Phase II Front-line Ponatinib in Adult Philadelphia+/BCR-ABL+ Acute Lymphoblastic Leukemia. (LAL1811)
|Philadelphia Positive BCR-ABL Positive Acute Lymphoblastic Leukemia||Drug: Ponatinib||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Official Title:||Front-line Treatment of Philadelphia Positive/BCR-ABL Positive Acute Lymphoblastic Leukemia With Ponatinib, a New Potent Tyrosine Kinase Inhibitor.|
- Proportion of patients who are in Complete Hematological Response (CHR). [ Time Frame: At 6 months from study entry. ]The primary endpoint is the proportion of patients who are in CHR at 6 months, calculated on the total number of patients who have been enroled and have received at least one dose of the first drug (prednisone).
- The rate of Complete Hematological Response (CHR). [ Time Frame: At 6, 12, 24, 36 and 48 weeks from study entry. ]
CHR requires that all of the following are present:
- Bone marrow with less than 5% blast cells
- Peripheral blood differential without blasts
- PMN ≥ 1.5 x 109/L
- PLT ≥ 100 x 109/L
- No evidence of extramedullary involvement from leukemia
- The rate of complete Cytogenetic Response (CgR). [ Time Frame: At 6, 12, 24, 36 and 48 weeks from study entry. ]
CgR is defined based on the percentage of Ph pos metaphases, as evaluated by chromosome banding analysis (CBA) of at least 20 marrow cell metaphases:
- Complete (CCgR) if Ph pos 0
- Partial (PCgR) if Ph pos 1-34%
- Minor (mCgR) if Ph pos 35-65%
- Minimal or none (min/none CgR) if Ph pos > 65% If only interphase FISH data are available, the response can be defined only as non-complete or complete - to be complete by FISH, it is required that less than 1% of nuclei (minimum number 200) have a positive signal.
- Duration of Complete Cytogenetic Response (CCgR). [ Time Frame: After four years from study entry. ]Duration of CCgR is measured by the date of the achievement of CCgR to the date of CCgR loss.
- The rate of Complete Molecular Response (CMoIR). [ Time Frame: At 12, 24, 36 and 48 weeks from study entry. ]
Molecular response is classified as:
• Complete if by RT-Q-PCR the BCR-ABL: ABL ratio is below 0.01, with a sensitivity of at least 30,000 molecules of ABL.
- The rate of major molecular response. [ Time Frame: At 12, 24, 36 and 48 weeks from study entry. ]
Molecular response (MR) is classified as:
• Major (MMolR) if by RT-Q-PCR the BCR-ABL: ABL ratio is lower than 0.10, with a sensitivity of at least 30,000 molecules of ABL.
- Duration of Complete molecular response (CMR). [ Time Frame: After four years from study entry. ]Duration of CMR is measured by the date of the achievement of CMR to the date of CMR loss.
- Type and number of BCR-ABL kinase domain mutations. [ Time Frame: At the end of the study. At four years after enrollment of first patient. ]
- Percentage of relationships between the response and the biomarkers. [ Time Frame: At six months from study entry. ]
- Event Free Survival. [ Time Frame: After four years from study entry. ]Events are induction failure, relapse and death whichever comes first.
- Overall survival [ Time Frame: At the end of study. After four years from enrolment. ]Overall survival is measured in all patients from the data of enrolment to the date of death, by any causes.
- Failure Free Survival [ Time Frame: After four years from study entry. ]
- Rate of Rate of side effects, adverse events and serious adverse events. [ Time Frame: After four years from study entry. ]
|Actual Study Start Date:||October 2014|
|Estimated Study Completion Date:||November 2019|
|Estimated Primary Completion Date:||November 2019 (Final data collection date for primary outcome measure)|
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. Patients must be discontinued from the trial in the event of myocardial infarction or stroke, or for development or progression of arterial disease necessitating revascularization. Once a complete hematologic response has been achieved, with a platelet count ≥ 50x109/L, patients can be treated with aspirin and/or a statin as clinically indicated, at investigator discretion.
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01641107
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01641107
|S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo|
|Azienda Ospedaliero - Universitaria Ospedali Riuniti Umberto I - G.M. LANCISI - G. SALESI|
|Dipartimento Area Medica - Presidio Ospedaliero "C. e G.Mazzoni"|
|Azienda Ospedaliera - Papa Giovanni XXIII|
|Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi|
|ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO|
|Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"|
|Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi|
|Policlinico di Careggi|
|Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino"|
|ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE|
|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|
|U.O. di Ematologia- Ospedale dell'Angelo - Mestre|
|Ospedale Niguarda " Ca Granda"|
|UO Ematologia - AOU Policlinico di Modena|
|S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro|
|Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga-Medicina Interna 2|
|Università degli Studi di Padova - Ematologia ed Immunologia Clinica|
|Ospedali Riuniti "Villa Sofia-Cervello"|
|S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo|
|Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della Misericordia|
|Div. di Ematologia di Muraglia - CTMO Ospedale San Salvator|
|U.O. Ematologia Clinica - Azienda USL di Pescara|
|Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza|
|Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia|
|Dipartimento Oncologico - Ospedale S.Maria delle Croci|
|Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"|
|Reggio Calabria, Italy|
|Complesso Ospedaliero S. Giovanni Addolorata|
|S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena|
|U.O.C. Ematologia - Ospedale S.Eugenio|
|Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia|
|Università degli Studi - Policlinico di Tor Vergata|
|UOC di Ematologia e Trapianti di Cellule Staminali Emopoietiche - AOU San Giovanni di Dio e Ruggi D'Aragona|
|U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"|
|Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista|
|Azienda U.L.S.S.9 - U.O. di Ematologia|
|Clinica Ematologica - Policlinico Universitario|
|Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi|
|ULSS N.6 Osp. S. Bortolo|
|Principal Investigator:||Michele Baccarani, Pr.||Dpt of Hematology and Oncology "Seràgnoli", "Sant'Orsola-Malpighi" University Hospital of Bologna|