Phase II Front-line Treatment of Adult Affected of Philadelphia+/BCR-ABL+ Acute Lymphoblastic Leukemia (ALL) With Ponatinib. (LAL1811)
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.
Acute Lymphoblastic Leukemia
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Front-line Treatment of Philadelphia Positive (Ph+)/BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL) With AP24534 (Ponatinib), a New Potent Tyrosine Kinase Inhibitor (TKI). A Phase II Exploratory Multicentric Study in Patients More Than 60 Years Old or Unfit for a Program of Intensive Chemotherapy and Stem Cell Transplantation.|
- Proportion of patients who are in Complete Hematological Response (CHR). [ Time Frame: At 6 months from study entry. ] [ Designated as safety issue: No ]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. ] [ Designated as safety issue: No ]
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. ] [ Designated as safety issue: No ]
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. ] [ Designated as safety issue: No ]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. ] [ Designated as safety issue: No ]
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. ] [ Designated as safety issue: No ]
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. ] [ Designated as safety issue: No ]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. ] [ Designated as safety issue: No ]
- Percentage of relationships between the response and the biomarkers. [ Time Frame: At six months from study entry. ] [ Designated as safety issue: No ]
- Event Free Survival. [ Time Frame: After four years from study entry. ] [ Designated as safety issue: No ]Events are induction failure, relapse and death whichever comes first.
- Overall survival [ Time Frame: At the end of study. After four years from enrolment. ] [ Designated as safety issue: No ]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. ] [ Designated as safety issue: No ]
- Rate of Rate of side effects, adverse events and serious adverse events. [ Time Frame: After four years from study entry. ] [ Designated as safety issue: Yes ]
|Study Start Date:||November 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01641107
|Contact: Paola Fazi, Dr.||email@example.com|
|Contact: Enrico Creafirstname.lastname@example.org|
|Dipartimento Area Medica - Presidio Ospedaliero "C. e G.Mazzoni"||Suspended|
|Azienda Ospedaliera - Papa Giovanni XXIII||Suspended|
|Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi||Suspended|
|ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO||Suspended|
|Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"||Suspended|
|Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi||Suspended|
|Policlinico di Careggi||Suspended|
|Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino"||Suspended|
|Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST||Suspended|
|Ospedale Niguarda " Ca Granda"||Suspended|
|S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro||Suspended|
|Ospedali Riuniti "Villa Sofia-Cervello"||Suspended|
|S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo||Suspended|
|U.O. Ematologia Clinica - Azienda USL di Pescara||Suspended|
|Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza||Suspended|
|Dipartimento Oncologico - Ospedale S.Maria delle Croci||Suspended|
|Università degli Studi - Policlinico di Tor Vergata||Suspended|
|Azienda U.L.S.S.9 - U.O. di Ematologia||Suspended|
|Clinica Ematologica - Policlinico Universitario||Suspended|
|Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi||Suspended|
|Principal Investigator:||Michele Baccarani, Pr.||Dpt of Hematology and Oncology "Seràgnoli", "Sant'Orsola-Malpighi" University Hospital of Bologna|