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

Chronic Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02398825
• Other study ID #: CML1315
• Secondary ID: 2015-001102-34
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 23, 2016
• Est. completion date: February 2023

Study information

• Verified date: August 2021
• Source: Gruppo Italiano Malattie EMatologiche dell'Adulto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 16
• Est. completion date: February 2023
• Est. primary completion date: February 23, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Adults
• Chronic Myeloid Leukemia
• Chronic Phase
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Drug:
• Ponatinib
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.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Gruppo Italiano Malattie EMatologiche dell'Adulto

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	After 52 weeks of ponatinib treatment start
Secondary	Number of Cardiovascular Adverse Events (AEs)		After three years from ponatinib treatment start
Secondary	Number of blood hypertension AEs		After three years from ponatinib treatment start
Secondary	Number of pancreatitis AEs		After three years from ponatinib treatment start
Secondary	Number of patients achieving Complete Cytogenetic Response (CCyR)		After 52 weeks of ponatinib treatment start
Secondary	Number of patients achieving major molecular response		After 52 weeks of ponatinib treatment start
Secondary	Number of patients with failure-free survival		At 36 months from ponatinib treatment start
Secondary	Number of patients with progression-free survival		At 36 months from ponatinib treatment start
Secondary	Number of patients in overal survival		At 36 months from ponatinib treatment start
Secondary	Number of patients in event-free survival		At 36 months from ponatinib treatment start
Secondary	Quality of Life patterns over time with the EORTC QLQ-C30 and the EORTC QLQ-CML24 questionnaires		At baseline and at at weeks 4, 12, 24, 36 and 52

External Links

•   GIMEMA Foundation