Vorinostat, Cladribine, and Rituximab in Treating Patients With Mantle Cell Lymphoma, Relapsed Chronic Lymphocytic Leukemia, or Relapsed B Cell Non-Hodgkin's Lymphoma

• Sponsor: OHSU Knight Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT00764517
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 57
• Locations: 2
• Arms: 2
• Duration (Months): 103
• Patients Per Site: 28.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This phase II trial studies how well giving vorinostat, cladribine, and rituximab together works in treating patients with mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), or B cell non-Hodgkin's lymphoma (NHL) that has returned after a period of improvement. Vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cladribine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Giving vorinostat together with cladribine and rituximab may kill more cancer cells.

Condition or Disease	Intervention/Treatment	Phase
Recurrent B-Cell Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Indolent Adult Non-Hodgkin Lymphoma; Refractory B-Cell Non-Hodgkin Lymphoma	Drug: Cladribine; Other: Laboratory Biomarker Analysis; Biological: Rituximab; Drug: Vorinostat	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine objective response rates of the SCR regimen (vorinostat, cladribine, and rituximab) in B-cell malignancies.

2. Determine the tolerability and toxicities of the SCR regimen.

SECONDARY OBJECTIVES:

1. Evaluate progression free survival in patients treated with SCR. II. Estimate event free survival for patients treated with SCR. III. Determine the contribution (if any) of deoxyribonucleic acid (DNA) methylation/histone deacetylation to disease progression and/or response to SCR combination chemotherapy.

2. Perform scientific correlates to determine if SCR treatment a) is associated with global and gene specific changes in transcription of messenger ribonucleic acid (mRNA)s and micro ribonucleic acid (MiRNA)s b) is acting as an inhibitor of DNA methylation c) is activating or silencing specific genes or miRNAs.

OUTLINE:

Patients receive vorinostat orally (PO) on days 1-14, cladribine intravenously (IV) over 2 hours on days 1-5, and rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2 years and then every 6 months thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 57 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Vorinostat (SAHA), Cladribine, and Rituximab (SCR) in Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, and Relapsed B Cell Non-Hodgkin Lymphoma
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Previously untreated Patients enrolled with untreated, newly diagnosed mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [Group I]. Patients receive vorinostat PO on days 1-14, cladribine IV over 2 hours on days 1-5, and rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Drug: Cladribine; Given IV; Other Names: 2-CdA 2CDA CdA Cladribina Leustat Leustatin Leustatine RWJ-26251 ; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Rituximab; Given IV; Other Names: BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody IDEC-102 IDEC-C2B8 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 PF-05280586 Rituxan Rituximab Biosimilar BI 695500 Rituximab Biosimilar PF-05280586 Rituximab Biosimilar RTXM83 RTXM83 ; Drug: Vorinostat; Given PO; Other Names: L-001079038 SAHA Suberanilohydroxamic Acid Suberoylanilide Hydroxamic Acid Zolinza
Experimental: Relapsed Patients with relapsed disease including indolent Non-Hodgkins Lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) [Group II]. Patients receive vorinostat PO on days 1-14, cladribine IV over 2 hours on days 1-5, and rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Drug: Cladribine; Given IV; Other Names: 2-CdA 2CDA CdA Cladribina Leustat Leustatin Leustatine RWJ-26251 ; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Rituximab; Given IV; Other Names: BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody IDEC-102 IDEC-C2B8 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 PF-05280586 Rituxan Rituximab Biosimilar BI 695500 Rituximab Biosimilar PF-05280586 Rituximab Biosimilar RTXM83 RTXM83 ; Drug: Vorinostat; Given PO; Other Names: L-001079038 SAHA Suberanilohydroxamic Acid Suberoylanilide Hydroxamic Acid Zolinza

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate [2 years]

   ORR defined as the percentage of patients who achieved a complete response (CR) or a partial response (PR). Assessed per the revised Cheson criteria. Response definitions per revised International Working Group Response Criteria. 95% confidence interval will be provided. Definitions: Complete response (CR) = disappearance of all evidence of disease; Partial response (PR) = regression of measurable disease and no new sites.

2. Toxicities as Assessed Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [6 months]

   Toxicity is determined percentage of patients that experienced an adverse event (AE) grade 3 or higher during the time frame, assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade refers to the severity of the AE increasing from Grade 1 to 5. Generally, Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant but not immediately life-threatening; Grade 4 = Life-threatening consequences; Grade 5 = Death related to AE.

3. Tolerability of Treatment [6 months]

   Tolerability is determined to be the percentage of patients who completed the full duration of treatment (all 6 cycles) regardless of adverse event status. % tolerability shows the rate of patients that tolerated the treatment for the full duration.

Secondary Outcome Measures

1. Progression-free Survival [Up to 5 years]

   Time from treatment start until disease progression or death. Estimated using the Kaplan-Meier method. A logrank test will be used to compare progression-free survival between Group I and Group II. A p-value less that 0.05 will be considered statistically significant.

2. Event-free Survival [Up to 5 years]

   Time from treatment start until disease progression, death, or discontinuation of treatment for adverse event (toxicity) Estimated using the Kaplan-Meier method. A logrank test will be used to compare progression-free survival between Group I and Group II. A p-value less that 0.05 will be considered statistically significant.

3. Contribution (if Any) of DNA Methylation/Histone Deacetylation [Up to 2 years]

   Determine the contribution (if any) of DNA methylation/histone deacetylation to disease progression and/or response to SCR combination chemotherapy. Outcome not evaluated due to technical challenges collecting the data, and lack of budget and personnel to complete the analysis.

4. Scientific Correlates [Baseline]

   Perform scientific correlates to determine if SCR treatment a) is associated with global and gene specific changes in transcription of mRNAs and MiRNAs b) is acting as an inhibitor of DNA methylation c) is activating or silencing specific genes or miRNAs. Outcome not evaluated due to technical challenges collecting the data, and lack of budget and personnel to complete the analysis.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must be able to provide informed consent according to institutional guidelines

• Patients must have: 1) MCL; or 2) relapsed or refractory cluster of differentiation (CD)20 positive B-cell indolent NHL; or 3) relapsed CLL

• Patients must have measurable disease/disease status requirements as follows:

• For CLL patients, symptomatic disease as defined by the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria that mandate treatment

• For B-cell NHL patients must have at least one of the following to be eligible:

• Positron emission tomography (PET) avid or measurable disease by computed tomography (CT) scan defined as at least 1 lesion that measures > 2 cm in a single dimension

• Significant bone marrow and/or peripheral blood involvement by NHL (i.e. leukemic phase) as determined by the investigator

• Patients with Waldenström macroglobulinemia (WM) are exempt from this requirement if they have symptomatic hyperviscosity or clinically relevant cytopenias and elevated serum immunoglobulin M (IgM)

• Patients must have adequate bone marrow reserve as indicated by an absolute neutrophil count (ANC) > 1.500/mm^{3 and platelet count > 150.000/mm}3 if no bone marrow involvement; however, if there is significant lymphoma/leukemia bone marrow infiltration, no pre-existing hematologic parameters must be met

• Patients must have a performance status of 0, 1, or 2 according to Eastern Cooperative Oncology Group

• Serum creatinine < 2.0 mg/dL or estimated glomerular filtration rate (GFR) > 60 mL/min

• Serum bilirubin =< 1.5 × upper limit of normal (ULN)

• Aspartate transaminase (AST)/alanine transaminase (ALT) =< 2.5 × ULN

• Alkaline phosphatase =< 2.5 × ULN

• Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment

• Male and female patients must agree to use an effective contraceptive method during the study and for a minimum of 6 months after study treatment

Exclusion Criteria:

• Significant hypersensitivity to cladribine or vorinostat; hypersensitivity to rituximab infusion is not an exclusion criterion; however, appropriate changes to infusion schedules will be made based on current or prior reactions

• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol

• Patients with a diagnosis of a relapsed/refractory aggressive cluster of differentiation antigen 20 (CD20)+ B-cell neoplasm defined as Burkitt's lymphoma or diffuse large B-cell lymphoma

• A diagnosis of acute lymphoplasmic leukemia, and lymphoblastic lymphoma

• Use of investigational agents or any anticancer therapy within 2 weeks before study entry with the exception of hydroxyurea and steroids; the patient must have recovered from all acute toxicities from any previous therapy

• Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo treatment

• Patients with a systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)

• Pregnant or lactating patients

• Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results

• Patients with acquired immunodeficiency syndrome (AIDS) or human immunodeficiency virus (HIV) associated complex are not eligible for treatment

• Patients with active hepatitis B or C are not eligible for the study

• Patients taking other histone deacetylases (HDAC) inhibitors; for example, patients taking valproic acid, there must be a 14 day washout period prior to enrollment in this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	OHSU Knight Cancer Institute	Portland	Oregon	United States	97239
2	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850

Sponsors and Collaborators

• OHSU Knight Cancer Institute
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stephen Spurgeon, OHSU Knight Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Stephen Spurgeon, Associate Professor, OHSU Knight Cancer Institute
• ClinicalTrials.gov Identifier: NCT00764517
• Other Study ID Numbers: IRB00004180; NCI-2011-03737; 4180; HEM-08002-L; CR00021415; IRB00004180; P30CA069533
• First Posted: Oct 2, 2008
• Last Update Posted: Dec 11, 2017
• Last Verified: Oct 1, 2017

• Additional relevant MeSH terms: Lymphoma; Leukemia; Lymphoma, Non-Hodgkin; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Lymphoma, B-Cell; Recurrence; Rituximab; Antineoplastic Agents, Immunological; Vorinostat; Cladribine; 2-chloro-3'-deoxyadenosine; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Previously Untreated	Relapsed
Arm/Group Description	Patients enrolled with untreated, newly diagnosed mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [Group I]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients with relapsed disease including indolent Non-Hodgkins Lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) [Group II]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	39	18
COMPLETED	24	4
NOT COMPLETED	15	14

Baseline Characteristics

Arm/Group Title	Previously Untreated	Relapsed	Total
Arm/Group Description	Patients enrolled with untreated, newly diagnosed mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [Group I]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients with relapsed disease including indolent Non-Hodgkins Lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) [Group II]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	39	18	57
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62	60	61.5
Sex: Female, Male (Count of Participants)
Female	5 12.8%	3 16.7%	8 14%
Male	34 87.2%	15 83.3%	49 86%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 5.1%	0 0%	2 3.5%
Not Hispanic or Latino	37 94.9%	18 100%	55 96.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 2.6%	0 0%	1 1.8%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	37 94.9%	18 100%	55 96.5%
More than one race	1 2.6%	0 0%	1 1.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	39 100%	18 100%	57 100%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate
Description	ORR defined as the percentage of patients who achieved a complete response (CR) or a partial response (PR). Assessed per the revised Cheson criteria. Response definitions per revised International Working Group Response Criteria. 95% confidence interval will be provided. Definitions: Complete response (CR) = disappearance of all evidence of disease; Partial response (PR) = regression of measurable disease and no new sites.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Previously Untreated	Relapsed
Arm/Group Description	Patients enrolled with untreated, newly diagnosed mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [Group I]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients with relapsed disease including indolent Non-Hodgkins Lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) [Group II]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	39	18
Number (95% Confidence Interval) [percentage of participants]	97 248.7%	39 216.7%

2. Primary Outcome

Title	Toxicities as Assessed Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Description	Toxicity is determined percentage of patients that experienced an adverse event (AE) grade 3 or higher during the time frame, assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade refers to the severity of the AE increasing from Grade 1 to 5. Generally, Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant but not immediately life-threatening; Grade 4 = Life-threatening consequences; Grade 5 = Death related to AE.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Previously Untreated	Relapsed
Arm/Group Description	Patients enrolled with untreated, newly diagnosed mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [Group I]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients with relapsed disease including indolent Non-Hodgkins Lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) [Group II]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	39	18
Number (95% Confidence Interval) [percentage of participants]	90 230.8%	83 461.1%

3. Primary Outcome

Title	Tolerability of Treatment
Description	Tolerability is determined to be the percentage of patients who completed the full duration of treatment (all 6 cycles) regardless of adverse event status. % tolerability shows the rate of patients that tolerated the treatment for the full duration.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Previously Untreated	Relapsed
Arm/Group Description	Patients enrolled with untreated, newly diagnosed mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [Group I]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients with relapsed disease including indolent Non-Hodgkins Lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) [Group II]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	39	18
Number (95% Confidence Interval) [percentage of participants]	62 159%	22 122.2%

4. Secondary Outcome

Title	Progression-free Survival
Description	Time from treatment start until disease progression or death. Estimated using the Kaplan-Meier method. A logrank test will be used to compare progression-free survival between Group I and Group II. A p-value less that 0.05 will be considered statistically significant.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Previously Untreated	Relapsed
Arm/Group Description	Patients enrolled with untreated, newly diagnosed mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [Group I]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients with relapsed disease including indolent Non-Hodgkins Lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) [Group II]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	39	18
Median (95% Confidence Interval) [Months]	NA	19.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Previously Untreated, Relapsed
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; 0.16 to 0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Event-free Survival
Description	Time from treatment start until disease progression, death, or discontinuation of treatment for adverse event (toxicity) Estimated using the Kaplan-Meier method. A logrank test will be used to compare progression-free survival between Group I and Group II. A p-value less that 0.05 will be considered statistically significant.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Previously Untreated	Relapsed
Arm/Group Description	Patients enrolled with untreated, newly diagnosed mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [Group I]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients with relapsed disease including indolent Non-Hodgkins Lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) [Group II]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	39	18
Median (95% Confidence Interval) [Months]	39.0	19.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Previously Untreated, Relapsed
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 95%; 0.21 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Contribution (if Any) of DNA Methylation/Histone Deacetylation
Description	Determine the contribution (if any) of DNA methylation/histone deacetylation to disease progression and/or response to SCR combination chemotherapy. Outcome not evaluated due to technical challenges collecting the data, and lack of budget and personnel to complete the analysis.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Data not collected and the outcome will never be analyzed.

Arm/Group Title	Previously Untreated	Relapsed
Arm/Group Description	Patients enrolled with untreated, newly diagnosed mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [Group I]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients with relapsed disease including indolent Non-Hodgkins Lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) [Group II]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	0	0

7. Secondary Outcome

Title	Scientific Correlates
Description	Perform scientific correlates to determine if SCR treatment a) is associated with global and gene specific changes in transcription of mRNAs and MiRNAs b) is acting as an inhibitor of DNA methylation c) is activating or silencing specific genes or miRNAs. Outcome not evaluated due to technical challenges collecting the data, and lack of budget and personnel to complete the analysis.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Data not collected and the outcome will never be analyzed.

Arm/Group Title	Previously Untreated	Relapsed
Arm/Group Description	Patients enrolled with untreated, newly diagnosed mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [Group I]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.	Patients with relapsed disease including indolent Non-Hodgkins Lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) [Group II]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Measure Participants	0	0

Adverse Events

Time Frame	Up to 25 weeks (6 cycles X 28 days + 1 week after last cycle. Toxicities and adverse experiences will be assessed at each visit using the NCI Common Terminology Criteria for Adverse Events v4.0. Adverse events evaluated and recorded using the NCI CTCAE, Version 4.0 for 1 week after last cycle.
Adverse Event Reporting Description	For reporting purposes here, Grade 4 will be considered to be serious adverse event (SAE). Events assessed at each visit during the study (every other week for Cycle 1, then monthly for Cycles 2 to 6)
Arm/Group Title	Previously Untreated		Relapsed
Arm/Group Description	Patients enrolled with untreated, newly diagnosed mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL) [Group I]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.		Patients with relapsed disease including indolent Non-Hodgkins Lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL) [Group II]. Patients receive 400 mg vorinostat PO on days 1-14, 5 mg/m^2 cladribine IV over 2 hours on days 1-5, and 375 mg/m^2 rituximab IV on day 3 (weekly for the first course). Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Previously Untreated		Relapsed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/39 (20.5%)		13/18 (72.2%)
Serious Adverse Events
	Previously Untreated		Relapsed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/39 (46.2%)		9/18 (50%)
Blood and lymphatic system disorders
Anemia	1/39 (2.6%)	1	1/18 (5.6%)	1
Febrile neutropenia	4/39 (10.3%)	4	1/18 (5.6%)	1
General disorders
Death NOS	0/39 (0%)	0	1/18 (5.6%)	1
Immune system disorders
Allergic reaction	1/39 (2.6%)	1	0/18 (0%)	0
Investigations
Alanine aminotransferase increased	1/39 (2.6%)	1	0/18 (0%)	0
Aspartate aminotransferase increased	1/39 (2.6%)	1	0/18 (0%)	0
Cardiac troponin I increased	1/39 (2.6%)	1	0/18 (0%)	0
INR increased	1/39 (2.6%)	1	0/18 (0%)	0
Neutrophil count decreased	9/39 (23.1%)	10	4/18 (22.2%)	4
Platelet count decreased	4/39 (10.3%)	4	4/18 (22.2%)	4
Metabolism and nutrition disorders
Hyperglycemia	1/39 (2.6%)	1	0/18 (0%)	0
Hypokalemia	1/39 (2.6%)	1	0/18 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary edema	1/39 (2.6%)	1	0/18 (0%)	0
Respiratory failure	0/39 (0%)	0	1/18 (5.6%)	1
Other (Not Including Serious) Adverse Events
	Previously Untreated		Relapsed
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/39 (71.8%)		14/18 (77.8%)
Blood and lymphatic system disorders
Anemia	3/39 (7.7%)	3	1/18 (5.6%)	1
Febrile neutropenia	9/39 (23.1%)	11	5/18 (27.8%)	5
Cardiac disorders
Aortic valve disease	1/39 (2.6%)	1	0/18 (0%)	0
Atrial fibrillation	0/39 (0%)	0	1/18 (5.6%)	1
heart failure	1/39 (2.6%)	1	0/18 (0%)	0
Supraventricular tachycardia	1/39 (2.6%)	1	0/18 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/39 (0%)	0	1/18 (5.6%)	1
Gastric hemorrhage	0/39 (0%)	0	1/18 (5.6%)	1
Vomiting	1/39 (2.6%)	1	0/18 (0%)	0
General disorders
Fatigue	5/39 (12.8%)	5	2/18 (11.1%)	2
Infusion related reaction	1/39 (2.6%)	1	0/18 (0%)	0
Pain	1/39 (2.6%)	1	0/18 (0%)	0
Infections and infestations
Appendicitis	0/39 (0%)	0	1/18 (5.6%)	1
Infection: pulmonary (lung)	0/39 (0%)	0	1/18 (5.6%)	1
Investigations
Activated partial thromboplastin time prolonged	0/39 (0%)	0	1/18 (5.6%)	1
Alanine aminotransferase increased	1/39 (2.6%)	1	0/18 (0%)	0
Aspartate aminotransferase increased	1/39 (2.6%)	1	0/18 (0%)	0
Cardiac troponin I increased	1/39 (2.6%)	1	0/18 (0%)	0
Hemoglobin decreased	1/39 (2.6%)	1	1/18 (5.6%)	1
Hemoglobin increased	0/39 (0%)	0	2/18 (11.1%)	2
INR increased	1/39 (2.6%)	1	1/18 (5.6%)	1
Neutrophil count decreased	7/39 (17.9%)	8	5/18 (27.8%)	6
Platelet count decreased	14/39 (35.9%)	15	5/18 (27.8%)	5
Weight loss	2/39 (5.1%)	2	1/18 (5.6%)	1
Metabolism and nutrition disorders
Anorexia	1/39 (2.6%)	1	1/18 (5.6%)	1
Hyperglycemia	1/39 (2.6%)	1	1/18 (5.6%)	1
Hyperkalemia	0/39 (0%)	0	1/18 (5.6%)	1
Hypocalcemia	1/39 (2.6%)	1	0/18 (0%)	0
Hypokalemia	2/39 (5.1%)	2	1/18 (5.6%)	1
Hyponatremia	1/39 (2.6%)	1	0/18 (0%)	0
Hypophosphatemia	1/39 (2.6%)	1	0/18 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	0/39 (0%)	0	1/18 (5.6%)	1
Nervous system disorders
Dizziness	1/39 (2.6%)	1	1/18 (5.6%)	1
Headache	1/39 (2.6%)	1	0/18 (0%)	0
Syncope	1/39 (2.6%)	1	0/18 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/39 (2.6%)	1	0/18 (0%)	0
Urinary frequency	1/39 (2.6%)	1	0/18 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/39 (5.1%)	2	0/18 (0%)	0
Hypoxia	0/39 (0%)	0	1/18 (5.6%)	1
Vascular disorders
Hypotension	2/39 (5.1%)	3	0/18 (0%)	0
Thromboembolic event	2/39 (5.1%)	2	0/18 (0%)	0

Limitations/Caveats

Secondary objectives and outcomes not evaluated due to technical challenges collecting the data, and lack of budget and personnel to complete the analysis.

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.