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Clofarabine and Rituximab in Treating Patients With Relapsed Non-Hodgkin Lymphoma

Primary Purpose

Lymphoma

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
rituximab
clofarabine
DNA methylation analysis
gene expression analysis
microarray analysis
polymerase chain reaction
high performance liquid chromatography
laboratory biomarker analysis
Sponsored by
OHSU Knight Cancer Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lymphoma focused on measuring extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult grade III lymphomatoid granulomatosis, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, cutaneous B-cell non-Hodgkin lymphoma

Eligibility Criteria

18 Years - 89 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

DISEASE CHARACTERISTICS:

  • Histologically or cytologically confirmed B-cell lymphoma

    • Relapsed disease
    • CD20-positive disease
  • Must have had bone marrow aspiration and biopsy (uni- or bilateral) within the past 42 days and chest CT and CT of the abdomen and pelvis within the past 28 days

  • Documented bidimensionally measurable disease within the past 28 days

    • Patients with non-measurable disease in addition to measurable disease must have all non-measurable disease assessed within 42 days prior to registration

PATIENT CHARACTERISTICS:

  • Eastern Cooperative Oncology Group(ECOG) performance status 0-2
  • Leukocyte count ≥ 3,000/μL
  • Absolute neutrophil count ≥ 1,500/μL
  • Platelet count ≥ 75,000/μL
  • Total bilirubin ≤ 2 times upper limit of normal (ULN)
  • AST and ALT ≤ 2.5 times ULN
  • Alkaline phosphatase ≤ 2.5 times ULN
  • Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 30 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for at least 6 months after completion of study therapy
  • No known AIDS or HIV-associated complex
  • No active hepatitis B infection
  • No other severe concurrent disease, 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
  • No uncontrolled systemic fungal, bacterial, viral, or other infection, defined as ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment
  • No history of intolerance or allergic reactions to clofarabine or rituximab
  • No significant concurrent disease, illness, or psychiatric disorder that would compromise the patient's safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results
  • No concurrent active GI disease that may impair absorption of oral clofarabine

PRIOR CONCURRENT THERAPY:

  • Recovered from all previous therapies
  • No prior gastrointestinal (GI) surgery that may impair absorption of oral clofarabine
  • More than 2 weeks since prior and no concurrent anticancer therapy, except for hydroxyurea
  • More than 4 weeks since prior radioimmunotherapy
  • More than 1 month since prior investigational agents
  • No concurrent cytotoxic therapy or investigational therapy
  • No other concurrent investigational or commercial agents or therapies administered with the intent to treat the patient's malignancy
  • No concurrent alternative medications (e.g., herbal or botanical for anticancer purposes)
  • No other concurrent chemotherapy or immunotherapy
  • No concurrent radiotherapy
  • No concurrent colony stimulating factors (phase I portion of the study)

Sites / Locations

  • Knight Cancer Institute at Oregon Health and Science University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Oral Clofarabine + Rituximab in Relapsed B Cell NHL

Arm Description

Phase I: Oral Clofarabine x 14 days for up to 8 cycles at assigned dose level below (1 cycle equals 14 days on drug, 14 days off). Rituximab weekly for 4 weeks than monthly for up to 8 cycles on day 1 of cycle 375 mg/m2 IV Dose Level 1: 2 mg Dose Level 2: 4 mg Dose Level 3: 6 mg Phase II: Oral Clofarabine x 14 days for up to 8 cycles (Dose determined from phase I) AND Rituximab weekly for 4 weeks than monthly for up to 8 cycles on day 1 of cycle 375 mg/m2 IV

Outcomes

Primary Outcome Measures

The Maximum Tolerated Dose (MTD) of Oral Clofarabine in Adult Patients With Relapsed CD20+ Non-Hodgkin Lymphoma(NHL)
Initially, 3 patients will be enrolled into a dose level during the dose-escalation portion: If no patient experiences dose-limiting toxicities during the first 4 weeks, then 3 patients will be enrolled into the next dose level. If one of the three patients develops dose-limiting toxicities, then 3 additional patients will be enrolled in that cohort. If none of the additional 3 patients experiences dose-limiting toxicities, then further dose-escalation occurs. If one additional patient experiences dose-limiting toxicities, then the maximum tolerated dose is exceeded.
Estimate Objective Response Rates of Oral Clofarabine in Combination With Rituximab in Relapsed CD20+NHL

Secondary Outcome Measures

Determine One-year Progression Free Survival Using the MTD of Clofarabine With Rituximab in Relapsed CD20+NHL
Determine the Safety and Efficacy of Clofarabine in Combination With Rituximab
Whether Clofarabine Acts as an Inhibitor of DNA Methylation Similar to Cladribine by Performing Scientific Correlates
Whether Response to Clofarabine Alone or in Combination With Rituximab Correlates With Changes in Global Serum DNA Methylation Index
Identity of the Gene Activated by Clofarabine Therapy by Using Genomic DNA and RNA Array Technology

Full Information

First Posted
June 4, 2008
Last Updated
November 15, 2019
Sponsor
OHSU Knight Cancer Institute
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00691652
Brief Title
Clofarabine and Rituximab in Treating Patients With Relapsed Non-Hodgkin Lymphoma
Official Title
Phase I/II Study of Oral Clofarabine + Rituximab in Relapsed B Cell NHL
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Terminated
Why Stopped
Funding ended when only one subject enrolled and subject withdrew early.
Study Start Date
May 2008 (undefined)
Primary Completion Date
January 2009 (Actual)
Study Completion Date
April 2009 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

5. Study Description

Brief Summary
RATIONALE: Drugs used in chemotherapy, such as clofarabine, 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, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving clofarabine together with rituximab may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of clofarabine when given together with rituximab and to see how well they work in treating patients with relapsed B-cell non-Hodgkin lymphoma.
Detailed Description
OBJECTIVES: Primary To determine the maximum tolerated dose of clofarabine in adult patients with relapsed CD20-positive B-cell non-Hodgkin lymphoma (NHL). To estimate objective response rates of clofarabine in combination with rituximab in these patients. Secondary To determine the 1-year progression-free survival of this regimen using the mean tolerated dose in these patients. To determine the safety and efficacy of this regimen in these patients. To determine if clofarabine acts as an inhibitor of DNA methylation similar to cladribine by performing scientific correlates. To determine whether response to clofarabine alone or in combination with rituximab correlates with changes in global serum DNA methylation index. To identify the gene activated by clofarabine therapy by using genomic DNA and RNA array technology. OUTLINE: This is a phase I, dose-escalation study of clofarabine followed by a phase II study. Patients receive oral clofarabine once daily on days 1-14 of all courses and rituximab IV on days 1, 8, 15, and 22 of course one and then on day 1 of courses 2-8. Courses repeat every 4 weeks. After 2 courses of therapy, patients who are eligible for stem cell transplantation may either undergo transplantation or continue receiving study drugs until disease progression or unacceptable toxicity for up to a total of 8 courses of treatment. Patients undergo blood sample collection periodically for correlative studies. Samples are analyzed to identify global DNA methylation differences and correlate changes in methylation index (MI) with patient outcome after treatment with clofarabine with or without rituximab via high performance liquid chromatography (HPLC); to determine differences in gene expression via microarray analysis and micro-RNA (miRNA) expression via quantitative polymerase chain reaction (PCR) in patients with high compared to low global DNA methylation index and miRNA expression for CD5+ B-lymphocytes obtained from pediatric tonsils and from B-lymphocytes of 5 healthy controls; and to determine gene expression and miRNA profiles in patients before and after treatment with clofarabine with or without rituximab via genomic DNA arrays. After completion of study treatment, patients are followed once a year for 2 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lymphoma
Keywords
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult grade III lymphomatoid granulomatosis, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, cutaneous B-cell non-Hodgkin lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Oral Clofarabine + Rituximab in Relapsed B Cell NHL
Arm Type
Experimental
Arm Description
Phase I: Oral Clofarabine x 14 days for up to 8 cycles at assigned dose level below (1 cycle equals 14 days on drug, 14 days off). Rituximab weekly for 4 weeks than monthly for up to 8 cycles on day 1 of cycle 375 mg/m2 IV Dose Level 1: 2 mg Dose Level 2: 4 mg Dose Level 3: 6 mg Phase II: Oral Clofarabine x 14 days for up to 8 cycles (Dose determined from phase I) AND Rituximab weekly for 4 weeks than monthly for up to 8 cycles on day 1 of cycle 375 mg/m2 IV
Intervention Type
Biological
Intervention Name(s)
rituximab
Intervention Description
Administered weekly times 4 weeks and then monthly during the study for up to 8 cycles and will be given on day 1 of clofarabine. A peripheral or central intravenous (IV) line will be established. The initial dose rate at the time of the first infusion should be 50/mg/hr for the first hour. If no toxicity is seen, the dose rate may be gradually escalated (50 mg/hr increments at 30 minute intervals) to a maximum of 300 mg/hr. If the first dose of rituximab is well tolerated, the starting flow rate for the administration of subsequent doses will be 100 mg/hr then gradually increased (100 mg/hr increments at 30 minute intervals) not to exceed 400 mg/hr.
Intervention Type
Drug
Intervention Name(s)
clofarabine
Intervention Description
Phase 1 dosing: Initially, 3 patients will be enrolled into a dose level during the dose escalation portion. Level 1: 2mg fixed dose times 14 days for up to 8 cycles. Level 2: 4mg fixed dose times 14 days for up to 8 cycles. Level 3: 6mg fixed dose times 14 days for up to 8 cycles. Phase II dosing: The phase II dose of oral clofarabine will be determined from the phase 1.
Intervention Type
Genetic
Intervention Name(s)
DNA methylation analysis
Intervention Description
We will use an HPLC assay developed by Yu et al31 to determine the DNA methylation (DMI) index in peripheral blood and bone marrow of patients entering this trial and after treatment with clofarabine and rituxan
Intervention Type
Genetic
Intervention Name(s)
gene expression analysis
Intervention Description
Total RNA will be processed for determination of gene expression by microarray
Intervention Type
Genetic
Intervention Name(s)
microarray analysis
Intervention Description
we will scan the microarray slides with an Axon scanner, and quantify data using the GeneSight software. Local background is subtracted and data points with no signal, high background, or spot asymmetry are eliminated. We will adjust genes with low expression and low signal intensity to a minimal raw value of 5: This avoids unwarranted mathematical distortions due to division by decimals << 1. After calculating the ratio of the Cy5 /Cy3 fluorescence signal intensity for each gene, we normalize the data relative to the mean intensity from all genes.
Intervention Type
Genetic
Intervention Name(s)
polymerase chain reaction
Intervention Type
Other
Intervention Name(s)
high performance liquid chromatography
Intervention Description
Fifteen µg of DNA will be sonicated for 60 seconds on ice into 200 bp-1000 bp fragments. Samples are then denatured at 1000C for 5 minutes and cooled on ice to prevent re-annealing. Sixty units of nuclease S1 (Invitrogen) and 112.5 mu of snake venom phosphodiesterase I (Sigma) in 12 µl of S1 dilution buffer is then added to the samples and incubated at 370C for 18 hours. Samples are reheated to 1000C for 5 minutes, snap cooled again on ice, and another sixty units of nuclease S1 and 112.5 mu of snake venom phosphodiesterase I are added and incubated at 370C for another 4 to 6 hours. The pH of each sample was raised to 8.5 with 0.5 M Tris, pH 10. Two and a half units of alkaline phosphatase (Sigma) are added and incubated for 2 additional hours at 370C. One hundred µl of 0.05M potassium phosphate, pH 7 is added to final samples before 50 µl of the clear supernatant is injected into the reverse-phase high performance liquid chromatography (HPLC).
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Other Intervention Name(s)
High Performance Liquid Chromatography (HPLC)
Intervention Description
50 µl of the clear supernatant is injected into the reverse-phase high performance liquid chromatography (HPLC).
Primary Outcome Measure Information:
Title
The Maximum Tolerated Dose (MTD) of Oral Clofarabine in Adult Patients With Relapsed CD20+ Non-Hodgkin Lymphoma(NHL)
Description
Initially, 3 patients will be enrolled into a dose level during the dose-escalation portion: If no patient experiences dose-limiting toxicities during the first 4 weeks, then 3 patients will be enrolled into the next dose level. If one of the three patients develops dose-limiting toxicities, then 3 additional patients will be enrolled in that cohort. If none of the additional 3 patients experiences dose-limiting toxicities, then further dose-escalation occurs. If one additional patient experiences dose-limiting toxicities, then the maximum tolerated dose is exceeded.
Time Frame
14 days for up to 8 cycles (1 cycle equals 14 days on drug, 14 days off drug) for a total of up to 224 days
Title
Estimate Objective Response Rates of Oral Clofarabine in Combination With Rituximab in Relapsed CD20+NHL
Time Frame
Oral Clofarabine x 14 days for up to 8 cycles (1 cycle equals 14 days on drug, 14 days off drug) for a total of up to 224 days AND Rituximab weekly for 4 weeks than monthly for up to 8 cycles on day 1 of cycle
Secondary Outcome Measure Information:
Title
Determine One-year Progression Free Survival Using the MTD of Clofarabine With Rituximab in Relapsed CD20+NHL
Time Frame
One year after study drug(s) have been given. Duration of study up to 1 year.
Title
Determine the Safety and Efficacy of Clofarabine in Combination With Rituximab
Time Frame
Duration of the study, up to 1 year.
Title
Whether Clofarabine Acts as an Inhibitor of DNA Methylation Similar to Cladribine by Performing Scientific Correlates
Time Frame
Duration of the study, up to 1 year.
Title
Whether Response to Clofarabine Alone or in Combination With Rituximab Correlates With Changes in Global Serum DNA Methylation Index
Time Frame
Duration of the study, up to 1 year.
Title
Identity of the Gene Activated by Clofarabine Therapy by Using Genomic DNA and RNA Array Technology
Time Frame
Twice monthly at standard of care visits for 3 months post last cycle of chemotherapy.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
89 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
DISEASE CHARACTERISTICS: Histologically or cytologically confirmed B-cell lymphoma Relapsed disease CD20-positive disease Must have had bone marrow aspiration and biopsy (uni- or bilateral) within the past 42 days and chest CT and CT of the abdomen and pelvis within the past 28 days Documented bidimensionally measurable disease within the past 28 days Patients with non-measurable disease in addition to measurable disease must have all non-measurable disease assessed within 42 days prior to registration PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group(ECOG) performance status 0-2 Leukocyte count ≥ 3,000/μL Absolute neutrophil count ≥ 1,500/μL Platelet count ≥ 75,000/μL Total bilirubin ≤ 2 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN Alkaline phosphatase ≤ 2.5 times ULN Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 30 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for at least 6 months after completion of study therapy No known AIDS or HIV-associated complex No active hepatitis B infection No other severe concurrent disease, 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 No uncontrolled systemic fungal, bacterial, viral, or other infection, defined as ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment No history of intolerance or allergic reactions to clofarabine or rituximab No significant concurrent disease, illness, or psychiatric disorder that would compromise the patient's safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results No concurrent active GI disease that may impair absorption of oral clofarabine PRIOR CONCURRENT THERAPY: Recovered from all previous therapies No prior gastrointestinal (GI) surgery that may impair absorption of oral clofarabine More than 2 weeks since prior and no concurrent anticancer therapy, except for hydroxyurea More than 4 weeks since prior radioimmunotherapy More than 1 month since prior investigational agents No concurrent cytotoxic therapy or investigational therapy No other concurrent investigational or commercial agents or therapies administered with the intent to treat the patient's malignancy No concurrent alternative medications (e.g., herbal or botanical for anticancer purposes) No other concurrent chemotherapy or immunotherapy No concurrent radiotherapy No concurrent colony stimulating factors (phase I portion of the study)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Craig Okada, MD, PhD
Organizational Affiliation
Oregon Health and Science University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Knight Cancer Institute at Oregon Health and Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239-3098
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Clofarabine and Rituximab in Treating Patients With Relapsed Non-Hodgkin Lymphoma

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