First-line Dasatinib Plus Conventional Chemotherapy in Adults With Newly Diagnosed Ph-Positive ALL

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Brief Title

First-line Dasatinib Plus Conventional Chemotherapy in Adults With Newly Diagnosed Ph-Positive ALL

Official Title

A Phase 2 Multicenter Study of First-line Dasatinib Plus Conventional Chemotherapy in Adults With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Brief Summary

      The main aim of the present study is to evaluate the clinical efficacy of first-line
      dasatinib plus conventional chemotherapy for newly diagnosed Ph-positive acute lymphoblastic
      leukemia. In this study, the investigators will analyze the clinical outcomes for entire
      patient population as well as those for transplants, respectively. In addition, the results
      of this study will be compared to those of the investigators current study (imatinib plus
      conventional chemotherapy). The safety of this treatment will also be studied.
    

Detailed Description

      Recent clinical trials on imatinib in combination with cytotoxic agents as a front-line
      treatment, have demonstrated an improved complete remission (CR) rate and a better outcome in
      adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL).
      Previously, we also demonstrated the positive impact of first-line imatinib interim therapy
      on the outcome of allogeneic stem cell transplantation (SCT) in adults with Ph-positive ALL.
      Nevertheless, a substantial proportion of patients continue to die as a result of disease
      progression. Recently, we demonstrated that a reduction in BCR-ABL transcript levels of at
      least 3 log after the completion of imatinib therapy was found to be the most powerful
      predictor of lower relapse and better disease-free survival after allogeneic SCT. In the
      light of disease aggressiveness and recurrence, mainly as a result of the outgrowth of
      leukemic subclones with imatinib-resistant BCR-ABL mutations, an improved strategy to induce
      more effective leukemic cell clearance during the pretransplantation treatment course is
      clearly needed.

      Dasatinib, a potent dual BCR-ABL/SRC family kinase inhibitor, demonstrated 325-fold greater
      activity against native BCR-ABL compared with imatinib and has shown efficacy against all
      imatinib-resistant BCR-ABL mutations with the exception of T315I. According to the START-L
      (SRC/ABL Tyrosine Kinase Inhibition Activity: Research Trials of Dasatinib) trial, dasatinib
      (70 mg twice daily) induced rapid hematologic and cytogenetic responses in a substantial
      proportion of patients with imatinib-resistant or intolerant Ph-positive ALL (hematologic CR
      rate, 33%; major cytogenetic response rate, 57%; cytogenetic CR rate, 54%). However, the
      median duration of a major cytogenetic response was 6.9 months. Considering this kinetics of
      resistance, it is felt likely that dasatinib monotherapy is not sufficient as a first-line
      treatment for Ph-positive ALL.

      Allogeneic SCT clearly benefits certain high-risk patients, such as those with Ph-positive
      ALL or those that show a poor initial response to chemotherapy, and long-term survival rates
      with SCT are markedly increased when patients are in CR. Recent studies suggest that among
      adults with ALL, transplantation from a matched unrelated donor could yield results similar
      to those achieved by matched related donor transplantation. While unrelated donor transplants
      are generally associated with more transplant-related complications than matched sibling
      transplants, a compensatory decrease in relapse rates due to a strong graft-versus-leukemia
      effect has narrowed the gap between the two approaches. In addition, reduced-intensity
      conditioning allogeneic SCT is increasingly being used for patients who are considered poor
      candidates for myeloablative conditioning SCT because of their advanced age or other
      concurrent medical conditions. Two recent reports of patients undergoing a transplant using
      related or unrelated donor and a reduced-intensity conditioning regimen (fludarabine plus
      melphalan) showed an optimistic outcome in a group of patients with ALL either at high risk
      during first CR or who were transplanted after achieving a subsequent CR. Recently, we also
      demonstrated an evidence of positive role of reduced-intensity conditioning SCT for the
      management of high-risk adult ALL who are ineligible for myeloablative transplantation with
      low leukemic cell burden (especially in first CR) through a prospective analysis (phase 2
      study). From this point of view, the role of first-line dasatinib plus conventional
      chemotherapy followed by allogeneic SCT should be clarified in the era of targeted drugs.

      Recently, the results of the phase 3 study in patients with chronic phase-chronic myeloid
      leukemia suggest that dasatinib (100 mg q.d.) offers the most favorable overall benefit-risk
      assessment. On the basis of these results, dasatinib will be administered orally at 100 mg
      once a day in this study.

      Induction regimen: "Modified Hyper-CVAD"

        -  Cyclophosphamide 300 mg/m2, IV for 2 hours, every 12 hours x 6 doses, days 1-3

        -  Vincristine 1.4 mg/m2/day (maximum 2 mg/day), IV for 30 minutes, days 4 & 11

        -  Daunorubicin 45 mg/m2/day, IV for 1 hour, days 4 & 11

        -  Dexamethasone 40 mg/day, IV push, days 1~4 & days 11-14

      First consolidation regimen: "Cytarabine and Mitoxantrone"

        -  Cytarabine 2 g/m2, IV for 3 hours, every 12 hours x 10 doses, days 1-5

        -  Mitoxantrone 12 mg/m2/day, IV for 30 minutes, days 1-2

      Second consolidation regimen: "Modified Hyper-CVAD"

        -  Cyclophosphamide 300 mg/m2, IV over 2 hours, every 12 hours x 6 doses, days 1-3

        -  Vincristine 1.4 mg/m2/day (maximum 2 mg/day), IV for 30 minutes, days 4 & 11

        -  Daunorubicin 45 mg/m2/day, IV for 1 hour, days 4 & 11

        -  Dexamethasone 40 mg/day, IV push, days 1-4 & days 11-14

      Dose of chemotherapeutic drugs (except vincristine, dexamethasone, and etoposide) will be
      reduced by 25% in patients aged between 50 and 59 years; and by 50% in patients 60 years or
      older. During the consolidation phase, serious toxicities (more than or equal to grade 3
      non-hematologic toxicities) will require subsequent dose reductions of 25% to 50% at the
      attending physician's discretion.

      Central nervous system prophylaxis will be performed by intrathecally administering triple
      agents (methotrexate 12 mg, cytarabine 40 mg, and hydrocortisone 50 mg; 6 times in total).

      After the completion of each induction and consolidation chemotherapy with recovery of
      leukocyte and platelet counts, dasatinib will be given as an alternative manner (100 mg once
      daily by mouth for 4 weeks).

      Dasatinib dose adjustment will be performed according to the guidelines for managing
      hematologic and nonhematologic adverse events during dasatinib treatment. Briefly,

        1. Dose escalation will be permitted in patients with no hematologic CR (to 140 mg daily;
           140 mg q.d. or 70 mg b.i.d.).

        2. Dose reduction (to 80 mg daily; 80 mg q.d. or 40 mg b.i.d.) and interruption will be
           permitted after dasatinib-related grades 3-4 hematologic toxicity or grades 2-4
           nonhematologic toxicity .

      Dasatinib will be administered until disease progression or intolerable toxicity, as
      determined by the treating physician.

      Patients with an HLA-matched or suitable donor will undergo allogeneic SCT.

      Patients without a donor will undergo continuous consolidation (up to 4 courses) and
      maintenance therapy (dasatinib 100 mg once daily for up to 2 years as long as the patients
      remain in hematologic CR with stable MRD level).

      The number of dasatinib plus conventional chemotherapy will be dependent on the speed of
      coordination process (for transplants) or the patient's tolerability (for non-transplants).

      SCT from an HLA-matched sibling or a suitably matched (less than or equal to 2-allele
      mismatched) family or unrelated donor will be performed according to the policies of the
      participating institutions. A preparative regimen will be started 7 days after the last day
      of the dasatinib treatment.

      No prophylactic dasatinib maintenance therapy is planned after SCT.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

To determine the clinical efficacy of dasatinib plus conventional chemotherapy for newly diagnosed Ph-positive ALL in terms of major molecular response rate

Secondary Outcome

 To evaluate the long-term clinical outcomes (including transplant outcomes) in terms of treatment toxicity, relapse, disease-free survival, and overall survival

Condition

Acute Lymphoblastic Leukemia

Intervention

Dasatinib

Study Arms / Comparison Groups

 Modified Hyper-CVAD + Dasatinib
Description:  Dasatinib: 100 mg once daily, PO, for 4 weeks Cyclophosphamide: 300 mg/m2, IV, every 12 hours, days 1~3 Vincristine: 1.4 mg/m2/day (maximum 2 mg/day), IV, days 4 & 11 Daunorubicin: 45 mg/m2/day, IV, days 4 & 11 Dexamethasone: 40 mg/day, IV, days 1~4 & days 11~14 Cytarabine: 2 g/m2, IV, every 12 hours, days 1~5 Mitoxantrone: 12 mg/m2/day, IV, days 1~2

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

51

Start Date

March 2010

Completion Date

April 2015

Primary Completion Date

April 2014

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with newly diagnosed acute lymphoblastic or biphenotypic leukemia (karyotypic
             or molecular evidence of Ph)

          -  Ages of 15-65 years

          -  Eastern Cooperative Oncology Group performance status of 0-2

          -  Adequate renal (serum creatinine less than 2 mg/dl, unless considered due to leukemia)
             and hepatic (serum bilirubin less than 3 mg/dl, unless considered due to leukemia)
             functions

          -  Adequate cardiac status (New York Heart Association Class less than or equal to 2)

          -  Signed informed consent

        Exclusion Criteria:

          -  Pregnant and lactating women will not be eligible. Women of childbearing potential
             should have a negative pregnancy test prior to entering on the study.

          -  Active cardiac dysfunction (New York Heart Association Class more than or equal to 3),
             uncontrolled angina, myocardial infarction (within 6 months), congenital long QT
             syndrome, any history of clinically significant ventricular arrhythmias (such as
             ventricular tachycardia or ventricular fibrillation), or prolonged QTc interval on
             pre-entry electrocardiogram (more than 470 msec)

          -  Patients with documented significant pleural or pericardial effusions unless they are
             thought to be secondary to their leukemia

          -  Patients with severe medical conditions that in the view of the investigator prohibits
             participation in the study

          -  Treatment with any other investigational antileukemic agents in the last 30 days
             before study entry
      

Gender

All

Ages

15 Years - 65 Years

Accepts Healthy Volunteers

No

Contacts

Seok Lee, M.D., , 

Location Countries

Korea, Republic of

Location Countries

Korea, Republic of

Administrative Informations


NCT ID

NCT01004497

Organization ID

KC09MIMS0255


Responsible Party

Principal Investigator

Study Sponsor

The Catholic University of Korea


Study Sponsor

Seok Lee, M.D., Principal Investigator, Catholic BMT Center, Seoul St. Mary's Hospital, The Catholic University of Korea


Verification Date

May 2015