Vorinostat, Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase I/II Study of Fludarabine, Cyclophosphamide, Rituximab, and Vorinostat Followed by Rituximab and Vorinostat Maintenance Therapy in Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Conditions
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Chronic Lymphocytic Leukemia, Stage I Chronic Lymphocytic Leukemia, Stage I Small Lymphocytic Lymphoma, Stage II Chronic Lymphocytic Leukemia, Stage II Small Lymphocytic Lymphoma, Stage III Chronic Lymphocytic Leukemia, Stage III Small Lymphocytic Lymphoma, Stage IV Chronic Lymphocytic Leukemia, Stage IV Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: Fludarabine Phosphate
* Drug: Cyclophosphamide
* Biological: Rituximab
* Drug: Vorinostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a confirmed diagnosis of CLL/SLL Patients with previously untreated cluster of differentiation (CD)20+ CLL/SLL must have either Rai stage III/IV disease or be Rai stage I/II with evidence of disease activity as defined by the National Cancer Institute (NCI) 1996 guidelines; patients with SLL must be Stage III or IV per Ann Arbor staging system Patient must have consented to participate in the study and signed and dated an appropriate institutional review board (IRB)-approved consent form that conforms to federal and institutional guidelines Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 Patient must have an anticipated (untreated) survival of at least 3 months Female patient of childbearing potential has a negative serum pregnancy test beta-human chorionic gonadotropin (hCG) within 2 weeks prior to receiving the first dose of vorinostat Female patient is either post menopausal, free from menses for >= 2 years, surgically sterilized or willing to use 2 adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from heterosexual activity throughout the study, starting with Visit 1 Male patients not sterilized must be willing to use adequate barrier methods of contraception to prevent pregnancy or agrees to abstain from heterosexual activity throughout the study, starting with Visit 1 Absolute Neutrophil Count (ANC) >= 1,500/mcL Platelets >= 100,000/mcL Hemoglobin >= 9 g/dL Prothrombin time or international normalized ratio (INR) =< 1.5 upper limit of normal (ULN) unless receiving therapeutic anticoagulation Partial thromboplastin time (PTT) =< 1.2 times the ULN unless the patient is receiving therapeutic anticoagulation Potassium level within normal limits Magnesium level within normal limits Serum creatinine =< 1.5 x ULN OR if creatinine is > 1.5 ULN the calculated creatinine clearance must be >= 60 mL/min Serum total bilirubin =< 1.5 times ULN; patients with Gilbert's disease or similar syndrome involving slow conjugation of bilirubin are eligible with total bilirubin > 1.5 times upper limit of normal; principal investigator (PI) review and approval required for anything above 2 times ULN Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 ULN Alkaline phosphatase =< 2.5 ULN Patients with cytopenias due to disease or pseudohyperkalemia that do not meet these criteria, will be considered eligible with review and approval by the PI or Co-PI prior to study entry Exclusion Criteria: Patients who have received cytotoxic chemotherapy, radiation therapy, immunotherapy, or cytokine treatment prior to study entry for CLL/SLL; patients who have received systemic steroids within 1 week of study entry are excluded, except patients on maintenance steroid therapy for a noncancerous disease Patients with active hemolysis Patients must not require sustained transfusion support of blood products Patients who have undergone treatment with either stem cell or bone marrow transplant Patients with active obstructive hydronephrosis Patients with evidence of any significant systemic illness, active hepatitis B infection, active viral hepatitis infection or other active infection at the time of study entry Patients with New York Heart Association class III or IV heart disease symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or other serious illness, such as acute or chronic graft versus host disease, that would preclude evaluation Patients with congenital long QT syndrome and patients taking antiarrhythmic medicines or other medicinal products that lead to QT prolongation will only be eligible if their baseline corrected QT (QTc) prolongation is =< 500 msec Patients with known human immunodeficiency virus (HIV) infection Patients who are pregnant or nursing Patients with known brain or leptomeningeal involvement by malignancy Patients who have, in the opinion of the investigator, other medical, social, or psychosocial factors that may negatively impact compliance or their safety by participation in this study Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drugs(s) Patient had prior treatment with an histone deacetylases (HDAC) inhibitor (e.g., romidepsin [Depsipeptide], NSC-630176, MS 275, LAQ-824, belinostat [PXD-101], LBH589, MGCD0103, CRA024781, etc); patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not enroll in this study; patients who have received such compounds for other indications, e.g. valproic acid for epilepsy, may enroll after a 30-day washout period Patient with a history of a prior malignancy with the exception of cervical intraepithelial neoplasia; non-melanoma skin cancer; adequately treated localized prostate carcinoma with prostate-specific antigen (PSA) =< 1.0; or who has undergone potentially curative therapy with no evidence of that disease for five years, and/or who is deemed at low risk for recurrence by his/her treating physician

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (induction and maintenance chemotherapy)<br>INDUCTION THERAPY: Patients receive vorinostat PO once daily on days 1-5 and 8-12; cyclophosphamide 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. | Drug: Fludarabine Phosphate<br>* Given IV<br>* Other names: SH T 586;Drug: Cyclophosphamide<br>* Given IV<br>Biological: Rituximab<br>* Given IV<br>* Other names: MOAB IDEC-C2B8;Drug: Vorinostat<br>* Given PO<br>* Other names: Suberoylanilide Hydroxamic Acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |  | 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). | After completion of maintenance therapy (24 months after start of maintenance) |