Acute Lymphoblastic Leukemia, BCR-ABL1 Fusion Protein Expression, Blast Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Philadelphia Chromosome Positive, Recurrent Acute Lymphoblastic Leukemia, t(9;22)
Conditions
Brief summary
This phase II trial studies how well combination chemotherapy and dasatinib works in treating participants with Philadelphia-positive or B-cell receptor-ABL positive acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, and cytarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving chemotherapy in combination with dasatinib may work better in treating participants with Philadelphia-positive or BCR-ABL positive acute lymphoblastic leukemia.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the clinical efficacy (event-free survival) of an intensive short-term chemotherapy regimen (Hyper- cyclophosphamide, vincristine, doxorubicin, dexamethasone \[CVAD\] program) given in combination with the tyrosine kinase inhibitor dasatinib for Philadelphia (Ph)-positive and/or B-cell receptor BCR-ABL-positive acute lymphoblastic leukemia (ALL). II. To evaluate other clinical efficacy (overall response rate and survival) and safety of an intensive short-term chemotherapy regimen (Hyper-CVAD program) given in combination with the tyrosine kinase inhibitor dasatinib for Philadelphia (Ph)-positive and/or BCR-ABL-positive acute lymphoblastic leukemia (ALL). OUTLINE: HYPER-CVAD THERAPY: Participants receive cyclophosphamide intravenously (IV) twice daily (BID) over 3 hours on days 1-3, vincristine IV over 30 minutes on days 4 and 11, and doxorubicin IV over 24-48 hours on day 4. Participants also receive dexamethasone orally (PO) or IV over 30 minutes on days 1-4 and 11-14, and dasatinib PO once daily (QD) on days 1-14 of course 1 and on days 1-21 for subsequent courses. Courses repeat every 21 days for up to 4 odd courses (1, 3, 5, and 7) in the absence of disease progression or unacceptable toxicity. METHOTREXATE PLUS CYTARABINE: Participants receive methotrexate IV over 24 hours on day 1, dasatinib PO on days 1-21, and cytarabine IV BID over 2 hours on days 2 and 3. Courses repeat every 21 days for up to 4 even courses (2, 4, 6, and 8) in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Participants receive vincristine IV over 30 minutes on day 1, prednisone PO on days 1-5, and dasatinib PO BID. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. During courses 6 and 13, participants may receive an additional course of hyper-CVAD therapy. After completion of study treatment, participants are followed for up to 12 months.
Interventions
DRUGCyclophosphamide
Given IV
DRUGCytarabine
Given IV or IT
DRUGDasatinib
Given PO
DRUGDexamethasone
Given IV or PO
DRUGDoxorubicin
Given IV
DRUGMethotrexate
Given IV or IT
DRUGPrednisone
Given PO
DRUGVincristine
Given IV
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of one of the following: Previously untreated Ph-positive acute lymphoblastic leukemia (ALL) (either t(9;22) and/or BCR-ABL positive) (includes patients initiated on first course of hyper-CVAD before cytogenetics known). These groups will be analyzed separately. After 1-2 courses of chemotherapy with or without imatinib mesylate (Gleevec). If they achieved complete response (CR), they are assessable only for event-free and overall survival, or if they failed to achieve CR, they are assessable for CR, event-free, and overall survival. Patients with relapsed Ph-positive ALL or lymphoid blast phase of chronic myelogenous leukemia (CML) * Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 * Adequate liver function (bilirubin less than or equal to 3.0 mg/dl, unless considered due to tumor), and renal function (creatinine less than or equal to 3.0 mg/dl, unless considered due to tumor) * Adequate cardiac function as assessed clinically * Signed informed consent
Exclusion criteria
* Active serious infection not controlled by oral or intravenous antibiotics * Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator * Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma or squamous cell carcinoma) that in the investigator's opinion will shorten survival to less than 1 year * Active grade III-V cardiac failure as defined by the New York Heart Association criteria. Uncontrolled angina, or myocardial infarction (MI) within 6 months. Diagnosed or suspected congenital long QT syndrome. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes). Prolonged corrected QT (QTc) interval on pre-entry electrocardiogram (\> 470 msec). Patients currently taking drugs that are generally accepted to have a risk of causing Torsades de Pointes (unless these can be changed to acceptable alternatives) * Prior history of treatment with dasatinib * Pregnant and lactating women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to practice methods of contraception. Women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 12 months. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control * History of significant bleeding disorder unrelated to cancer, including: * Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease) * Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies) * Patients with documented significant pleural or pericardial effusions unless they are thought to be secondary to their leukemia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival Rate (EFS) | Up to 17 years, 4 months, 2 days | Time from date of treatment start until the date of failure or death from any cause. |
| Disease-free Survival | Up to 17 years, 4 months, 2 days | Time from date of treatment start until the date of first objective documentation of disease-relapse. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With a Response | Up to 17 years, 4 months, 2 days | Participants achieving complete remission (CR) + partial remission (PR) - Complete Remission (CR): Normalization of the peripheral blood and bone marrow with 5% or less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 10\^9/L or above, and platelet count of 100 x 10\^9/L. Complete resolution of all sites of extramedullary disease is required for CR. |
| Overall Survival | Up to 17 years, 4 months, 2 days | Time from date of treatment start until date of death due to any cause or last Follow-up. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Chemotherapy, Dasatinib) See detailed description in outline.
Cyclophosphamide: Given IV
Cytarabine: Given IV or IT
Dasatinib: Given PO
Dexamethasone: Given IV or PO
Doxorubicin: Given IV
Methotrexate: Given IV or IT
Prednisone: Given PO
Vincristine: Given IV | 107 |
| Total | 107 |
Baseline characteristics
| Characteristic | Treatment (Chemotherapy, Dasatinib) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 20 Participants |
| Age, Categorical Between 18 and 65 years | 87 Participants |
| Age, Continuous | 53 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 30 Participants |
| Race (NIH/OMB) White | 60 Participants |
| Region of Enrollment United States | 107 participants |
| Sex: Female, Male Female | 48 Participants |
| Sex: Female, Male Male | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 107 |
| other Total, other adverse events | 0 / 107 |
| serious Total, serious adverse events | 38 / 107 |
Outcome results
Primary
Disease-free Survival
Time from date of treatment start until the date of first objective documentation of disease-relapse.
Time frame: Up to 17 years, 4 months, 2 days
Population: Of the 107 participants registered on study, 95 were evaluable for Disease Free Survival.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Chemotherapy, Dasatinib) | Disease-free Survival | 25.3 Months |
Primary
Event-free Survival Rate (EFS)
Time from date of treatment start until the date of failure or death from any cause.
Time frame: Up to 17 years, 4 months, 2 days
Population: Of the 107 participants registered on study, 106 were evaluable for Event Free Survival.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Chemotherapy, Dasatinib) | Event-free Survival Rate (EFS) | 21.3 Months |
Secondary
Overall Survival
Time from date of treatment start until date of death due to any cause or last Follow-up.
Time frame: Up to 17 years, 4 months, 2 days
Population: Of the 107 participants registered on study, 106 were evaluable for Overall Survival.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Chemotherapy, Dasatinib) | Overall Survival | 42.9 Months |
Secondary
Participants With a Response
Participants achieving complete remission (CR) + partial remission (PR) - Complete Remission (CR): Normalization of the peripheral blood and bone marrow with 5% or less blasts in normocellular or hypercellular marrow with a granulocyte count of 1 x 10\^9/L or above, and platelet count of 100 x 10\^9/L. Complete resolution of all sites of extramedullary disease is required for CR.
Time frame: Up to 17 years, 4 months, 2 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Chemotherapy, Dasatinib) | Participants With a Response | 95 Participants |