Clinical trial NCT00708721
Conditions: Cancer Chronic Myelomonocytic Leukemia
Keywords: hypomethylating therapy CML myelodysplastic syndromes
Sponsor: University of Utah
Start date: 2008-03-01; Completion date: 2014-11-01
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Study and Dose Rationale The safety profile of clofarabine appears acceptable within the target populations studied to date in the clinical studies summarized in Section 2.3. clofarabine has demonstrated anti-cancer activity through inhibition of DNA synthesis and repair, induction of apoptosis, and possibly through other mechanisms. The effect of clofarabine on DNA methylation has not been determined. Numerous responses have been observed after treatment with clofarabine in heavily pre-treated relapsed/refractory patients with ALL or AML.

Recently 2 small studies were conducted at the M.D. Anderson Cancer Center looking at the use of clofarabine in the treatment of MDS.31 The first study randomized patients in a Bayesian fashion to 15 vs. 30 mg/m2 given IV daily for 5 days every 4 to 8 weeks. In the 15 mg/m2 arm 3 of 7 patients had a complete remission according to the International Working Group (IWG)32 criteria for response. In the 30 mg/m2 arm, 2 of 6 patients had a complete remission while 1 patient had hematologic improvement according to IWG criteria. In the second study, patients were treated with oral clofarabine at a dose of 40 mg/m2 daily for 5 days every 4 to 8 weeks. Two of 7 patients had hematologic improvement according to IWG criteria. The main toxicities in both trials were prolonged myelosuppression and liver function abnormalities.

Preclinical animal models have shown increased clofarabine activity against multiple different tumors with repetitive daily dosing for prolonged periods of time.33 The use of an oral therapy is advantageous for the treatment of a chronic malignancy such as MDS. Furthermore, based on the pre-clinical data mentioned above daily repetitive dosing over a protracted period may provide increased efficacy. Since most MDS patients are elderly and may not tolerate aggressive therapy, a schedule of administration of low dose oral clofarabine over a protracted period may provide the advantage of increased efficacy without severe toxicity. The safety of a protracted daily dosage of oral clofarabine in humans has not been determined. The dosing scheme for this study will therefore include a dose escalating phase I component followed by a phase II component. The starting dose will be 5 mg (fixed dose) orally daily for 10 days. This dose will be escalated in cohorts of 3 patients as tolerated up to a maximal dose of 15 mg (fixed dose) orally for 10 consecutive days. Note that at the latter dose a patient will receive a total of 150 mg of clofarabine per cycle, which far lower than the MD Anderson study of oral clofarabine in MDS whereby patients received 200 mg/m2 per cycle.

OBJECTIVES:

Study Overview The purpose of this study is to determine the efficacy and toxicity of Clofarabine administered orally at a low daily dose for the treatment of myelodysplastic syndromes.

Detailed description:
Primary Objectives

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 (dysplastic type).

Secondary Objectives

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. 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 therapy.

Arms: arm 1: All participants enrolled.
Interventions: intervention 1: Clofarabine
Intervention descriptions: intervention 1: Clofarabine is a rationally designed, second generation purine nucleoside analogue. Clofarabine was designed as a hybrid molecule to overcome the limitations and incorporate the best qualities of both fludarabine (F-ara-A) and cladribine (2-CdA, CdA) both of which are currently approved by various regulatory authorities for treatment of hematologic malignancies.

Protocol documents: