This phase I/II trial studies the side effects and best dose of vorinostat when given together with fludarabine phosphate, cyclophosphamide, and rituximab and to see how well they work in treating patients with previously untreated B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Giving vorinostat together with fludarabine phosphate, cyclophosphamide, and rituximab may be a better treatment for CLL or SLL.
PRIMARY OBJECTIVES: I. To estimate the maximum tolerated dose (MTD) of vorinostat that can be combined with fludarabine (fludarabine phosphate), cyclophosphamide and rituximab (FCR) in patients with previously untreated CLL/SLL. II. To evaluate potential efficacy in terms of 2-year after FCR plus vorinostat induction followed by rituximab plus vorinostat maintenance therapy for previously untreated CLL/SLL patients. SECONDARY OBJECTIVES: I. To eliminate residual disease (documented by flow cytometry and/or polymerase chain reaction \[PCR\]) in patients who have achieved a complete response (CR) after FCR plus vorinostat. II. To estimate the rate of conversion of partial response (PR) to CR after FCR plus vorinostat. OUTLINE: This is a phase I, dose-escalation study of vorinostat followed by a phase II study. INDUCTION THERAPY: Patients receive vorinostat orally (PO) once daily on days 1-5 and 8-12; cyclophosphamide intravenously (IV) over 30-60 minutes and fludarabine phosphate IV over 30-60 minutes on days 1-3; and rituximab IV on day 1, 2, 3, 4, or 5. Treatment repeats every 28 days for 4-6 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Beginning 3 months after the completion of induction therapy, patients receive vorinostat PO on days 1-14 and rituximab IV on day 1. Treatment repeats every 3 months for 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 6 months for 5 years and then annually thereafter.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
Swedish Cancer Institute-Breast Center at First Hill Campus
Seattle, Washington, United States
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States
Maximum Tolerated Dose (MTD) of Vorinostat That Can be Combined With Fludarabine Phosphate, Cyclophosphamide and Rituximab (FCR) (Phase I)
The MTD of vorinostat in combination with FCR will be defined as the dose level immediately below the dose level at which greater than or equal to 2 patients out of 6 of a cohort experience dose-limiting toxicity. Toxicities will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Doses of vorinostat analyzed to reach the MTD were 200 mg, 300 mg and 400 mg.
Time frame: 28 days
Percentage of Patients With Progression-free Survival at 2 Years
Progression-free survival (PFS): The length of time during and after the treatment that a patient lives with the disease but it does not get worse. Progressive disease is specified by the NCI (National Cancer Institute) working group guidelines and additional CT (computerized tomography) scan requirements: Lymphadenopathy, \> 50% increase in the sum of the products of at least two lymph nodes on two consecutive determinations; one lymph node must be at least 2 cm. An increase in the liver or spleen size by 50% or more by CT scan or the de novo appearance of hepatomegaly or splenomegaly. An increase in the number of blood lymphocytes by 50% or more with at least 5000 B lymphocytes per microliter. Transformation to a more aggressive histology or occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.
Time frame: 2 years
Overall Survival
Overall survival (OS): The percentage of people in a study who are still alive at for a certain period of time after they started treatment.
Time frame: 2 years
To Eliminate Residual Disease (Documented by Flow Cytometry and/or Polymerase Chain Reaction [PCR]) in Patients Who Have Achieved Complete Response (CR) After Fludarabine, Cyclophosphamide, and Rituximab (FCR) Plus Vorinostat
Time frame: Within 21 days prior to starting maintenance therapy
To Estimate the Rate of Conversion of Partial Response (PR) to Complete Response (CR) After Fludarabine, Cyclophosphamide and Rituximab (FCR) Plus Vorinostat
Responses were measured after completion of FCR+ vorinostat induction therapy (within 21 days of starting maintenance) and again after completion of maintenance therapy (24 months after the start of maintenance therapy). Maintenance therapy began within 3 months after completion of induction therapy with FCR+vorinostat. Criteria for response are specified by the National Cancer Institute (NCI) working group guidelines; in addition, patients were required to meet computed tomography (CT) criteria as described in the protocol. Response categories include Complete Response (CR), Partial Response (PR), Nodular Partial Response (nPR), Stable Disease (SD) or Progressive Disease (PD).
Time frame: After completion of maintenance therapy (24 months after start of maintenance)
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.