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Phase I/II Study of Oral Clofarabine + Rituximab in Relapsed B Cell NHL

Phase 1/Phase 2
18 Years
89 Years
Not Enrolling

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Trial Information

Phase I/II Study of Oral Clofarabine + Rituximab in Relapsed B Cell NHL



- 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.


- 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

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.

Inclusion Criteria


- 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


- 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


- 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

- 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

- No other concurrent chemotherapy or immunotherapy

- No concurrent radiotherapy

- No concurrent colony stimulating factors (phase I portion of the study)

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The Maximum Tolerated Dose (MTD) of Oral Clofarabine in Adult Patients With Relapsed CD20+ Non-Hodgkin Lymphoma(NHL)

Outcome 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.

Outcome 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

Safety Issue:


Principal Investigator

Craig Okada, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Oregon Health and Science University


United States: Food and Drug Administration

Study ID:




Start Date:

May 2008

Completion Date:

April 2009

Related Keywords:

  • Lymphoma
  • 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
  • Lymphoma
  • Lymphoma, Non-Hodgkin



Knight Cancer Institute at Oregon Health and Science University Portland, Oregon  97239-3098