Tumori
City
Milano
Country
Italy
Facility Name
Ao Di Rilievo Nazionale Antonio Cardarelli - Napoli - Uoc Ematologia Con Trapianto Di Midollo
City
Napoli
Country
Italy
Facility Name
Aou Federico Ii - Napoli - Uoc Ematologia
City
Napoli
Country
Italy
Facility Name
Aou San Luigi Gonzaga - Orbassano - Scdu Ematologia Generale E Oncoematologia
City
Orbassano
Country
Italy
Facility Name
Ao Ospedali Riuniti Villa Sofia Cervello - Palermo - Uo Ematologia Con Utmo
City
Palermo
Country
Italy
Facility Name
Aou Policlinico P. Giaccone - Palermo - Uo Ematologia
City
Palermo
Country
Italy
Facility Name
Fondazione Ircss Policlinico San Matteo - Pavia - Uo Ematologia
City
Pavia
Country
Italy
Facility Name
Asl Pescara, Presidio Ospedaliero 'Spirito Santo' - Uoc Ematologia Clinica
City
Pescara
Country
Italy
Facility Name
Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto
City
Piacenza
Country
Italy
Facility Name
Aou Pisana - Uo Ematologia Universitaria
City
Pisa
Country
Italy
Facility Name
Ausl Della Romagna, Ospedale "Santa Maria Delle Croci" - Ravenna - Ematologia
City
Ravenna
Country
Italy
Facility Name
Ausl Della Romagna, Ospedale "Infermi" - Rimini - Uo Ematologia
City
Rimini
Country
Italy
Facility Name
Ao San Camillo Forlanini - Roma - Uoc Ematologia E Trapianto Cellule Staminali
City
Roma
Country
Italy
Facility Name
Asl Roma 2, Ospedale S. Eugenio- Ospedale S.Eugenio - Uoc Ematologia
City
Roma
Country
Italy
Facility Name
Roma Uoc Pronto Soccorso E Accettazione Ematologica - Dipartimento Biotecnologie Cellulari Ed Ematologia - Università Degli Studi Di Roma "Sapienza"
City
Roma
Country
Italy
Facility Name
Ente Ecclesiastico Casa Sollievo Della Sofferenza - San Giovanni Rotondo - Ematologia
City
San Giovanni Rotondo
Country
Italy
Facility Name
Aou Senese - Uoc Ematologia E Trapianti
City
Siena
Country
Italy
Facility Name
Ao S. Maria - Terni - Sc Onco Ematologia
City
Terni
Country
Italy
Facility Name
Unità Operativa Di Ematologia - Presidio Ospedaliero Di Treviso - Azienda Ulss N.2 Marca Trevigiana
City
Treviso
Country
Italy
Facility Name
Aou Integrata Di Verona, Policlinico G.B. Rossi - Uoc Ematologia
City
Verona
Country
Italy
Facility Name
Aulss 8 Berica - Ospedale Di Vicenza - Uoc Ematologia
City
Vicenza
Country
Italy

12. IPD Sharing Statement

Links:
URL
http://www.gimema.it
Description
GIMEMA Foundation

Learn more about this trial

Activity and Risk Profile of Ponatinib in Chronic Phase Patients With Chronic Myeloid Leukemia Resistant to Imatinib

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