A Phase II Study of Combination Nilotinib and Hyper-CVAD in Patients Newly Diagnosed With Philadelphia-Chromosome Positive Acute Lymphoblastic Leukemia or Chronic Myeloid Leukemia Blast-Phase Lymphoid Lineage
I. To determine the clinical efficacy (2-year disease-free survival rate) of nilotinib and
combination chemotherapy in adult patients newly diagnosed with Philadelphia chromosome
positive B-cell acute lymphoblastic leukemia or blast crisis of chronic myeloid leukemia.
I. Determine the 2-year overall survival rate. II. Determine the complete response (CR)
rates (hematological, cytogenetic, and molecular) in patients treated with this regimen.
III. Determine the CR duration in patients treated with this regimen. IV. Assess the safety
and toxicity of this regimen by National Cancer Institute (NCI) Common Terminology Criteria
for Adverse Events (CTCAE) version 4.0.
I. Assess the prognostic and predictive factors for patients treated with this regimen.
II. Assess the cerebrospinal fluid (CSF) penetration for Nilotinib (CSF Nilotinib levels) in
III. Assess the Abelson (ABL) kinase domain mutations frequency at diagnosis, during
therapy, and at relapse.
INDUCTION AND CONSOLIDATION SCHEDULE A (COURSES 1, 3, 5, 7): Patients receive
cyclophosphamide intravenously (IV) twice daily (BID) over 2 hours on days 1-3, mesna IV
continuously on days 1-3, doxorubicin hydrochloride IV push on day 4, vincristine sulfate IV
on days 4 and 11, dexamethasone IV or orally (PO) on days 1-4 and 11-14, methotrexate
intrathecally (IT) on day 2, cytarabine IT on day 8, and nilotinib PO BID on days 1-14.
Patients with CD20-positive disease also receive rituximab IV on days 1 and 11.
INDUCTION AND CONSOLIDATION SCHEDULE B (COURSES 2, 4, 6, 8): Patients receive methotrexate
IV continuously over 24 hours on day 1, cytarabine IV over 2 hours on days 2-3, leucovorin
calcium IV every 6 hours on days 2-3, methotrexate IT on day 2, cytarabine IT on day 8, and
nilotinib PO BID on days 1-14. Patients with CD20-positive disease also receive rituximab IV
on days 1 and 11.
MAINTENANCE (COURSES 9-32): Patients receive nilotinib PO BID on days 1-28 (days 1-14 for
minimal residual disease [MRD]-positive patients), vincristine sulfate IV on day 1, and
prednisone PO on days 1 to 5. Patients also receive rituximab IV on day 1 of each course if
CD20-positive, every sixth course if MRD-negative, or every third course if MRD-positive.
INTENSIFICATION: Patients receive treatment as in Schedule A in courses 14 and 21 of
maintenance therapy and treatment as in Schedule B in courses 15 and 22 of maintenance
DELAYED MAINTENANCE (COURSES 33-36): Patients receive nilotinib PO BID on days 1 to 84.
Treatment repeats every 84 days for up to 4 courses.
Treatment continues in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6-12 months for 4 years.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Disease-free survival rate, defined as a patient who is alive and relapse-free, in patients who achieve a CR during the first 2 courses out to 2 years
The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.
Aref Al-Kali, M.D.
United States: Food and Drug Administration
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