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.
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.
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.
- 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