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Brief Title: Phase II Front-line Ponatinib in Adult Philadelphia+/BCR-ABL+ Acute Lymphoblastic Leukemia.
Official Title: Front-line Treatment of Philadelphia Positive/BCR-ABL Positive Acute Lymphoblastic Leukemia With Ponatinib, a New Potent Tyrosine Kinase Inhibitor.
Study ID: NCT01641107
Brief Summary: Drug resistance resulting from emergence of Imatinib-resistant BCR-ABL clones is a significant problem in Ph positive ALL patients because after a very good initial response to one TKI inhibitor, many patients relapse within one year, relapse being almost always associated with a BCR-ABL kinase domain point mutation. The patients who relapse after treatment with one TKI can be rescued to remission with another TKI, but the second remission is usually shorter than the previous one. A more potent TKI inhibitor, and pan-active not only on all the BCR-ABL variants (including the second generation TKI resistant T315I mutant), but also on others molecular targets can do better. In this context, Ponatinib is a novel synthetic orally active tyrosine kinase inhibitor (TKI), specifically developed to inhibit BCR-ABL, the fusion protein that is the product of the Philadelphia chromosome (Ph) in chronic myeloid leukemia (CML) and in a subset of acute lymphoblastic leukemia (Ph+ ALL). It potently inhibits the BCR-ABL protein as well as mutated forms of the protein that arise in patients resistant to prior therapies with TKIs. Ponatinib has been demonstrated to inhibit all the mutations that have been detected so far, in vitro and in vivo and to uniformly suppress the emerge of single-mutant clones in a mutagenesis assay. In the Phase II study, 41% of Philadelphia chromosome positive acute lymphoblastic leukemia patients treated with Ponatinib achieved major hematologic response, 47% had a major cytogenetic response, 38% obtained a complete cytogenetic response, showing that Ponatinib provides significant benefit despite previous intolerance or refractoriness to other TKIs. The Phase I trial showed that patients with a more recent diagnosis had increased rates of major molecular response: 79% for 14 patients with 0 to 5 years since diagnosis vs. 29% for 14 patients with more than 5 to 9 years since diagnosis (P=0.02) and 27% for 15 patients with more than 9 to 24 years since diagnosis (P=0.009). These characteristics support the hypothesis for a role of Ponatinib not only in patients resistant to prior TKI therapy but also in untreated ALL Ph+ patients, in order to prevent the emergence of resistant caused by the selection of mutated Ph+ clones and in order to avoid rapid progression of the disease.
Detailed Description: This is a multi-center, phase 2, single arm unblinded trial of oral Ponatinib in patients with Ph+ Acute Lymphoblastic Leukemia. Patients will receive daily oral administration of Ponatinib at a dose of 45 mg/day for 6 weeks (defined as one course) for 8 courses, same dose and schedule, for a total of 48 weeks. Each patient will be followed for the subsequent 24 months, every 3 month, providing survival information and monitoring serious adverse event. Each patient should be treated for a minimum of 6 weeks. Then a patient can be discontinued in the following situation: * at the end of first course (6 weeks), in case of lack of CHR; * at the end of third course (18 weeks), in case of lack of CCgR; * any time in case of loss of CHR or CCgR. If they remain on therapy after 48 weeks, they will be able to continue treatment during the extension phase of the study, if it is of interest of the patient, or they will be allowed to receive any treatment that is in their interest. For all the patients remaining on trial, response, outcome and toxicity will be followed for the subsequent 24 months.The 6-weeks periodicity must be rigidly respected, irrespective of the temporary discontinuation of study drug (eg, if a patient will take Ponatinib only for 4 weeks and will remain off-treatment for the subsequent two weeks because of AE, when the 7th week begins this patient will restart Ponatinib as a second course, as per protocol). Prednisone (P) will be administered to all patients for 7-14 days, before Ponatinib, so as to make it possible to wait for the results of cytogenetic and molecular tests, and to evaluate the response to P alone, hence for another 21 days. Intrathecal therapy (IT) with MTX/AraC/DEX is mandatory, every 28 days, in patients without clinical-cytologic evidence of meningeal involvement. In patients with CNS disease, IT is performed twice weekly until a complete clearance of cerebrospinal fluid blast cells is achieved, hence once weekly for 4 weeks, hence once monthly.
Minimum Age: 18 Years
Eligible Ages: ADULT, OLDER_ADULT
Sex: ALL
Healthy Volunteers: No
S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo, Alessandria, , Italy
Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. LANCISI - G. SALESI, Ancona, , Italy
Dipartimento Area Medica - Presidio Ospedaliero "C. e G.Mazzoni", Ascoli, , Italy
Az.Ospedaliera S.G.Moscati, Avellino, , Italy
Azienda Ospedaliera - Papa Giovanni XXIII, Bergamo, , Italy
Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi, Bologna, , Italy
ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO, Cagliari, , Italy
Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto", Catania, , Italy
Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi, Ferrara, , Italy
Policlinico di Careggi, Firenze, , Italy
Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino", Genova, , Italy
ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE, Lecce, , Italy
Unità Operativa Complessa - Medicina Generale - Sezione di Ematologia - Ospedale Versilia USL 12 Toscana, Lido di Camaiore, , Italy
Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST, Meldola, , Italy
U.O. di Ematologia- Ospedale dell'Angelo - Mestre, Mestre, , Italy
Ospedale Niguarda " Ca Granda", Milano, , Italy
UO Ematologia - AOU Policlinico di Modena, Modena, , Italy
S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro, Novara, , Italy
Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2, Orbassano, , Italy
Università degli Studi di Padova - Ematologia ed Immunologia Clinica, Padova, , Italy
Ospedali Riuniti "Villa Sofia-Cervello", Palermo, , Italy
S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo, Pavia, , Italy
Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della Misericordia, Perugia, , Italy
Div. di Ematologia di Muraglia - CTMO Ospedale San Salvator, Pesaro, , Italy
U.O. Ematologia Clinica - Azienda USL di Pescara, Pescara, , Italy
Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza, Piacenza, , Italy
Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia, Pisa, , Italy
Dipartimento Oncologico - Ospedale S.Maria delle Croci, Ravenna, , Italy
Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli", Reggio Calabria, , Italy
Ospedale "Infermi", Rimini, , Italy
Complesso Ospedaliero S. Giovanni Addolorata, Roma, , Italy
S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena, Roma, , Italy
U.O.C. Ematologia - Ospedale S.Eugenio, Roma, , Italy
Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia, Roma, , Italy
Università degli Studi - Policlinico di Tor Vergata, Roma, , Italy
UOC di Ematologia e Trapianti di Cellule Staminali Emopoietiche - AOU San Giovanni di Dio e Ruggi D'Aragona, Salerno, , Italy
U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte", Siena, , Italy
Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista, Torino, , Italy
Azienda U.L.S.S.9 - U.O. di Ematologia, Treviso, , Italy
Clinica Ematologica - Policlinico Universitario, Udine, , Italy
Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi, Verona, , Italy
ULSS N.6 Osp. S. Bortolo, Vicenza, , Italy
Name: Michele Baccarani, Pr.
Affiliation: Dpt of Hematology and Oncology "Seràgnoli", "Sant'Orsola-Malpighi" University Hospital of Bologna
Role: PRINCIPAL_INVESTIGATOR