Salt Lake City,
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
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.
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
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
A bone marrow biopsy confirmed diagnosis of MDS or CMML (dysplastic subtype) according to
WHO criteria within 2 weeks of registration.
1. Patients must have an International Prognostic Scoring System (IPSS), see Appendix D,
score of INT-1 or higher at study entry.35 Patients with an IPSS score of INT-1 with
the 5q- deletion should have failed Lenalidomide therapy and should have more than 5%
blasts in the bone marrow or a platelet count < 50,000/mm3 or an absolute neutrophil
count < 500/mm3 or be requiring therapy (e.g. being transfusion dependent). Patients
with CMML must have a WBC < 12,000/mm3 documented within 4 weeks prior to study entry
(two sets of counts that are 2 weeks apart will be taken).
2. Patients with MDS should have failed or relapsed after treatment with one regimen of
hypomethylating agents (5-Azacytidine or Decitabine) but no more than 2 prior
therapies including only 1 hypomethylating agent... Patients with CMML (dysplastic
subtype) may be enrolled even if they have not received any prior therapy.
3. Untreated patients who are ineligible for or unwilling to undergo hypomethylating
agent therapy can be enrolled
4. Age ≥ 18 years.
5. Patients must have and ECOG performance status of 0 - 2.
6. Provide signed written informed consent.
7. Have adequate renal and hepatic functions as indicated by the following laboratory
- Serum creatinine 1.0 mg/dL; if serum creatinine 1.0 mg/dL, then the estimated
glomerular filtration rate (GFR) must be 30 mL/min/1.73 m2 as calculated by the
Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73
m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient
is female) x (1.212 if patient is black)
- Serum bilirubin ≤1.5 mg/dL × upper limit of normal (ULN)
- Aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 × ULN
- Alkaline phosphatase 2.5 × ULN
8. Capable of understanding the investigational nature, potential risks and benefits of
the study, and able to provide valid informed consent.
9. Female patients of childbearing potential must have a negative serum pregnancy test
within 2 weeks prior to enrollment.
10. Male and female patients must use an effective contraceptive method during the study
and for a minimum of 6 months after study treatment
1. Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as
specified in the protocol.
2. Pre-treatment with more than 2 previous regimens.
3. Use of investigational agents within 30 days or any anticancer therapy within 30 days
before study entry with the exception of hydroxyurea. The patient must have
recovered from all acute toxicities from any previous therapy.
4. Have any other severe concurrent disease, or have a 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.
5. Patients with a systemic fungal, bacterial, viral, or other infection not controlled
(defined as exhibiting ongoing signs/symptoms related to the infection and without
improvement, despite appropriate antibiotics or other treatment).
6. Pregnant or lactating patients.
7. Any significant concurrent disease, illness, or psychiatric disorder that would
compromise patient safety or compliance, interfere with consent, study participation,
follow up, or interpretation of study results.