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
- 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
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
After completion of study treatment, patients are followed once a year for 2 years.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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.
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
Craig Okada, MD, PhD
Oregon Health and Science University
United States: Food and Drug Administration
|Knight Cancer Institute at Oregon Health and Science University||Portland, Oregon 97239-3098|