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

Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02398825

Collaborator

(none)

Enrollment

Locations

Arm

79.3

Anticipated Duration (Months)

0.4

Patients Per Site

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myeloid Leukemia Chronic Phase Adults	Drug: Ponatinib	Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

16 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jun 23, 2016

Actual Primary Completion Date :

Feb 23, 2021

Anticipated Study Completion Date :

Feb 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ponatinib	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.

Arm

Intervention/Treatment

Experimental: Ponatinib

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.

Outcome Measures

Primary Outcome Measures

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: 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) [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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Aos Ss. Antonio E Biagio E C. Arrigo - Soc Ematologia	Alessandria	Italy
2	Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. Lancisi - G. Salesi	Ancona	Italy
3	Azienda Ospedaliera Di Bologna Policlinico S. Orsola - Malpighi	Bologna	Italy	40138
4	Asst Degli Spedali Civili Di Brescia - Uo Ematologia	Brescia	Italy
5	Ao Brotzu, Presidio Ospedaliero A. Businco - Sc Ematologia E Ctmo	Cagliari	Italy
6	Ctc U.O Di Ematologia Con Trapianto Di Midollo Osseo	Catania	Italy
7	Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"	Catania	Italy
8	Ao Di Catanzaro "Pugliese-Ciaccio", Presidio Ospedaliero "Ciaccio - de Lellis" - Ematologia	Catanzaro	Italy
9	Aou Arcispedale Sant'Anna - Cona (Fe) - Uoc Ematologia E Fisiopatologia Della Coagulazione	Cona	Italy
10	Aso S. Croce E Carle - Cuneo - Sc Ematologia	Cuneo	Italy
11	Irccs Aou San Martino - Genova - Uo Clinica Ematologica	Genova	Italy
12	Asl Lecce, Ospedale 'V. Fazzi' - Uo Ematologia	Lecce	Italy
13	.R.S.T. Srl Irccs - Meldola - Sc Oncologia Medica	Meldola	Italy
14	Aou Policlinico "G. Martino" - Messina - Uoc Ematologia	Messina	Italy
15	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia- Padiglione Marcora 2° piano	Milano	Italy
16	Irccs Ospedale S. Raffaele - Milano - Uo Oncoematologia	Milano	Italy
17	Milano Unità Trapianto di Midollo Ist. Nazionale Tumori	Milano	Italy
18	Ao Di Rilievo Nazionale Antonio Cardarelli - Napoli - Uoc Ematologia Con Trapianto Di Midollo	Napoli	Italy
19	Aou Federico Ii - Napoli - Uoc Ematologia	Napoli	Italy
20	Aou San Luigi Gonzaga - Orbassano - Scdu Ematologia Generale E Oncoematologia	Orbassano	Italy
21	Ao Ospedali Riuniti Villa Sofia Cervello - Palermo - Uo Ematologia Con Utmo	Palermo	Italy
22	Aou Policlinico P. Giaccone - Palermo - Uo Ematologia	Palermo	Italy
23	Fondazione Ircss Policlinico San Matteo - Pavia - Uo Ematologia	Pavia	Italy
24	Asl Pescara, Presidio Ospedaliero 'Spirito Santo' - Uoc Ematologia Clinica	Pescara	Italy
25	Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto	Piacenza	Italy
26	Aou Pisana - Uo Ematologia Universitaria	Pisa	Italy
27	Ausl Della Romagna, Ospedale "Santa Maria Delle Croci" - Ravenna - Ematologia	Ravenna	Italy
28	Ausl Della Romagna, Ospedale "Infermi" - Rimini - Uo Ematologia	Rimini	Italy
29	Ao San Camillo Forlanini - Roma - Uoc Ematologia E Trapianto Cellule Staminali	Roma	Italy
30	Asl Roma 2, Ospedale S. Eugenio- Ospedale S.Eugenio - Uoc Ematologia	Roma	Italy
31	Roma Uoc Pronto Soccorso E Accettazione Ematologica - Dipartimento Biotecnologie Cellulari Ed Ematologia - Università Degli Studi Di Roma "Sapienza"	Roma	Italy
32	Ente Ecclesiastico Casa Sollievo Della Sofferenza - San Giovanni Rotondo - Ematologia	San Giovanni Rotondo	Italy
33	Aou Senese - Uoc Ematologia E Trapianti	Siena	Italy
34	Ao S. Maria - Terni - Sc Onco Ematologia	Terni	Italy
35	Unità Operativa Di Ematologia - Presidio Ospedaliero Di Treviso - Azienda Ulss N.2 Marca Trevigiana	Treviso	Italy
36	Aou Integrata Di Verona, Policlinico G.B. Rossi - Uoc Ematologia	Verona	Italy
37	Aulss 8 Berica - Ospedale Di Vicenza - Uoc Ematologia	Vicenza	Italy