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

Primary Purpose

Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Chronic Lymphocytic Leukemia, Recurrent Indolent Adult Non-Hodgkin Lymphoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cladribine
Laboratory Biomarker Analysis
Rituximab
Vorinostat
Sponsored by
OHSU Knight Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent B-Cell Non-Hodgkin Lymphoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • OHSU Knight Cancer Institute
  • Penn State Milton S Hershey Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Previously untreated

Relapsed

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Objective Response Rate
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.
Toxicities as Assessed Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
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.
Tolerability of Treatment
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

Progression-free Survival
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.
Event-free Survival
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.
Contribution (if Any) of DNA Methylation/Histone Deacetylation
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.
Scientific Correlates
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.

Full Information

First Posted
October 1, 2008
Last Updated
November 9, 2017
Sponsor
OHSU Knight Cancer Institute
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00764517
Brief Title
Vorinostat, Cladribine, and Rituximab in Treating Patients With Mantle Cell Lymphoma, Relapsed Chronic Lymphocytic Leukemia, or Relapsed B Cell Non-Hodgkin's Lymphoma
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 Type
Interventional

2. Study Status

Record Verification Date
October 2017
Overall Recruitment Status
Completed
Study Start Date
August 2008 (undefined)
Primary Completion Date
January 2015 (Actual)
Study Completion Date
March 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
OHSU Knight Cancer Institute
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. 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.
Detailed Description
PRIMARY OBJECTIVES: I. Determine objective response rates of the SCR regimen (vorinostat, cladribine, and rituximab) in B-cell malignancies. II. Determine the tolerability and toxicities of the SCR regimen. SECONDARY OBJECTIVES: I. 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. IV. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Chronic Lymphocytic Leukemia, Recurrent Indolent Adult Non-Hodgkin Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
57 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Previously untreated
Arm Type
Experimental
Arm Description
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.
Arm Title
Relapsed
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Cladribine
Other Intervention Name(s)
2-CdA, 2CDA, CdA, Cladribina, Leustat, Leustatin, Leustatine, RWJ-26251
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Biological
Intervention Name(s)
Rituximab
Other Intervention Name(s)
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
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Vorinostat
Other Intervention Name(s)
L-001079038, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic Acid, Zolinza
Intervention Description
Given PO
Primary Outcome Measure Information:
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
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
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
Secondary Outcome Measure Information:
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
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
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
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen Spurgeon
Organizational Affiliation
OHSU Knight Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
OHSU Knight Cancer Institute
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Penn State Milton S Hershey Medical Center
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033-0850
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
31177537
Citation
Spurgeon SE, Sharma K, Claxton DF, Ehmann C, Pu J, Shimko S, Stewart A, Subbiah N, Palmbach G, LeBlanc F, Latour E, Chen Y, Mori M, Hasanali Z, Epner EM. Phase 1-2 study of vorinostat (SAHA), cladribine and rituximab (SCR) in relapsed B-cell non-Hodgkin lymphoma and previously untreated mantle cell lymphoma. Br J Haematol. 2019 Sep;186(6):845-854. doi: 10.1111/bjh.16008. Epub 2019 Jun 9.
Results Reference
derived

Learn more about this trial

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

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