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

Phase 2

• Conditions: Chronic Myeloid Leukemia; Chronic Phase; Adults
• Interventions: Drug: Ponatinib

• Registration Number: NCT02398825
• Lead Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto

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.

Study Timeline

• Study First Submitted: 2015-03-15
• Study First Submitted QC: 2015-03-20
• Study First Posted: 2015-03-26
• Study Start: 2016-06-23
• Primary Completion: 2021-02-23
• Status Verified: 2021-08
• Last Update Submitted: 2022-01-04
• Last Update Posted: 2022-01-05
• Study Completion: 2023-02

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 16

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ponatinib	Ponatinib	-

Primary Outcome Measures

Name	Time	Method
Number of patients with major cytogenetic response	After 52 weeks of ponatinib treatment start	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: 1. Major Cytogenetic Response if Ph pos metaphases \< 35%; 2. Complete (CCyR) if Ph pos metaphases 0 or FISH BCR-ABL1 nuclei minor or equal to 1%; 3. Partial (PCyR) if Ph pos metaphases 1-34%; 4. Minor (mCyR) if Ph pos metaphases 35-65%; 5. 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

Name	Time	Method
Number of Cardiovascular Adverse Events (AEs)	After three years from ponatinib treatment start
Number of blood hypertension AEs	After three years from ponatinib treatment start
Number of pancreatitis AEs	After three years from ponatinib treatment start
Number of patients achieving Complete Cytogenetic Response (CCyR)	After 52 weeks of ponatinib treatment start
Number of patients achieving major molecular response	After 52 weeks of ponatinib treatment start
Number of patients with failure-free survival	At 36 months from ponatinib treatment start
Number of patients with progression-free survival	At 36 months from ponatinib treatment start
Number of patients in overal survival	At 36 months from ponatinib treatment start
Number of patients in event-free survival	At 36 months from ponatinib treatment start
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

Trial Locations

Locations (37)

Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi; 🇮🇹 Bologna, Italy

Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi; 🇮🇹 Ancona, Italy

Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"; 🇮🇹 Catania, Italy

Ao Brotzu, Presidio Ospedaliero A. Businco - Sc Ematologia E Ctmo; 🇮🇹 Cagliari, Italy

Aso S. Croce E Carle - Cuneo - Sc Ematologia; 🇮🇹 Cuneo, Italy

Ausl Della Romagna, Ospedale "Santa Maria Delle Croci" - Ravenna - Ematologia; 🇮🇹 Ravenna, Italy

Aou Policlinico "G. Martino" - Messina - Uoc Ematologia; 🇮🇹 Messina, Italy

Ao Ospedali Riuniti Villa Sofia Cervello - Palermo - Uo Ematologia Con Utmo; 🇮🇹 Palermo, Italy

Milano Unità Trapianto di Midollo Ist. Nazionale Tumori; 🇮🇹 Milano, Italy

Aou Arcispedale Sant'Anna - Cona (Fe) - Uoc Ematologia E Fisiopatologia Della Coagulazione; 🇮🇹 Cona, 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

Asl Pescara, Presidio Ospedaliero 'Spirito Santo' - Uoc Ematologia Clinica; 🇮🇹 Pescara, Italy

Aou Pisana - Uo Ematologia Universitaria; 🇮🇹 Pisa, Italy

Aou Integrata Di Verona, Policlinico G.B. Rossi - Uoc Ematologia; 🇮🇹 Verona, Italy

Aos Ss. Antonio E Biagio E C. Arrigo - Soc Ematologia; 🇮🇹 Alessandria, Italy

Asst Degli Spedali Civili Di Brescia - Uo Ematologia; 🇮🇹 Brescia, Italy

Ctc U.O Di Ematologia Con Trapianto Di Midollo Osseo; 🇮🇹 Catania, Italy

Ao Di Catanzaro "Pugliese-Ciaccio", Presidio Ospedaliero "Ciaccio - de Lellis" - Ematologia; 🇮🇹 Catanzaro, 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 Federico Ii - Napoli - Uoc Ematologia; 🇮🇹 Napoli, Italy

Ao Di Rilievo Nazionale Antonio Cardarelli - Napoli - Uoc Ematologia Con Trapianto Di Midollo; 🇮🇹 Napoli, Italy

Aou San Luigi Gonzaga - Orbassano - Scdu Ematologia Generale E Oncoematologia; 🇮🇹 Orbassano, Italy

Aou Policlinico P. Giaccone - Palermo - Uo Ematologia; 🇮🇹 Palermo, Italy

Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto; 🇮🇹 Piacenza, Italy

Fondazione Ircss Policlinico San Matteo - Pavia - Uo Ematologia; 🇮🇹 Pavia, 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

Ente Ecclesiastico Casa Sollievo Della Sofferenza - San Giovanni Rotondo - Ematologia; 🇮🇹 San Giovanni Rotondo, Italy

Roma Uoc Pronto Soccorso E Accettazione Ematologica - Dipartimento Biotecnologie Cellulari Ed Ematologia - Università Degli Studi Di Roma "Sapienza"; 🇮🇹 Roma, Italy

Aou Senese - Uoc Ematologia E Trapianti; 🇮🇹 Siena, Italy

Unità Operativa Di Ematologia - Presidio Ospedaliero Di Treviso - Azienda Ulss N.2 Marca Trevigiana; 🇮🇹 Treviso, Italy

Ao S. Maria - Terni - Sc Onco Ematologia; 🇮🇹 Terni, Italy

Aulss 8 Berica - Ospedale Di Vicenza - Uoc Ematologia; 🇮🇹 Vicenza, Italy