Clinical trial NCT01361438: De Novo Adult Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Patients
Official title: A Multicenter Total Therapy Strategy for De Novo Adult Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Patients. GIMEMA Protocol LAL1509, EudraCT Number 2010-019119-39
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: ALL Ph Positive
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2011-05-26
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will enroll adult de novo Ph+ acute lymphoblastic leukemia (ALL) patients (≥18 years, ≤60 years). Induction treatment will consist of 12 weeks of Dasatinib oral administration (140 mg QD). Patients will initiate treatment with steroids 7 days prior to starting Dasatinib and will continue up to day 31. Patients will continue treatment with Dasatinib up to day 84, except for disease progression, intolerable toxicity, or withdrawal from study.

Detailed description: This study will enroll adult de novo Ph+ acute lymphoblastic leukemia (ALL) patients (≥18 years, ≤60 years). Induction treatment will consist of 12 weeks of Dasatinib oral administration (140 mg QD). Patients will initiate treatment with steroids 7 days prior to starting Dasatinib and will continue up to day 31. Patients will continue treatment with Dasatinib up to day 84, except for disease progression, intolerable toxicity, or withdrawal from study.

Thereafter:

* patients in hematological and molecular CR will receive a post-remissional treatment consisting of Dasatinib alone for a 6 months period
* patients in hematological CR with persistence of molecular disease will be allografted or, if not eligible or a donor is not available, treated with 2 cycles of a Clofarabine-Cyclophosphamide schedule.

After allograft:

* MRD negative patients (i.e. in CHR and PCR negative) will receive a 6 months Dasatinib maintenance treatment;
* MRD positive patients (i.e. in CHR and PCR positive) will receive Dasatinib as maintenance treatment until relapse or progression.

Patients not transplanted and treated with Clofarabine/Cyclophosphamide will also receive Dasatinib as maintenance treatment until relapse or progression.

Eligibility criteria: Inclusion Criteria:

* Patients with de novo Ph+ and/or BCR/ABL+ ALL.
* Age ≥18 years old ≤60 years.
* No prior treatment with any anti-leukemic drugs with the exception of steroids for no more than 14 days (including the 7-day pretreatment already scheduled in the protocol).
* WHO performance status ≤2.
* No evidence of central nervous system (CNS) leukemia.
* Normal serum level of potassium, total calcium corrected for serum albumin magnesium and phosphorus, or correctable with supplements.
* ALT and AST ≤2.5 x ULN or ≤5.0 x ULN if considered due to leukemia.
* Alkaline phosphatase ≤2.5 x ULN unless considered to leukemia.
* Serum bilirubin ≤2 x ULN.
* Serum creatinine ≤3 x ULN.
* Serum amylase ≤1.5 x ULN and serum lipase ≤1.5 x ULN.
* Normal cardiac function.
* Written informed consent prior to any study procedures being performed. In addition, patients must be thoroughly informed about all aspects of the study, including the study visit schedule and required evaluations and all regulatory requirements for informed consent.

Exclusion Criteria:

* Impaired cardiac function, including any one of the following:

  * LVEF \<45% as determined by MUGA scan or echocardiogram.
  * Complete left bundle branch block.
  * Use of a cardiac pacemaker.
  * ST depression of \>1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads.
  * Congenital long QT syndrome.
  * History of or presence of significant ventricular or atrial arrhythmia.
  * Clinically significant resting bradycardia (\<50 beats per minute).
  * QTc \>450 msec on screening ECG (using the QTcF formula).
  * Right bundle branch block plus left anterior hemiblock, bifascicular block.
  * Myocardial infarction within 3 months prior to starting Dasatinib.
  * Angina pectoris.
  * Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).
* Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Dasatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
* Use of therapeutic warfarin.
* Acute or chronic liver or renal disease considered unrelated to leukemia.
* Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol.
* Active uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
* Treatment with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GMCSF) ≤1 week prior to starting study drug.
* Patients who are currently receiving treatment with any of the medications listed in "Appendix H" and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in "Appendix H" have the potential to prolong the QT interval.
* Patients who have received any antileukemic agents and treatments including steroids. for more than 14 days including 7 days pretreatment that is part of the protocol.
* Patients who have received any investigational drug in the last 2 weeks.
* Patients who have undergone major surgery ≤2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
* Patients who are pregnant or 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 Dasatinib. Post-menopausal women must be amenorrhoeic 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 drug.
* Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory).
* Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
* Non compliant to oral medication patients.
* Significant pleural effusion on baseline chest X-Ray (CXR) or pericardial effusion on baseline echocardiogram.
* Use of H2 blockers or proton pump inhibitors.

Primary outcomes:
measure: The primary objective of the trial is to estimate the feasibility of a total therapy strategy in de novo adult Ph positive ALL.
timeFrame: at 42 months
Secondary outcomes:
measure: The median value of the minimum of PCR levels achieved in each patient during the Dasatinib treatment within day +85, whenever achieved from the start of the Dasatinib.
timeFrame: at 42 months
measure: The rate of patients who become PCR negative after Dasatinib induction.
timeFrame: at 42 months
measure: Out of patients who become PCR negative after induction, the rate of patients who remain persistently negative during maintenance treatment with Dasatinib (without chemotherapy or allogeneic transplant).
timeFrame: at 42 months
measure: The median value of the minimum of PCR levels achieved in each patient after an allogeneic transplant or Clofarabine-Cyclophosphamide treatment as consolidation therapy.
timeFrame: at 42 months
measure: The rate of patients alive in CHR who have completed the maintenance program with Dasatinib after an allogeneic transplant or two cycles of Clofarabine-Cyclophosphamide as consolidation therapy.
timeFrame: at 42 months
measure: Disease free survival estimation starting from the date of evaluation of CHR.
timeFrame: at 42 months
measure: Cumulative incidence of relapse estimation starting from the date of evaluation of CHR.
timeFrame: at 42 months
measure: Overall survival estimation starting from date of inclusion.
timeFrame: at 42 months
Other outcomes:
Locations:
city: Rionero in Vulture
country: Italy
facility: Centro Oncologico Basilicata
state: Potenza
city: Ancona
country: Italy
facility: Azienda Ospedaliera - Nuovo Ospedale "Torrette"
city: Ascoli Piceno
country: Italy
facility: Dipartimento Area Medica P.O.
city: Avellino
country: Italy
facility: Az. Ospedaliera S. G. Moscati
city: Bari
country: Italy
facility: Unità Operativa Ematologia 1 - Università degli Studi di Bari
city: Bologna
country: Italy
facility: Ist.Ematologia e Oncologia Medica L.e A. Seragnoli
city: Brindisi
country: Italy
facility: Osp. Reg. A. Di Summa
city: Cagliari
country: Italy
facility: CTMO - Ematologia - Ospedale "Binaghi"
city: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia
city: Cosenza
country: Italy
facility: U.O. Ematologia - P.O. Annunziata - A.O. di Cosenza
city: Ferrara
country: Italy
facility: Sez.Ematologia e Dip. scienze Biomediche Arcispedale S. Anna
city: Foggia
country: Italy
facility: Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria
city: Genova
country: Italy
facility: Clinica Ematologica - Università degli Studi
city: Latina
country: Italy
facility: Divisione di Ematologia Ospedale "Santa Maria Goretti"
city: Lecce
country: Italy
facility: ASL Le1 P.O. Vito Fazzi - U.O. di Ematologia
city: Messina
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte" di Messina
city: Messina
country: Italy
facility: Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina
city: Milano
country: Italy
facility: Ospedale Niguarda " Ca Granda"
city: Modena
country: Italy
facility: Centro Oncologico Modenese - Dipartimento di Oncoematologia
city: Napoli
country: Italy
facility: Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli"
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
city: Napoli
country: Italy
facility: Servizio Sanitario Nazionale - Azienda Ospedaliera di Rilievo Nazionale "A. Cardarelli" - Struttura Complessa di Ematologia - Div. TERE
city: Nocera Inferiore
country: Italy
facility: Prof. D'Arco
city: Novara
country: Italy
facility: S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro
city: Orbassano
country: Italy
facility: Dip. di Scienze Cliniche e Biologiche - Ospedale S. Luigi Gonzaga
city: Palermo
country: Italy
facility: Ospedale Cervello
city: Palermo
country: Italy
facility: Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"
city: Palermo
country: Italy
facility: La Maddalena Casa di Cura di Alta Specialità Dipartimento Oncologico di III Livello
city: Pavia
country: Italy
facility: Div. di Ematologia IRCCS Policlinico S. Matteo
city: Pescara
country: Italy
facility: U.O. Ematologia Clinica - Azienda USL di Pescara
city: Pisa
country: Italy
facility: Università di Pisa Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Div. di Ematologia
city: Potenza
country: Italy
facility: Ematologia - Ospedale San Carlo
city: Ravenna
country: Italy
facility: Ospedale S.Maria delle Croci
city: Reggio Calabria
country: Italy
facility: Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
city: Reggio Emilia
country: Italy
facility: Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
city: Roma
country: Italy
facility: Divisione Ematologia - Università Campus Bio-Medico
city: Roma
country: Italy
facility: Umberto I di Roma - Dipartimento di Biotecnologie Cellulari ed Ematologia
city: Roma
country: Italy
facility: Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
city: Roma
country: Italy
facility: Complesso Ospedaliero S. Giovanni Addolorata
city: Roma
country: Italy
facility: Divisione di Ematologia - Ospedale S. Camillo
city: Roma
country: Italy
facility: S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena
city: Roma
country: Italy
facility: Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
city: Rome
country: Italy
facility: Policlinico di Tor Vergata
city: Rome
country: Italy
facility: Ospedale S.Eugenio
city: San Giovanni Rotondo
country: Italy
facility: Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Sassari
country: Italy
facility: Serv. di Ematologia Ist. di Ematologia ed Endocrinologia
city: Trani
country: Italy
facility: Struttura Complessa Ematologia - Azienda Sanitaria Locale BAT1- Presidio Ospedaliero Bisceglie-Trani
city: Tricase
country: Italy
facility: U.O. di Ematologia - Azienda Ospedaliera - Pia Fondazione di Culto e di Religione Card. G.Panico
city: Udine
country: Italy
facility: Policlinico Universitario - Clinica Ematologia
city: Verona
country: Italy
facility: Policlinico G.B. Rossi
Study officials:
affiliation: Università Sapienza di Roma
name: Roberto Foà, Pr.
role: STUDY_CHAIR
References: