Phase I/II Study of Low-dose Oral Clofarabine for the Treatment of IPSS INT-1, INT-2 or HIGH Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia (Dysplastic Type) Patients Who Have Failed Hypomethylating Therapy
1. Phase I: To determine the MTD within the planned dose range for this patient population
and assess the toxicity of oral clofarabine
2. Phase II: To estimate the overall response rate (complete, partial and hematologic
improvement by modified IWG criteria) in response to low dose daily oral clofarabine in
patients with high risk myelodysplastic syndrome or chronic myelomonocytic leukemia
1. To evaluate the toxicity of low dose daily oral clofarabine in this patient population.
2. To determine the time to progression to acute myeloid leukemia (AML) of MDS patients
treated with low dose daily oral clofarabine.
3. To determine the duration of response, overall survival (OS) and progression free
survival (PFS) of MDS patients treated with low dose daily oral clofarabine.
4. To determine the effect of low dose daily oral clofarabine on global methylation in
patients with MDS.
5. To determine the effect of low dose daily oral clofarabine on miRNA and mRNA expression
patterns in patients with MDS.
Treatment Patients will take Clofarabine by mouth once daily for 10 days followed by 18 days
of no Clofarabine. This 28 day period of time is called one treatment cycle. After they
complete three cycles of treatment they will have bone marrow and blood tests done to find
out if their MDS or CMML is responding to the treatment. If these tests show the MDS or CMML
is responding to treatment they will continue taking the same dose of Clofarabine for 3 more
cycles. If the tests show that the MDS or CMML is not responding to treatment the dose of
Clofarabine will be increased and they will continue on the same schedule (10 days on, 18
days off) for 3 more cycles.
After 6 cycles patients will again have bone marrow and blood tests done to find out if the
MDS or CMML is responding to the treatment. If the tests show that the MDS or CMML is not
responding to treatment the dose of Clofarabine will be increased again and they will
continue on the same schedule (10 days on, 18 days off) for 6 more cycles.
5-3-11 Update: The phase I portion of the study has now been closed to accrual. Based on the
Phase I experience with significant cytopenias observed with 10 days of consecutive oral
clofarabine administration, the Phase II dose was determined to be 1 mg per day for 7
consecutive days given on a 28 day cycle. The Phase II portion of the trial will enroll up
to 20 patients. Patients will be evaluated on a weekly basis for toxicity. At the completion
of cycle 3 and within 1 week of starting cycle 4, patients will receive a bone marrow
aspirate and biopsy in addition to a complete blood count in order to evaluate for response
according to IWG criteria. Patients who have evidence of a response to therapy or stable
disease will be continued on the same dose and schedule of oral clofarabine. Bone marrow
evaluation for response will be obtained at the completion of 6 and then 12 cycles. If the
patient continues treatment after cycle 12 a bone marrow evaluation will be done at the
discretion of the investigator. Treatment will continue at the same dose and schedule
indefinitely until either disease progression, the development of unacceptable toxicity or
the patient decides to go off study.
Follow-up For this protocol, all patients, including those who discontinue protocol therapy
early, will be followed for response until progression and for survival for 5 years from the
date of registration. All patients must also be followed through completion of all protocol
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Phase I: To determine the MTD within the planned dose range for this patient population and assess the toxicity of oral clofarabine
Paul J Shami, MD
Huntsman Cancer Institute
United States: Food and Drug Administration
|Huntsman Cancer Institute||Salt Lake City, Utah 84112|