new trial for ponatinib
PhII Front-line Treatment of Adult Affected of Ph+/BCR-ABL+ ALL With Ponatinib. (LAL1811)
This study is not yet open for participant recruitment.
Verified July 2012 by Gruppo Italiano Malattie EMatologiche dell'Adulto
First Received on July 12, 2012. No Changes Posted
Sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Information provided by (Responsible Party): Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier: NCT01641107
Purpose
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 short. A more potent TKI inhibitor, and pan-active on all the BCR-ABL variants (including the second generation TKI resistant T315I mutant), can do better. Ponatinib is a novel synthetic orally active tyrosine kinase inhibitor (TKI). Ponatinib was 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; for this reason, it is a pan-BCR-ABL inhibitor. Ponatinib has been demonstrated to inhibit all the mutations that have been detected so far, in vitro and in vivo. 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 avoid the selection of mutated Ph+ clones.
Condition Intervention Phase
Philadelphia Positive
BCR-ABL Positive
Acute Lymphoblastic Leukemia
Drug: Ponatinib
Phase 2
Study Type: Interventional
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.
Resource links provided by NLM:
MedlinePlus related topics: Acute Lymphocytic Leukemia Chronic Lymphocytic Leukemia Leukemia
U.S. FDA Resources
Further study details as provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:
Primary Outcome Measures:
•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).
Secondary Outcome Measures:
•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:
1.Complete (CCgR) if Ph pos 0
2.Partial (PCgR) if Ph pos 1-34%
3.Minor (mCgR) if Ph pos 35-65%
4.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 ]
Estimated Enrollment: 44
Study Start Date: October 2012
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ponatinib Drug: Ponatinib
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.
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.
Eligibility
Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
1.To be classified as having Ph+ ALL, patients must have >20% blasts in bone marrow at the time of diagnosis and no prior history of CML.
2.Patients with previously untreated Ph+ and/or BCR/ABL + ALL:
?age = 60 years old or
?age = 18 years old, but unfit for program of intensive therapy and allogeneic SCT
3.Signed written informed const according to ICH/EU/GCP and national local laws.
4.Effective contraception.
Exclusion Criteria:
1.Uncontrolled congestive heart failure or/and uncontrolled hypertension.
2.History of myocardial infarction within 3 months, or uncontrolled angina pectoris.
3.Significant electric heart abnormalities, including history or presence of significant ventricular or atrial tachyarrhythmias, congenital long QT syndrome and/or QTc > 450 msec on screening ECG (using the QTcF formula) .
4.WHO performance status = 50% (Karnofsky) or = 3 (ECOG).
5.Active HBV or HCV hepatitis, or AST/ALT = 2.5 x ULN and bilirubine = 1.5 x ULN.
6.Creatinine level > 2.5mg/dl or Glomerular Filtration Rate (GFR) < 20 ml/min or proteinuria > 3.5 g/day.
7.History of acute pancreatitis within 1 year of study, or history of chronic pancreatitis, history of alcohol abuse; ongoing or active infection; uncontrolled hypertriglyceridemia (triglicerides > 450 mg/dL).
8.Impairment of gastrointestinal (GI) function, or a GI disease that may significantly alter the absorption of study drugs (e.g., severe malabsorption syndrome, or extended small bowel resection).
9.Patients who are currently receiving treatment with any of the medications listed in Appendix D if the medications cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in Appendix D have the potential to prolong QT.
10.Patients who have received any investigational drug = 4 weeks.
11.Patients who have undergone major surgery = 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
12.Patients who are pregnant or breast feeding and adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of Ponatinib). Post menopausal women must be amenorrhoic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drugs.
13.Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
14.Patients unwilling or unable to comply with the protocol.
Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01641107
Contacts
Contact: Paola Fazi, Dr. p.fazi@gimema.it
Contact: Enrico Crea e.crea@gimema.it
Locations
Italy
ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO Not yet recruiting
Cagliari, Italy
Contact: Emanuele Angelucci, Pr.
Principal Investigator: Emanuele Angelucci, Pr.
Sub-Investigator: Claudio Romani, Dr.
Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto" Not yet recruiting
Catania, Italy
Contact: Francesco Di Raimondo, Pr.
Principal Investigator: Francesco Di Raimondo, Pr.
Sub-Investigator: Maria Rita, Dr.
Policlinico di Careggi Not yet recruiting
Firenze, Italy
Contact: Alberto Bosi, Pr.
Principal Investigator: Alberto Bosi, Pr.
Sub-Investigator: Antonella Gozzini, Dr.
Divisione Ematologia 1 - Azienda Ospedaliera Universitaria "San Martino" Not yet recruiting
Genova, Italy
Contact: Angelo Michele Carella, Pr.
Principal Investigator: Angelo Michele Carella, Pr.
Ospedali Riuniti "Villa Sofia-Cervello" Not yet recruiting
Palermo, Italy
Contact: Francesco Fabbiano, Pr.
Principal Investigator: Francesco Fabbiano, Pr.
Sub-Investigator: Rosaria Felice, Dr.
S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo Not yet recruiting
Pavia, Italy
Contact: Carlo Castagnola, Pr.
Principal Investigator: Carlo Castagnola, Dr.
Sub-Investigator: Marianna Rossi, Dr.
Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza Not yet recruiting
Piacenza, Italy
Contact: Daniele Vallisa, Pr.
Principal Investigator: Daniele Vallisa, Pr.
Sub-Investigator: Elena Trabacchi, Dr.
Dipartimento Oncologico - Ospedale S.Maria delle Croci Not yet recruiting
Ravenna, Italy
Contact: Alfonso Zaccaria, Pr.
Principal Investigator: Alfonso Zaccaria, Pr.
Sub-Investigator: Eliana Zuffa, Dr.
Università degli Studi - Policlinico di Tor Vergata Not yet recruiting
Roma, Italy
Contact: Sergio Amadori, Pr.
Principal Investigator: Sergio Amadori, Pr.
Sub-Investigator: Adriano Venditti, Pr.
Clinica Ematologica - Policlinico Universitario Not yet recruiting
Udine, Italy
Contact: Anna Candoni, Dr.
Principal Investigator: Anna Candoni, Dr.
Sub-Investigator: Erica Simeone, Dr.
Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi Not yet recruiting
Verona, Italy
Contact: Giovanni Pizzolo, Pr.
Principal Investigator: Giovanni Pizzolo, Pr.
Sub-Investigator: Massimiliano Bonifacio, Dr.
Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
Investigators
Principal Investigator: Michele Baccarani, Pr. Dpt of Hematology and Oncology "Seràgnoli", "Sant'Orsola-Malpighi" University Hospital of Bologna
More Information
Additional Information:
Gimema Foundation Website
No publications provided
Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier: NCT01641107 History of Changes
Other Study ID Numbers: LAL1811, 2012-002761-35
Study First Received: July 12, 2012
Last Updated: July 12, 2012
Health Authority: Italy: The Italian Medicines Agency
Keywords provided by Gruppo Italiano Malattie EMatologiche dell'Adulto:
Ph+
BCR-ABL+
ALL
Ponatinib
stem cell transplantation
Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
ClinicalTrials.gov processed this record on July 15, 2012
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