First-line Dasatinib Plus Conventional Chemotherapy in Adults With Newly Diagnosed Ph-Positive ALL
|First Received Date ICMJE||October 29, 2009|
|Last Updated Date||April 29, 2013|
|Start Date ICMJE||March 2010|
|Estimated Primary Completion Date||March 2014 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||To determine the clinical efficacy of dasatinib plus conventional chemotherapy for newly diagnosed Ph-positive ALL in terms of major molecular response rate [ Time Frame: by the second 4-week dasatinib therapy ] [ Designated as safety issue: Yes ]|
|Original Primary Outcome Measures ICMJE
||To determine the clinical efficacy of dasatinib plus conventional chemotherapy for newly diagnosed Ph-positive ALL in terms of molecular CR rate [ Time Frame: after the second 4-week dasatinib therapy ] [ Designated as safety issue: Yes ]|
|Change History||Complete list of historical versions of study NCT01004497 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||To evaluate the long-term clinical outcomes (including transplant outcomes) in terms of treatment toxicity, relapse, disease-free survival, and overall survival [ Time Frame: at 2 years after transplantation (for all transplants); at 2 years after starting dasatinib maintenance (for all non-transplants) ] [ Designated as safety issue: Yes ]|
|Original Secondary Outcome Measures ICMJE
||To evaluate the long-term clinical outcomes (including transplant outcomes) in terms of treatment toxicity, relapse, disease-free survival, and overall survival [ Time Frame: after completion of study ] [ Designated as safety issue: Yes ]|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||First-line Dasatinib Plus Conventional Chemotherapy in Adults With Newly Diagnosed Ph-Positive ALL|
|Official Title ICMJE||A Phase 2 Multicenter Study of First-line Dasatinib Plus Conventional Chemotherapy in Adults With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia|
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.
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"
First consolidation regimen: "Cytarabine and Mitoxantrone"
Second consolidation regimen: "Modified Hyper-CVAD"
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,
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 Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Condition ICMJE||Acute Lymphoblastic Leukemia|
|Study Arm (s)||Experimental: Modified Hyper-CVAD + Dasatinib
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 *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Estimated Enrollment ICMJE||51|
|Estimated Completion Date||September 2014|
|Estimated Primary Completion Date||March 2014 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||15 Years to 65 Years|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Location Countries ICMJE||Korea, Republic of|
|NCT Number ICMJE||NCT01004497|
|Other Study ID Numbers ICMJE||KC09MIMS0255|
|Has Data Monitoring Committee||Yes|
|Responsible Party||Seok Lee, The Catholic University of Korea|
|Study Sponsor ICMJE||The Catholic University of Korea|
|Collaborators ICMJE||Not Provided|
|Information Provided By||The Catholic University of Korea|
|Verification Date||April 2013|
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