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

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00918723
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 40
• Locations: 2
• Arm: 1
• Actual Duration (Months): 88
• Patients Per Site: 20
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Fludarabine Phosphate; Drug: Cyclophosphamide; Biological: Rituximab; Drug: Vorinostat	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

2. 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:

1. 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.

2. 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 Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Oct 1, 2016
• Actual Study Completion Date: Oct 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 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.

Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP Beneflur SH T 586 ; Drug: Cyclophosphamide; Given IV; Biological: Rituximab; Given IV; Other Names: MOAB IDEC-C2B8 ; Drug: Vorinostat; Given PO; Other Names: L-001079038 SAHA Suberanilohydroxamic Acid Suberoylanilide Hydroxamic Acid

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Vorinostat That Can be Combined With Fludarabine Phosphate, Cyclophosphamide and Rituximab (FCR) (Phase I) [28 days]

   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.

2. Percentage of Patients With Progression-free Survival at 2 Years [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.

3. Overall Survival [2 years]

   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.

Secondary Outcome Measures

1. 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]

2. To Estimate the Rate of Conversion of Partial Response (PR) to Complete Response (CR) After Fludarabine, Cyclophosphamide and Rituximab (FCR) Plus Vorinostat [After completion of maintenance therapy (24 months after start of maintenance)]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Swedish Cancer Institute-Breast Center at First Hill Campus	Seattle	Washington	United States	98104
2	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mazyar Shadman, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00918723
• Other Study ID Numbers: PSOC 2401; NCI-2010-00324; PSOC 2401; P30CA015704
• First Posted: Jun 11, 2009
• Last Update Posted: Feb 25, 2020
• Last Verified: Feb 1, 2020

• Additional relevant MeSH terms: Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate; Vorinostat

Study Results

Participant Flow

Arm/Group Title	Treatment (Induction and Maintenance Chemotherapy)
Arm/Group Description	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. Fludarabine Phosphate: Given IV Cyclophosphamide: Given IV Rituximab: Given IV Vorinostat: Given PO
Period Title: Overall Study
STARTED	40
COMPLETED	40
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Induction and Maintenance Chemotherapy)
Arm/Group Description	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. Fludarabine Phosphate: Given IV Cyclophosphamide: Given IV Rituximab: Given IV Vorinostat: Given PO
Overall Participants	40
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	8 20%
Male	32 80%
Rai stage at the time of diagnosis (Count of Participants)
Rai stage 0	15 37.5%
Rai stage I/II	19 47.5%
Rai stage III/IV	6 15%
Rai stage at the time of treatment (Count of Participants)
Rai stage 0	0 0%
Rai stage I/II	23 57.5%
Rai stage III/IV	17 42.5%
Time to treatment (months) [Mean (Full Range) ]
Mean (Full Range) [months]	27
B symptoms (Count of Participants)
Count of Participants [Participants]	13 32.5%
del 17p (Cytogenetics/immunophenotypic characteristics) (Count of Participants)
Count of Participants [Participants]	2 5%
del 11q (Cytogenetics/immunophenotypic characteristics) (Count of Participants)
Count of Participants [Participants]	2 5%
Trisomy 12 (Cytogenetics/immunophenotypic characteristics) (Count of Participants)
Count of Participants [Participants]	4 10%
del 13q (Cytogenetics/immunophenotypic characteristics) (Count of Participants)
Count of Participants [Participants]	3 7.5%
Normal cytogenetic (Cytogenetics/immunophenotypic characteristics) (Count of Participants)
Count of Participants [Participants]	14 35%
Other chromosomal abnormalities (Cytogenetics/immunophenotypic characteristics) (Count of Participants)
Count of Participants [Participants]	6 15%
High CD38 expression (> 30%) (Cytogenetics/immunophenotypic characteristics) (Count of Participants)
Count of Participants [Participants]	20 50%
High ZAP-70 (> 20%) (Cytogenetics/immunophenotypic characteristics) (Count of Participants)
Count of Participants [Participants]	14 35%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Vorinostat That Can be Combined With Fludarabine Phosphate, Cyclophosphamide and Rituximab (FCR) (Phase I)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MTD for Vorinostat During Induction Therapy	MTD for Vorinostat During Maintenance Therapy
Arm/Group Description	MTD for patients who started induction therapy with FCR + vorinostat. 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. Fludarabine Phosphate: Given IV Cyclophosphamide: Given IV Rituximab: Given IV Vorinostat: Given PO	MTD for patients who started Rituximab + Vorinostat Maintenance Therapy. Maintenance therapy: Following 4-6 cycles of FCR plus vorinostat, maintenance Rituximab + Vorinostat will be given every 3 months (+/- two weeks) for 2 years. Vorinostat is given PO on days 1-14 of cycles. Rituximab: Given IV Vorinostat: Given PO
Measure Participants	40	26
Number [mg]	400	400

2. Primary Outcome

Title	Percentage of Patients With Progression-free Survival at 2 Years
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Induction and Maintenance Chemotherapy)
Arm/Group Description	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. Fludarabine Phosphate: Given IV Cyclophosphamide: Given IV Rituximab: Given IV Vorinostat: Given PO
Measure Participants	40
Number (95% Confidence Interval) [percentage of participants]	87 217.5%

3. Primary Outcome

Title	Overall Survival
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Induction and Maintenance Chemotherapy)
Arm/Group Description	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. Fludarabine Phosphate: Given IV Cyclophosphamide: Given IV Rituximab: Given IV Vorinostat: Given PO
Measure Participants	40
Number (95% Confidence Interval) [percentage of participants]	90 225%

4. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

Patients who achieved a complete response (CR) after induction therapy and had minimal residual disease (MRD) status tested using flow cytometry

Arm/Group Title	Treatment (Induction and Maintenance Chemotherapy)
Arm/Group Description	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. Fludarabine Phosphate: Given IV Cyclophosphamide: Given IV Rituximab: Given IV Vorinostat: Given PO
Measure Participants	23
MRD negative	21 52.5%
MRD positive	2 5%

5. Secondary Outcome

Title	To Estimate the Rate of Conversion of Partial Response (PR) to Complete Response (CR) After Fludarabine, Cyclophosphamide and Rituximab (FCR) Plus Vorinostat
Description	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)

Outcome Measure Data

Analysis Population Description

Participants who had a partial response (PR) or nodular partial response (nPR) after FCR+vorinostat induction therapy, as measured within 21 days of starting maintenance therapy. Maintenance therapy began within 3 months after completion of induction therapy with FCR+vorinostat.

Arm/Group Title	Treatment (Induction and Maintenance Chemotherapy)
Arm/Group Description	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. Fludarabine Phosphate: Given IV Cyclophosphamide: Given IV Rituximab: Given IV Vorinostat: Given PO
Measure Participants	6
Conversion from PR to CR	50 125%
Conversion from nPR (nodular PR) to CR	100 250%

Adverse Events

Time Frame	For each participant, adverse events were collected during treatment and for 30 days after the last dose of study drug.
Arm/Group Title	Treatment (Induction and Maintenance Chemotherapy)
Arm/Group Description	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. Fludarabine Phosphate: Given IV Cyclophosphamide: Given IV Rituximab: Given IV Vorinostat: Given PO
All Cause Mortality
	Treatment (Induction and Maintenance Chemotherapy)
	Affected / at Risk (%)	# Events
Total	1/40 (2.5%)
Serious Adverse Events
	Treatment (Induction and Maintenance Chemotherapy)
	Affected / at Risk (%)	# Events
Total	17/40 (42.5%)
Blood and lymphatic system disorders
Neutropenia Grade 3	1/40 (2.5%)	1
Cardiac disorders
Bradychardia Grade 3	1/40 (2.5%)	1
Gastrointestinal disorders
Gastroenteritis Grade 3	1/40 (2.5%)	1
Diarrhea Grade 3	1/40 (2.5%)	1
General disorders
Infusion reaction Grade 3	2/40 (5%)	2
Dehydration Grade 3	1/40 (2.5%)	1
Elective surgery	2/40 (5%)	2
Immune system disorders
Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome - Grade 3	1/40 (2.5%)	1
Infections and infestations
Sepsis Grade 5	1/40 (2.5%)	1
Bronchiectasis Grade 3	1/40 (2.5%)	1
Sepsis Grade 4	2/40 (5%)	2
Pneumonia Grade 3	1/40 (2.5%)	1
Sepsis Grade 3	1/40 (2.5%)	1
Skin and subcutaneous tissue disorders
Rash Grade 3	1/40 (2.5%)	1
Vascular disorders
Venous thromboemoblism Grade 4	1/40 (2.5%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Induction and Maintenance Chemotherapy)
	Affected / at Risk (%)	# Events
Total	40/40 (100%)
Blood and lymphatic system disorders
Anemia Grade 3	2/40 (5%)	2
Neutropenia Grade 2	10/40 (25%)	10
Neutropenia Grade 3	8/40 (20%)	8
Leukopenia Grade 3	12/40 (30%)	12
Neutropenia Grade 4	16/40 (40%)	16
Leukopenia Grade 4	8/40 (20%)	8
Thrombocytopenia Grade 2	6/40 (15%)	6
Thrombocytopenia Grade 3	6/40 (15%)	6
Thrombocytopenia Grade 4	4/40 (10%)	4
Cardiac disorders
Hypertension Grade 3	1/40 (2.5%)	1
Vasovagal episode Grade 3	1/40 (2.5%)	1
Gastrointestinal disorders
Nausea Grade 3	4/40 (10%)	4
Vomiting Grade 3	2/40 (5%)	2
Constipation Grade 3	2/40 (5%)	2
Diarrhea Grade 3	4/40 (10%)	4
Gastroenteritis Grade 3	1/40 (2.5%)	1
Dehydration Grade 3	1/40 (2.5%)	1
General disorders
Infusion reaction Grade 2	14/40 (35%)	14
Infusion reaction Grade 3	4/40 (10%)	4
Infusion reaction Grade 4	1/40 (2.5%)	1
Fatigue Grade 1	1/40 (2.5%)	1
Fatigue Grade 3	4/40 (10%)	4
Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome Grade 3	1/40 (2.5%)	1
Hepatobiliary disorders
Cholecystitis Grade 4	1/40 (2.5%)	1
Infections and infestations
Pneumonia Grade 4	1/40 (2.5%)	1
Bronchiectasis Grade 3	1/40 (2.5%)	1
Investigations
Hyperbilirubinemia Grade 2	4/40 (10%)	4
Hyperbilirubinemia Grade 3	1/40 (2.5%)	1
Elevated alkaline phosphatase Grade 3	1/40 (2.5%)	1
Elevated AST Grade 4	1/40 (2.5%)	1
Elevated AST Grade 3	1/40 (2.5%)	1
Hypoalbuminemia Grade 3	1/40 (2.5%)	1
Elevated lipase Grade 3	1/40 (2.5%)	1
Hypokalemia Grade 3	2/40 (5%)	2
Hypokalemia Grade 4	1/40 (2.5%)	1
Hypophosphatemia Grade 3	3/40 (7.5%)	3
Hyponatremia Grade 3	1/40 (2.5%)	1
Hypouricemia Grade 4	1/40 (2.5%)	1
Hypocalcemia Grade 3	1/40 (2.5%)	1
Metabolism and nutrition disorders
Hyperglycemia Grade 3	1/40 (2.5%)	1
Musculoskeletal and connective tissue disorders
Back pain Grade 3	1/40 (2.5%)	1
Inguinal pain Grade 3	1/40 (2.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma Grade 3	2/40 (5%)	2
Nervous system disorders
Headache Grade 3	1/40 (2.5%)	1
Psychiatric disorders
Mood alteration Grade 3	1/40 (2.5%)	1
Renal and urinary disorders
Renal dysfunction Grade 2	1/40 (2.5%)	1
Renal dysfunction Grade 3	1/40 (2.5%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonia Grade 3	1/40 (2.5%)	1
Acute respiratory distress syndrome Grade 4	1/40 (2.5%)	1
Skin and subcutaneous tissue disorders
Rash Grade 3	1/40 (2.5%)	1
Vascular disorders
Venous thromboembolism Grade 3	2/40 (5%)	2
Venous thromboembolism Grade 4	1/40 (2.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.