STI 571 (GLIVEC) in the Treatment of Adult Acute Lymphoblastic Leukemia

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Brief Title

STI 571 (GLIVEC) in the Treatment of Adult Acute Lymphoblastic Leukemia

Official Title

STI 571 (GLIVEC) in the Treatment of Philadelphia-chromosome Positive and/or BCR/ABL Rearranged Adult Acute Lymphoblastic Leukemia. GIMEMA LAL 0201.

Brief Summary

      This proposal, developed in the framework of the GIMEMA, will permit:

        -  to evaluate the activity and toxicity of imatinib in the treatment of Ph+ acute
           lymphoblastic leukemia;

        -  to evaluate the molecular response to the treatment, and to monitor the molecular status
           of remission in all cases achieving or not a molecular response.

      The GIMEMA has activated a network to centralize all biological samples (bone marrow and
      peripheral blood) at diagnosis from all new ALL patients. This will permit to identify, in
      particular, Ph + and/or BCR/ABL + cases within 5 days from diagnosis, thus permitting to
      treat these patients according to different programs on the basis of the presence of Ph
      chromosome.
    

Detailed Description

      Imatinib shows a specific activity for the ABL protein- tyrosine kinase at the in vitro and
      in vivo level. The compound exerts a direct inhibition on the proliferation of BCR/ABL+ve
      cells, in cell lines derived from ALL and CML patients, inducing apoptosis. Induction of
      apoptosis by imatinib was observed also in primary samples of leukemic cells obtained from
      Ph+ve ALL patients. Since activated BCR/ABL tyrosine kinase is present in nearly all patients
      with CML and in 25-30% of those with ALL, these two diseases are the ideal targets to verify
      the potential therapeutic activity of this ABL specific tyrosine kinase inhibitor. So far
      only limited experiences on the therapeutic benefit of imatinib in ALL patients have been
      referred. In one of these studies, all 10 treated patients had received prior
      chemotherapeutic treatment for their leukemia. Imatinib was administered as daily oral
      therapy and all patients were treated on outpatient basis. Different dosages were tested:
      300, 400, 500 mg/day for 28 days. Some responding patients showed prolonged myelosuppression,
      but only a minority of these required hospitalization, while other side effects appeared
      acceptable. Although these results demonstrated that Imatinib, as a single agent, is active
      in BCR/ABL +ve ALL, being able to induce a high response rate, however these responses
      appeared to be short. This occurred mainly in patients with advanced leukemia, thus it could
      be hypothesized that early relapse, in these patients, may due to a pre-existing resistance
      or developed resistance to Imatinib. In vitro studies as well as limited preclinical
      experiences are showing enhanced antileukemic effects of Imatinib in combination with
      cytotoxic drugs, thus further clinical trials should be aimed to ascertain, mainly in
      previously untreated patients, which are the optimal dosage and the best duration of
      treatment for maximal therapeutic benefit and to test if this agent, combined with
      conventional chemotherapy, could really enhance its antileukemic activity.

      The Gimema Group will run two distinct studies among the same protocol to verify the
      antileukemic activity and safety of imatinib in Ph+ve and/or BCR/ABL +ve ALL:

      Study A: Imatinib as post-consolidation therapy in adult (>=18 and <=60 yrs) ALL patients in
      1st CHR; Study B: Imatinib without chemotherapy for remission induction in elderly (>60
      years) ALL patients.

      This proposal, developed in the framework of the GIMEMA, will include:

        1. centralization of all biological samples (bone marrow and peripheral blood) at diagnosis
           from all new ALL patients, to identify, in particular, Ph + and/or BCR/ABL + cases;

        2. evaluation of the molecular response to the treatment, and monitoring the molecular
           status during the hematological remission in all cases in CR;

        3. treatment of all adult patients with the same induction and consolidation treatment
           already used in the past by GIMEMA for Ph+ ALL, to have also the possibility of an
           historical control versus patients treated before the "imatinib era".

      Study A: Imatinib in Ph +ve and/or BCR/ABL +ve adult (age <60 years) ALL patients in first
      CHR after induction and consolidation treatment.

      Aimed to verify the activity and safety of STI 571 administered after the induction and
      consolidation therapy in Ph+ve and/or Bcr/Abl+ve ALL patients in 1st CHR (+CMR). A cohort of
      38 patients will be enrolled. All Gimema Centers can join this study. Quantitative Rt-PCR
      assay is mandatory before start of Imatinib treatment.

      Patients will receive on an out-patients basis Imatinib p.o. at the dosage of 400 mg x
      2/daily for 6 months. After completing the 6-months therapy, and in absence of safety
      concerns, patients may receive additional therapy with Imatinib, provided that, in the
      opinion of investigator, the patient has benefited from treatment.

      Study B: Imatinib as induction treatment in newly diagnosed Ph+ and/or Bcr/Abl+ elderly (age
      >60 years) ALL patients.

      Aimed to verify the activity and safety of Imatinib combined with steroids during the
      induction phase in elderly (>60 years) Ph+ve and/or Bcr/Abl+ve ALL patients. A cohort of 53
      patients will be enrolled. All Gimema Centers can join this study. The cytogenetic and/or
      molecular diagnosis must be obtained within 5 days from diagnosis.

      Patients will receive Imatinib p.o at the dosage of 400 mg x 2/daily for 30 days on an
      out-patients basis. After completing induction therapy patients may receive additional
      therapy with Imatinib, provided that, in the opinion of investigator, the patient benefited
      from treatment.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

for Study A, the primary endpoint for activity is overall CMR rate

Secondary Outcome

 complete hematological or molecular remission duration

Condition

Acute Lymphoblastic Leukemia

Intervention

Imatinib


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

105

Start Date

December 2001

Completion Date

February 2011

Primary Completion Date

June 2010

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with Ph +ve and/or BCR/ABL +ve ALL, either in 1st CHR (independently from the
             molecular status) for study A, or at diagnosis and untreated for study B;

          -  Age >18 years and <60 for study A, >60 for study B;

          -  Written voluntary informed consent.

        Exclusion Criteria:

          -  Patients of childbearing potential without a negative pregnancy test prior to the
             initiation of study. Barrier contraceptive precautions are to be used throughout the
             trial in both sexes;

          -  Pretreatment with steroids for more than 10 days in study B;

          -  Serum bilirubin and creatinine values >3 the upper limit of normal range;

          -  SGOT and SGPT values >3 the upper limit of the normal range;

          -  Patients who had received any other investigational agent within 4 weeks before the
             enrollment;

          -  Patients with cardiovascular diseases grade >3 according to the New York Heart
             Association (see Appendix 1);

          -  Patients with a history of non compliance to medical regimen or who are considered
             potentially unreliable;

          -  Patients with moderate/severe mood or psychiatric disorders;

          -  Concomitant neoplasia.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Michele Baccarani, , 

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT00376467

Organization ID

LAL0201


Responsible Party

Sponsor

Study Sponsor

Gruppo Italiano Malattie EMatologiche dell'Adulto


Study Sponsor

Michele Baccarani, Principal Investigator, Università degli Studi di Udine


Verification Date

February 2014