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
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
In this study researchers want to find out more about the side effects of a new drug for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML) blastic phase (BP) and if this disease will respond better to nilotinib combined with standard hyper-CVAD therapy rather than hyper-CVAD alone. Hyper-CVAD is a combination of cyclophosphamide, mesna, vincristine (vincristine sulfate), doxorubicin (doxorubicin hydrochloride), dexamethasone, methotrexate, cytarabine, and rituximab (only for patients with cluster of differentiation [CD]20 positive disease). Researchers don't know all the ways that this drug may affect people
PRIMARY OBJECTIVES:
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.
SECONDARY OBJECTIVES:
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.
TERTIARY OBJECTIVES:
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 humans.
III. Assess the Abelson (ABL) kinase domain mutations frequency at diagnosis, during therapy, and at relapse.
OUTLINE:
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 therapy.
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.
Inclusion Criteria:
Exclusion Criteria:
Any of the following because this study involves investigational agent(s) whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive (even if on highly active antiretroviral therapy [HAART])
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
Other active malignancy =< 3 years prior to registration; EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix
History of myocardial infarction =< 12 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
Previous treatment with chemotherapy or any other tyrosine kinase inhibitor (prior imatinib or dasatinib for CML-CP/-AP is allowed)
Impaired cardiac function including any one of the following:
Patients receiving any medications or substances that are strong or moderate inhibitors of cytochrome P450 3A4 (CYP3A4); use of the following strong or moderate inhibitors are prohibited =< 7 days prior to registration:
Strong Inhibitors of CYP3A4; > 5-fold increase in the plasma area under the curve (AUC) values or more than 80% decrease in clearance
Moderate Inhibitors of CYP3A4; > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance
Patients receiving any medications or substances that are inducers of CYP3A4; use of the following inducers are prohibited =< 7 days prior to registration
* Inducers of CYP3A4
Patients currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug
Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection or gastric bypass surgery)
Acute or chronic pancreatic disease
Known cytopathologically confirmed central nervous system (CNS) infiltration
Acute or chronic liver disease or severe renal disease considered unrelated to the cancer
History of significant congenital or acquired bleeding disorder unrelated to cancer
Major surgery =< 4 weeks prior to registration or not recovered from prior surgery
Treatment with other investigational agents =< 14 days of registration