PRIMARY OBJECTIVES:
I. To test whether the relapse-free survival after allogeneic stem cell transplantation among Philadelphia chromosome positive and/or BCR/ABL positive acute lymphoblastic leukemia (ALL) patients given an intensive short-term chemotherapy regimen of hyper-CVAD in combination with the tyrosine kinase inhibitor dasatinib is sufficiently high to warrant further investigation.
SECONDARY OBJECTIVES:
I. To test whether the continuous complete remission rate for previously untreated Philadelphia chromosome positive and/or BCR/ABL positive acute lymphoblastic leukemia (ALL) patients given an intensive short-term chemotherapy regimen of hyper-CVAD in combination with the tyrosine kinase inhibitor dasatinib is sufficiently high to warrant Phase III investigation.
II. To investigate in a preliminary manner the relative effectiveness of MRD detection using real-time quantitative PCR for BCR/ABL versus flow cytometry to predict the outcome of patients treated by the hyper-CVAD + dasatinib regimen and/or allogeneic stem cell transplant.
TERTIARY OBJECTIVES:
I. To estimate the frequency and severity of toxicities of the intensive short-term chemotherapy regimen in these patients.
II. To estimate the overall survival of all patients on this study.
OUTLINE: This is a multicenter study.
Patients are stratified according to prior treatment and response (untreated vs achieved complete remission [CR] with or without [CRi] hematopoietic recovery vs treated, refractory, and no CR or CRi).
INDUCTION/CONSOLIDATION THERAPY: All patients receive both of the following regimens in alternating courses:
COURSES 1, 3, 5, 7 or 3, 5, 7, 9: Patients receive cyclophosphamide intravenously (IV) over 3 hours twice daily on days 1-3; doxorubicin hydrochloride IV over 24 hours on day 4; vincristine sulfate IV over 30 minutes on days 4 and 11; dexamethasone IV or orally (PO) once daily on days 1-4 and 11-14; dasatinib PO once daily on days 1-14; cytarabine intrathecally (IT) on day 7; methotrexate IT on day 2; and filgrastim (G-CSF) subcutaneously (SC) once or twice daily.
COURSES 2, 4, 6, 8: Patients receive high-dose methotrexate IV over 24 hours on day 1; methylprednisolone IV over 30 minutes twice daily on days 1-3; dasatinib PO once daily on days 1-14; high-dose cytarabine IV over 2 hours twice daily on days 2-3; leucovorin calcium IV on days 2 or 3; methotrexate IT on day 2; cytarabine IT on day 7; and G-CSF SC once or twice daily.
Treatment repeats every 14-21 days for 8 courses in the absence of disease progression, unacceptable toxicity, or if patient achieves CR or CRi.
MAINTENANCE THERAPY*: Patients receive vincristine sulfate IV over 30 minutes on day 1, prednisone PO once daily on days 1-5, and dasatinib PO once daily on days 1-28.
Treatment repeats every month for 24 courses in the absence of disease progression or unacceptable toxicity or until the transplant is ready.
INTENSIFICATION: For courses 6 and 13, patients receive cyclophosphamide IV over 3 hours twice daily on days 1-3; doxorubicin hydrochloride IV over 24 hours on day 4; vincristine sulfate IV over 30 minutes on days 4 and 11; dexamethasone IV or orally once daily on days 1-4 and 11-14; dasatinib PO once daily on days 1-14; and G-CSF SC once or twice daily.
NOTE: *Only if transplantation is not ready after induction/consolidation therapy or patients are not undergoing a transplant.
ALLOGENEIC STEM CELL TRANSPLANTATION (FOR PATIENTS ACHIEVING CR OR CRi):
CONDITIONING REGIMEN: Patients receive 1 of the following regimens:
REGIMEN A: Patients receive total-body irradiation (TBI) once daily on days -7 to -4 and cyclophosphamide IV on days -3 and -2.
REGIMEN B: Patients receive TBI twice daily on days -6 to -4 and cyclophosphamide IV on days -3 and -2.
REGIMEN C: Patients receive cyclophosphamide IV on days -7 and -6 and TBI once daily on days -4 to -1.
REGIMEN D: Patients receive cyclophosphamide IV on days -6 and -5 and TBI twice daily on days -3 to -1.
REGIMEN E: Patients receive TBI once daily on days -7 to -4 and etoposide IV on day -3.
REGIMEN F: Patients receive TBI twice daily on days -6 to -4 and etoposide IV on day -3.
ALLOGENEIC STEM CALL TRANSPLANTATION: Patients undergo allogeneic stem cell transplantation on day 0.
GRAFT-VS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients receive 1 of the following regimens:
REGIMEN A: Patients receive sirolimus PO and tacrolimus IV continuously (changing to PO twice daily) beginning on day -3 and continuing for 6 months.
REGIMEN B: Patients receive tacrolimus IV continuously (changing to PO twice daily) and continuing for 6 months, and methotrexate IV on days 1, 3, 6, and 11.
SINGLE-AGENT THERAPY: After completion of maintenance therapy or beginning on day 100 post-transplantation, patients receive dasatinib PO once daily for up to 5 years.
Bone marrow and blood samples are collected periodically for cytogenetic analysis by PCR and flow cytometry.
After completion of study therapy, patients are followed every 6 months for up to 5 years.
Inclusion Criteria:
- Morphologic diagnosis of acute lymphoblastic leukemia (ALL) with evidence of involvement in bone marrow and/or blood
- No extramedullary disease in the absence of bone marrow or blood involvement
- Philadelphia chromosome (Ph)- and/or BCR/ABL-positive as confirmed by standard cytogenetics, FISH, and/or PCR
- No minimally differentiated acute myeloid leukemia (M0), mixed lineage leukemia, or L3 (Burkitt) ALL
- Lineage (B-cell, T-cell, or mixed B/T cell) must be determined
- Appropriate marker studies, including CD19 (B-cell), CD10, CD5, and CD7 (T-cell) must be performed
- Co-expression of myeloid antigens (CD13 and CD33) allowed
- Must be enrolled on clinical trials SWOG-9007, and ECOG-E3903 or CALGB-8461 (for ECOG and CALGB sites)
- Patients may have received no more than one course of remission induction therapy for ALL; patients who have received any post-remission therapy for ALL or who have relapsed from complete remission are not eligible; (patients with previously untreated ALL can be eligible, and patients who have received one course of remission induction therapy for ALL can be eligible, regardless of their response to therapy); patients may have received no more than 14 days of tyrosine kinase inhibitor therapy prior to registration; any prior induction chemotherapy must have been completed no more than 28 days prior to registration
- NOTE: If the patient has been initiated on the protocol defined regimen (i.e. the hyperCVAD regimen without a Tyrosine kinase inhibitor) before the Ph/BCR-ABL status was known, the patient may be registered on the protocol and start dasatinib; in this first course, dasatinib will be administered up to Day 14 (i.e. if the patient is registered on Day 5 and starts therapy on Day 6, only 8 days of dasatinib will be administered and dasatinib will be completed on Day 14)
- No active pericardial effusion, ascites, or pleural effusion of any grade
- Available matched donor meeting the following criteria:
- Completely matched (i.e., HLA-A, -B, DRβ1) sibling donor OR 10/10-matched non-sibling donor
- Must not be monozygotic identical twin of patient
- Zubrod performance status 0-2
- Bilirubin ≤ 3.0 times upper limit of normal (ULN)
- AST and/or ALT ≤ 3.0 times ULN
- Serum creatinine ≤ 3.0 times ULN
- Patients must not be pregnant or nursing because of the teratogenic potential of the drugs used in this study; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures
- HIV-positive patients allowed except in transplantation portion of the study
- No prolonged QTc interval (QTc > 480 msec)
- No other prior malignancy except for any of the following:
- Adequately treated basal cell or squamous cell skin cancer
- In situ cervical cancer
- Adequately treated stage I or II cancer from which the patient is currently in complete remission
- Any other cancer from which the patient has been disease-free for 5 years
- No known history of type I hypersensitivity or anaphylactic reactions to doxorubicin
- More than 28 days since prior induction chemotherapy
- Collection and submission of pre-treatment cytogenetic specimens must be completed within 28 days prior to registration on S0805
Last updated: 04/01/2013
NCT ID: NCT00792948
IRB Number:10-007558
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