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

NCT ID: NCT00691652

Last Updated: 2019-11-27

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 2 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-05-31
• Study Completion Date: 2009-04-30

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.

Conditions

Lymphoma

Study Design

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

Study Groups

Oral Clofarabine + Rituximab in Relapsed B Cell NHL

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

Group Type: EXPERIMENTAL

rituximab

Intervention Type: BIOLOGICAL

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.

clofarabine

Intervention Type: DRUG

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.

DNA methylation analysis

Intervention Type: GENETIC

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

gene expression analysis

Intervention Type: GENETIC

Total RNA will be processed for determination of gene expression by microarray

microarray analysis

Intervention Type: GENETIC

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.

polymerase chain reaction

Intervention Type: GENETIC

high performance liquid chromatography

Intervention Type: OTHER

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).

laboratory biomarker analysis

Intervention Type: OTHER

50 µl of the clear supernatant is injected into the reverse-phase high performance liquid chromatography (HPLC).

Interventions

rituximab

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: BIOLOGICAL

clofarabine

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: DRUG

DNA methylation analysis

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

gene expression analysis

Total RNA will be processed for determination of gene expression by microarray

Intervention Type: GENETIC

microarray analysis

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

polymerase chain reaction

Intervention Type: GENETIC

high performance liquid chromatography

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

laboratory biomarker analysis

50 µl of the clear supernatant is injected into the reverse-phase high performance liquid chromatography (HPLC).

Intervention Type: OTHER

Other Intervention Names

High Performance Liquid Chromatography (HPLC)

Eligibility Criteria

Inclusion 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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 89 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

OHSU Knight Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Craig Okada, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Oregon Health and Science University

Locations

Knight Cancer Institute at Oregon Health and Science University

Portland, Oregon, United States

Countries

United States

Other Identifiers

P30CA069533

Identifier Type: NIH

Identifier Source: secondary_id

View Link

OHSU-HEM-07156-L

Identifier Type: -

Identifier Source: secondary_id

IRB#4101

Identifier Type: -

Identifier Source: secondary_id

GENZYME-OHSU-HEM-07156-L

Identifier Type: -

Identifier Source: secondary_id

CDR0000597410

Identifier Type: -

Identifier Source: org_study_id