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

NCT ID: NCT00918723

Last Updated: 2020-02-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-06-30
• Study Completion Date: 2016-10-31

Brief Summary

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

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.

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (induction and maintenance chemotherapy)

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.

Group Type: EXPERIMENTAL

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Cyclophosphamide

Intervention Type: DRUG

Given IV

Rituximab

Intervention Type: BIOLOGICAL

Given IV

Vorinostat

Intervention Type: DRUG

Given PO

Interventions

Fludarabine Phosphate

Given IV

Intervention Type: DRUG

Cyclophosphamide

Given IV

Intervention Type: DRUG

Rituximab

Given IV

Intervention Type: BIOLOGICAL

Vorinostat

Given PO

Intervention Type: DRUG

Other Intervention Names

2-F-ara-AMP; Beneflur; SH T 586; MOAB IDEC-C2B8; L-001079038; SAHA; Suberanilohydroxamic Acid; Suberoylanilide Hydroxamic Acid

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Mazyar Shadman

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Locations

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

Countries

United States

Other Identifiers

NCI-2010-00324

Identifier Type: REGISTRY

Identifier Source: secondary_id

PSOC 2401

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA015704

Identifier Type: NIH

Identifier Source: secondary_id

View Link

PSOC 2401

Identifier Type: -

Identifier Source: org_study_id