A Study of Dasatinib Plus Reduced Intensive Consolidation Chemotherapy in Ph+ Adult ALL

Study Overview
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Brief Summary
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This project is a key clinical research project approved by the Clinical Research Center of the First Affiliated Hospital of Xi'an Jiaotong University. Tyrosine kinase inhibitors (TKI) combined with intensive chemotherapy has markedly improved the outcomes of philadelpha-positive lymphoblastic leukemia (Ph+ ALL). However, a considerable proportion of patients failed to complete the intended chemotherapy and some even died early. The optimal balance between the intensity of chemotherapy and safety should be explored. In this study, Ph+ ALL patients who achieve complete remission (CR) after VP regimen (vincristine and prednisone) plus dasatinib as induction are enrolled and then the participants will receive different consolidation chemotherapy. Patients in the group A will continue to use VP regimen plus dasatinib, while the group B receives hyper-CVAD/methotrexate-cytarabine regimen plus dasatinib. The measurable residual disease (MRD), CR, adverse effects (AE), overall survival (OS) and disease free survival (DFS) will be observed to determine the proper consolidation chemotherapy regimen.

Detailed Description
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About 25% of adult patients with acute lymphoblastic leukemia (ALL) are associated with t (9; 22), positive philadelphia chromosome (Ph+ ALL), in whom BCR/ABL fusion gene can be detected in the bone marrow and peripheral blood. The use of tyrosine kinase inhibitors (TKI) plus intensive chemotherapy has markedly improved the outcomes of Ph+ ALL. However, it's reported that 74% pf patients failed to complete the intended chemotherapy, and early death occured in a considerable proportion of patients during induction. The optimal balance between the intensity of chemotherapy and safety need to be explored. In this study, Ph+ ALL patients are enrolled. The participants will receive dasatinib and induction chemotherapy using VP regimen (vincristine and prednisone) to achieve complete remission (CR). Then the participants will be randomly divided into two groups. The subjects inthe group A will continue to use VP regimen plus dasatinib as consolidation, while the patients in the group B receive hyper-CVAD/methotrexate-cytarabine regimen plus dasatinib. The measurable residual disease (MRD), CR, adverse effects (AE), overall survival (OS) and disease free survival (DFS) will be observed to determine the proper consolidation chemotherapy regimen.

Official Title
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A Randomized Controlled Study of Dasatinib Combined With Reduced Intensive Consolidation Chemotherapy in Newly Diagosed Philadelphia Chromesome Positive Adult Lymphoblastic Leukemia

Conditions
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ALL, Adult, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Philadelphia-Positive Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: dasatinib plus consolidation chemotherapy with vincristine and prednisone
* Drug: dasatinib plus consolidation chemotherapy with high-dose methotrexate and cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-65 years old, newly diagnosed as Ph+ALL. Sign the informed consent. Accept consolidation chemotherapy. Accept follow-up. Exclusion Criteria: Liver and kidney function impairment: serum transaminase > 2 times of the upper limit of normal value, total bilirubin > 1.5 times of the upper limit of normal value, serum inosine > the upper limit of normal value (97 umol/L). Active hepatitis B, hepatitis C or tuberculosis infection. Can not tolerate the adverse effects of dasatinib. Pregnancy. Diagnosis of mental disorders. Do not accept follow-up.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dasatinib, Vincristine and Prednisone<br>After induction therapy, the patients in the 'Dasatinib, Vincristine and Prednisone' group will receive dasatinib and consolidation chemotherapy with vincristine and prednisone. | Drug: dasatinib plus consolidation chemotherapy with vincristine and prednisone<br>* After induction therapy, the patients in the 'Dasatinib, Vincristine and Prednisone' group will receive dasatinib and consolidation chemotherapy with vincristine and prednisone.<br>* Other names: Dasatinib + VP Regimen;|
| Experimental: Dasatinib, Methotrexate and Cytarabine<br>After induction therapy, the patients in the 'Dasatinib, Methotrexate and Cytarabine' group will receive dasatinib and consolidation chemotherapy with high-dose methotrexate and cytarabine. | Drug: dasatinib plus consolidation chemotherapy with high-dose methotrexate and cytarabine<br>* After induction therapy, the patients in the 'Dasatinib, Methotrexate and Cytarabine' group will receive dasatinib and consolidation chemotherapy with high-dose methotrexate and cytarabine.<br>* Other names: Dasatinib + HyperB Regimen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Measurable Residual Disease (MRD) Positivity | MRD refers to the subclinical levels of residual leukemia. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months. | 
| Percentage of Participants with Complete Remission (CR) | CR means that the blood counts have returned to normal, the leukemia cannot be seen when a bone marrow sample is examined under the microscope, and the signs and symptoms of the ALL are gone. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| disease-free survival (DFS), months | The measure of time after consolidation chemotherapy during which no sign of ALL is found. | From date of consolidation chemotherapy until disease progression, the end of follow-up or the date of death from any cause, whichever came first. | 
| overall survival (OS), months | The length of time from the date of diagnosis that Ph+ ALL patients are still alive. | From date of consolidation chemotherapy until the end of follow-up or the date of death from any cause, whichever came first. | 
| adverse effects (AE) | An adverse effect is any untoward medical occurrence in clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. | From date of consolidation chemotherapy until the end of follow-up or the date of death from any cause, whichever came first. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Philadelphia-Positive, Adult Acute Lymphoblastic Leukemia, Tyrosine Kinase Inhibitor, Consolidation Chemotherapy