Clofarabine is a chemotherapy drug that is designed to interfere with the growth and
development of cancer cells. Ara-C is a chemotherapy drug which is approved for the
treatment of AML and MDS. Although there is experience with the combination of both drugs,
there have not been any phase 1 trials that explored the particular doses and schedule of
clofarabine plus ara-C that a patient may receive.
Ara-C is one of the most active antileukemic agents and is the backbone of many combination
regimens for patients with acute leukemias. Clofarabine is a novel nucleoside analogue that
was found to be active as a single agent in patients with advanced leukemias, especially
AML. Thus, a combination of ara-C and clofarabine in older patients with newly diagnosed,
previously untreated AML may achieve even better results and is worth exploring in a phase
Ara-C requires intracellular phosphorylation to the triphosphate compound ara-CTP to become
biologically active. Cellular pharmacology studies have shown accumulation of ara-CTP to
several hundred mM/L using high doses of ara-C. Furthermore, correlations have been
demonstrated between the accumulation of ara-CTP and clinical responses in patients with
relapsed AML. However, high doses of ara-C are associated with substantial toxicities
especially in older patients. Studies by Plunkett et al. (Semin Oncol 1987; 14: 159-166)
have demonstrated that accumulation of ara-CTP by human leukemia cells in vivo is saturated
at ara-C plasma concentrations that are achieved by intermediate doses of ara-C (dose range
of 1 to 2 g/m2/day) thus obviating the need for high-dose ara-C regimens and associated
complications at least in some patients.
Clofarabine acts through inhibition of DNA synthesis and repair. Importantly, clofarabine is
also a potent inhibitor of ribonucleotide reductase (RnR) and thus ideally suited for
biochemical modulation strategies with other nucleoside analogs such as ara-C. RnR
inhibitors can be used successfully to modulate ara-CTP accumulation in leukemic cells.
Inhibition of RnR by clofarabine will result in a decrease in the levels of deoxynucleotides
causing a subsequent decrease in the feedback inhibition of deoxycytidine kinase, the
rate-limiting step in the synthesis of ara-CTP. The combination of clofarabine with ara-C
would thus lead to increased retention of ara-CTP in leukemic cells so that the antileukemic
activity of clofarabine is complemented by a biochemical synergy between these agents that
should result in greater clinical efficacy.
Based on the observations made in the phase I clinical trial, the maximum (MTD) of
clofarabine for acute leukemias is 40mg/m2/day i.v. daily for 5 days. Hepatotoxicity was
defined as the dose limiting toxicity (DLT). In an ongoing phase I/II study of the identical
combination in patients for relapsed and refractory acute leukemias, ara-C was given at the
dose of 1g/m2/day i.v. over 2 hours from days 1-5, and the clofarabine dose was escalated
over 15, 22.5, 30, to 40mg/m2/day i.v. on days 2-6 in combination with ara-C. No DLTs
occurred including the 40mg/m2/day dose level of clofarabine and the combination at these
dose levels is considered as feasible and safe.
However, especially older patients have reduced tolerance for chemotherapy necessitating
interruptions, delays, and dose modifications with on-going therapy. As the optimal
induction of older patients with AML has not been defined, and as encouraging results have
been reported with clofarabine, we propose to randomize patients with AML and high-risk MDS
older than 60 years to either receive clofarabine alone or clofarabine in combination with
ara-C. In order to investigate novel doses and schedules of these drugs alone or in
combination we propose a dose of clofarabine of 30mg/m2 with ara-C at a low dose schedule of
20mg/m2 subcutaneously (s.c.).
The MRC group randomized patients age 60 years to low dose ara-C 20mg/m2 s.c. daily x 4
versus hydroxyurea (the standard of care in England). They show low-dose ara-C to be
significantly better in relation to CR rate (15% versus 1%; p<0.001) and survival (12-month
survival 20% versus < 10%) (Alan Burnett, personal communication). The current design will
answer several questions: 1) what is the single agent activity of clofarabine in this group
of patients; 2) is clofarabine better than low dose ara-C?; 3) is the combination of
clofarabine plus ara-C better than clofarabine alone and is it well tolerated? This will
then prepare us for potential FDA pivotal trials of either single agent clofarabine, or
clofarabine versus low dose ara-C, or clofarabine plus ara-c versus low-dose ara-C.
- Previously untreated AML and high-risk MDS ( > 10% blasts, or IPSS intermediate-2).
Prior therapy with hydroxyurea, single agent chemotherapy (e.g. decitabine),
hematopoietic growth factors, biological or "targeted" therapies are allowed.
- Age > 60 years.
- ECOG performance status </= 2.
- Sign a written informed consent form.
- Adequate liver function (total bilirubin < 2mg/dL, SGPT or SGOT < x 4 ULN) and renal
function (serum creatinine < 2mg/dL).
- Patients with >= NYHA grade 3 heart disease as assessed by history and/or physical