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Vincristine Sulfate

Farhad Ravandi-Kashani

This phase II trial is studying the side effects of giving combination chemotherapy together with or without donor stem cell transplant and to see how well it works in treating patients with acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect).

PRIMARY OBJECTIVES:

I. To test whether the relapse-free survival after allogeneic stem cell transplantation among Philadelphia chromosome positive and/or breakpoint cluster region (BCR)/Abelson murine leukemia viral oncogene (ABL) positive acute lymphoblastic leukemia (ALL) patients given an intensive short-term chemotherapy regimen of fractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (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 minimal residual disease (MRD) detection using real-time quantitative polymerase chain reaction (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:

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 (BID) 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 (QD) on days 1-4 and 11-14; dasatinib PO QD on days 1-14; cytarabine intrathecally (IT) on day 7; methotrexate IT on day 2; and filgrastim (G-CSF) subcutaneously (SC) QD or BID.

COURSES 2, 4, 6, 8: Patients receive high-dose methotrexate IV over 24 hours on day 1; methylprednisolone IV over 30 minutes BID on days 1-3; dasatinib PO QD on days 1-14; high-dose cytarabine IV over 2 hours BID 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 QD or BID.

Treatment repeats every 14-21 days for 8 courses in the absence of disease progression, unacceptable toxicity, or if patient achieves complete remission (CR) or complete remission with incomplete platelet recovery (CRi).

MAINTENANCE THERAPY\*: Patients receive vincristine sulfate IV over 30 minutes on day 1, prednisone PO QD on days 1-5, and dasatinib PO QD 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 BID 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 PO QD on days 1-4 and 11-14; dasatinib PO QD on days 1-14; and G-CSF SC QD or BID.

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) QD on days -7 to -4 and cyclophosphamide IV on days -3 and -2.

REGIMEN B: Patients receive TBI BID 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 QD on days -4 to -1.

REGIMEN D: Patients receive cyclophosphamide IV on days -6 and -5 and TBI BID on days -3 to -1.

REGIMEN E: Patients receive TBI QD on days -7 to -4 and etoposide IV on day -3.

REGIMEN F: Patients receive TBI BID 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 BID) beginning on day -3 and continuing for 6 months.

REGIMEN B: Patients receive tacrolimus IV continuously (changing to PO BID) 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 QD for up to 5 years.

After completion of study therapy, patients are followed every 6 months for up to 5 years.

Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia

Phase II Study of Combination of Hyper-CVAD and Dasatinib (NSC-732517) With or Without Allogeneic Stem Cell Transplant in Patients With Philadelphia (Ph) Chromosome Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL) (A BMT Study)

OS will be estimated using the method of Kaplan-Meier.

Correlation between the two measures of MRD measured on the same remission specimens will be examined using scatterplots and correlation analysis. The prognostic effect for relapse of each measure will be illustrated using cumulative incidence plots, and estimated using Cox regression models. This outcome will be reported as funding allows.

Will be estimated using the method of Kaplan-Meier.

Will be testing using an exact binomial test

National Cancer Institute (NCI)

Analysis includes eligible patients who were assessed for adverse events.

Patients receive up to 8 courses, alternating between hyper-CVAD plus dasatinib and high dose methotrexate and cytarabine plus dasatinib. There are nine possible induction/consolidation courses.

Induction/Consolidation

Patients receive vincristine IV on day 1, prednisone PO on days 1 to 5, and dasatinib PO on days 1 to 28 for up to 24 courses or until transplant is available.

Vincristine/Prednisone/Dasatinib

Patients who have an available sibling donor or a 10/10 matched unrelated donor will be removed from therapy and proceed directly to allogeneic stem cell transplant after achieving CR or CRi.

Allogeneic Stem Cell Transplant

Patients receive Single-Agent Dasatinib therapy PO every day for up to five years from original registration.

Treatment

Age, Continuous

Sex: Female, Male

Analysis includes eligible patients who received treatment.

Leukemia Committee Statistician

See Detailed Description

Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic stem cell transplant

Cyclophosphamide: Given IV

Cytarabine: Given IT

Dasatinib: Given PO

Dexamethasone: Given IV or PO

Doxorubicin Hydrochloride: Given IV

Etoposide: Given IV

Filgrastim: Given SC

Laboratory Biomarker Analysis: Correlative studies

Leucovorin Calcium: Given IV

Methotrexate: Given IV or IT

Methylprednisolone: Given IV

Peripheral Blood Stem Cell Transplantation: Undergo allogeneic stem cell transplant

Prednisone: Given PO

Sirolimus: Given PO

Tacrolimus: Given IV

Total-Body Irradiation: Undergo TBI

Vincristine Sulfate: Given IV

Patients who received allogeneic stem cell transplant

Relapse-free Survival (RFS) After Allogeneic Stem Cell Transplantation

Patients who had not received prior ALL therapy

Continuous Complete Remission (CCR) Rate

Overall Survival (OS)

MRD as Assessed Using Real-time Quantitative Polymerase Chain Reaction and Flow Cytometry

Overall Study

Spots Global Cancer Trial Database for adult l2 acute lymphoblastic leukemia