Clinical trial NCT02398825: 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
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia
Chronic Phase
Adults
Keywords: Chronic myeloid leukemia
Chronic phase
Adults
Ponatinib
Imatinib resistant
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2015-03-26
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of patients with major cytogenetic response
timeFrame: After 52 weeks of ponatinib treatment start
Secondary outcomes:
measure: Number of Cardiovascular Adverse Events (AEs)
timeFrame: After three years from ponatinib treatment start
measure: Number of blood hypertension AEs
timeFrame: After three years from ponatinib treatment start
measure: Number of pancreatitis AEs
timeFrame: After three years from ponatinib treatment start
measure: Number of patients achieving Complete Cytogenetic Response (CCyR)
timeFrame: After 52 weeks of ponatinib treatment start
measure: Number of patients achieving major molecular response
timeFrame: After 52 weeks of ponatinib treatment start
measure: Number of patients with failure-free survival
timeFrame: At 36 months from ponatinib treatment start
measure: Number of patients with progression-free survival
timeFrame: At 36 months from ponatinib treatment start
measure: Number of patients in overal survival
timeFrame: At 36 months from ponatinib treatment start
measure: Number of patients in event-free survival
timeFrame: At 36 months from ponatinib treatment start
measure: Quality of Life patterns over time with the EORTC QLQ-C30 and the EORTC QLQ-CML24 questionnaires
timeFrame: At baseline and at at weeks 4, 12, 24, 36 and 52
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: Aos Ss. Antonio E Biagio E C. Arrigo - Soc Ematologia
city: Ancona
country: Italy
facility: Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi
city: Bologna
country: Italy
facility: Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi
city: Brescia
country: Italy
facility: Asst Degli Spedali Civili Di Brescia - Uo Ematologia
city: Cagliari
country: Italy
facility: Ao Brotzu, Presidio Ospedaliero A. Businco - Sc Ematologia E Ctmo
city: Catania
country: Italy
facility: Ctc U.O Di Ematologia Con Trapianto Di Midollo Osseo
city: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Catanzaro
country: Italy
facility: Ao Di Catanzaro "Pugliese-Ciaccio", Presidio Ospedaliero "Ciaccio - de Lellis" - Ematologia
city: Cona
country: Italy
facility: Aou Arcispedale Sant'Anna - Cona (Fe) - Uoc Ematologia E Fisiopatologia Della Coagulazione
city: Cuneo
country: Italy
facility: Aso S. Croce E Carle - Cuneo - Sc Ematologia
city: Genova
country: Italy
facility: Irccs Aou San Martino - Genova - Uo Clinica Ematologica
city: Lecce
country: Italy
facility: Asl Lecce, Ospedale 'V. Fazzi' - Uo Ematologia
city: Meldola
country: Italy
facility: .R.S.T. Srl Irccs - Meldola - Sc Oncologia Medica
city: Messina
country: Italy
facility: Aou Policlinico "G. Martino" - Messina - Uoc Ematologia
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia- Padiglione Marcora 2° piano
city: Milano
country: Italy
facility: Irccs Ospedale S. Raffaele - Milano - Uo Oncoematologia
city: Milano
country: Italy
facility: Milano Unità Trapianto di Midollo Ist. Nazionale Tumori
city: Napoli
country: Italy
facility: Ao Di Rilievo Nazionale Antonio Cardarelli - Napoli - Uoc Ematologia Con Trapianto Di Midollo
city: Napoli
country: Italy
facility: Aou Federico Ii - Napoli - Uoc Ematologia
city: Orbassano
country: Italy
facility: Aou San Luigi Gonzaga - Orbassano - Scdu Ematologia Generale E Oncoematologia
city: Palermo
country: Italy
facility: Ao Ospedali Riuniti Villa Sofia Cervello - Palermo - Uo Ematologia Con Utmo
city: Palermo
country: Italy
facility: Aou Policlinico P. Giaccone - Palermo - Uo Ematologia
city: Pavia
country: Italy
facility: Fondazione Ircss Policlinico San Matteo - Pavia - Uo Ematologia
city: Pescara
country: Italy
facility: Asl Pescara, Presidio Ospedaliero 'Spirito Santo' - Uoc Ematologia Clinica
city: Piacenza
country: Italy
facility: Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto
city: Pisa
country: Italy
facility: Aou Pisana - Uo Ematologia Universitaria
city: Ravenna
country: Italy
facility: Ausl Della Romagna, Ospedale "Santa Maria Delle Croci" - Ravenna - Ematologia
city: Rimini
country: Italy
facility: Ausl Della Romagna, Ospedale "Infermi" - Rimini - Uo Ematologia
city: Roma
country: Italy
facility: Ao San Camillo Forlanini - Roma - Uoc Ematologia E Trapianto Cellule Staminali
city: Roma
country: Italy
facility: Asl Roma 2, Ospedale S. Eugenio- Ospedale S.Eugenio - Uoc Ematologia
city: Roma
country: Italy
facility: Roma Uoc Pronto Soccorso E Accettazione Ematologica - Dipartimento Biotecnologie Cellulari Ed Ematologia - Università Degli Studi Di Roma "Sapienza"
city: San Giovanni Rotondo
country: Italy
facility: Ente Ecclesiastico Casa Sollievo Della Sofferenza - San Giovanni Rotondo - Ematologia
city: Siena
country: Italy
facility: Aou Senese - Uoc Ematologia E Trapianti
city: Terni
country: Italy
facility: Ao S. Maria - Terni - Sc Onco Ematologia
city: Treviso
country: Italy
facility: Unità Operativa Di Ematologia - Presidio Ospedaliero Di Treviso - Azienda Ulss N.2 Marca Trevigiana
city: Verona
country: Italy
facility: Aou Integrata Di Verona, Policlinico G.B. Rossi - Uoc Ematologia
city: Vicenza
country: Italy
facility: Aulss 8 Berica - Ospedale Di Vicenza - Uoc Ematologia
Study officials:
affiliation: Department of Hematology, S. Orsola-Malpighi University of Bologna
name: Fausto Castagnetti
role: STUDY_CHAIR
References: