A multi-center, randomized, double-blind, placebo-controlled clinical trial of deferasirox in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload (TELESTO)

Myelodysplastic syndromes (MDS) are clonal stem cell disorders characterized
by ineffective hematopoiesis in one or more cell lineages and has the potential
to evolve to acute myeloid leukemia (AML). Treatment goals for patients with
low/int-1 risk MDS primarily involve managing cytopenias. While specific
therapies and the use of growth factors may alleviate transfusion requirements
in some patients, 60-80% of patients do not respond and require ongoing
platelet and red blood cell (RBC) transfusions due to impaired hematopoiesis.
In many patients, this leads to chronic RBC transfusion therapy and the
development of secondary iron overload (IO). Liver dysfunction, cirrhosis and
endocrinopathies have been described in multi-transfused MDS patients (even
with a short-term duration of transfusion), where even mild liver function
abnormalities have been associated with marked hepatic iron overload and portal
fibrosis on biopsy (Schafer 1981, Jaeger 1992). Cardiac complications of iron
overload secondary to long-term transfusion therapy are well-described in *-
thalassemia major, but have not yet been well-described for the MDS population.
Iron chelation therapy (ICT) has a long history in transfusion-dependent
patients with hemaglobinopathies, primarily *-thalassemia major, with
demonstrated improvement in organ dysfunction and survival in patients who are
compliant with therapy (Olivieri 1997). Use of deferoxamine (DFO) in
iron-overloaded MDS patients has been reported to improve organ dysfunction
(Jensen 2003, Schafer 1985), and even improve cytopenias (Jensen 1996). With
the use of ICT, there have also been reports of improvements in glucose
metabolism in iron-overloaded thalassemia major patients (Farmaki 2006), and
reduced insulin requirements in MDS patients (Schafer 1985). However, poor
patient compliance associated with the necessity of repeated subcutaneous
infusions, as well as the potential for increased bruising/bleeding in patients
with thrombocytopenia and/or platelet dysfunction are significant problems with
DFO, particularly with elderly MDS patients. Therefore, the need exists for an
iron chelator which could be administered via the more convenient oral route.

Iron overload may impact survival in MDS, which is especially relevant for
low-risk patients. A recent retrospective analysis of 467 MDS patients
demonstrated that cardiac failure and liver cirrhosis constituted 51% and 8%,
respectively, of the non-leukemic causes of death (Malcovati 2005).

Moreover, secondary iron overload, reflected by a serum ferritin level greater
than 1,000 ng/mL, was associated with a poorer overall survival (OS). Recent,
uncontrolled studies suggest a benefit of ICT upon survival in MDS (Leitch
2007, Rose 2010, Sanz 2008). Leitch et al. reported results of a retrospective
review of 178 MDS patients (60% with low/int-1 MDS).

Eighteen patients received ICT for a median of 15 months. In low/int-1
patients, the median OS was 40 months for those not receiving ICT compared with
a median OS not reached at 160 months for patients receiving ICT. Also, 80% of
patients receiving ICT survived to 4 years from the time of diagnosis compared
to 44% without ICT. In a non-randomized, prospective 2 year follow-up of 165
MDS patients (59% low/int-1 risk) in an outpatient setting, Rose reported a
median survival from time of diagnosis of 115 months in patients receiving ICT
compared
with 51 months in those who did not receive ICT. Sanz reported that the
development of iron overload and transfusion dependency were strongly
associated with AML transformation risk in MDS.These studies included patients
with a wide range of transfusional iron intake, time since diagnosis of MDS and
co-morbidities.

Deferasirox (Exjade®) is approved for the treatment of transfusional iron
overload in over 90 countries. Data on 47 MDS patients were included in the
registration dossier (Study CICL670A0108). Efficacy was demonstrated based on
changes in serum ferritin and liver iron content.

The relationship between serum ferritin levels and clinical outcome is well
described in patients with *-thalassemia (Cappellini 2006), but has not been
well described in a prospective study until now.

Use of iron chelation therapy has demonstrated benefits in terms of morbidity
and mortality for chronically-transfused thalassemia patients with iron
overload. Recent retrospective data (Leitch 2007, Rose 2010, Sanz 2008) suggest
that overall survival may be improved in adult patients with MDS who receive
iron chelation therapy. The purpose of this study is to demonstrate in
low/int-1 risk MDS patients, treated as per standard practice, the clinical
superiority of deferasirox to placebo, while rigorously monitoring relevant
clinical parameters (cardiac and liver function and transformation to Acute
Leukemia AML)) potentially affected by iron overload complications.

This is a prospective, randomized, double-blind, placebo-controlled, parallel
group design study with a maximum of two interim analyses for efficacy and
safety. The recruitment period is planned to last 24 months. Patients will be
assigned to either deferasirox or matching placebo (2:1 ratio in favor of
deferasirox) by stratified randomization using an interactive voice response
system (IVRS) and strata defined by IPSS (low vs int-1 MDS risk patients) and
geographical region (Asian countries versus non-Asian countries) since the
Asian population have a longer survival. (Matsuda 2005).

The end of study is expected to occur 5 years after first patient first visit
(FPFV) when 244 events for the composite primary endpoint have been observed.
The end of study treatment may occur if a patient meets any non-fatal component
of the composite primary endpoint (confirmed by the EAC). His/her individual
randomized study treatment will be unblinded and discontinued at that time. The
subsequent iron chelation treatment is subject to patient*s and the
investigator*s decision. Patients will continue to be followed every 6 months
for iron chelation therapies and overall survival once he/she discontinues from
the study treatment.

Patients who discontinue study treatment without an event (e.g., for an adverse
event) will continue to be evaluated at specified time intervals. Once patients
stop study evaluations they will be followed for at least every 6 months for
overall survival and any iron chelation therapies they are receiving up to the
end of study
.
The EAC is responsible for ensuring whether pre-specified endpoint criteria
were met for all non-fatal events. The role of the EAC is to ensure that all
events that have been reported by the sites are judged uniformly using the same
criteria. The EAC is blinded to study treatment allocation. Interim analyses
for safety and efficacy are planned when approximately 50% and 75% of the
required number of events (244) will have been observed.

Having completed the screening period, patients enrolled and randomized to
deferasirox (ICL670, Exjade®) or matching placebo will begin study treatment.

The following dosing schedule is to be followed:
* 10 mg/kg/day (once daily) for 2 weeks, followed by 20 mg/kg/day (once daily)
* After 3 months oftreatment at thedose of 20mg/kg/day the dose can be adjusted
by 5 or 10 mg/kg/day up to 40 mg/kg/day based on serum ferritin response

Joining this study requires quite a lot of the patient. The patient will need
to come to the hopsital at regular intervals for a period of 5 years for
monitoring and testing. Most tests would also happen if the patient did not
participate in the study, although the timing and number might be different.

The study medication should be taken every day at about the same time and 30
minutes before the meal on an empty stomach.

The patient must come to the hospital for a maximum of 5 years once a month
(every 4 weeks). Each visit will last approximately 1 hour or less.

The researcher performs a complete physical exam and checks weight and vital
signs. There will also be a chest X-ray taken, except if one was made in the
last 6 months and results are available. During 3 weeks after randomization,
the patient will visit the study doctor once a week. The patient undergoes a
simple blood test to check the kidneys, each time approximately 8.5 ml of blood
will be taken. After four weeks of treatment, the patient will come to the
hospital once a month (approximately every 4 weeks). During the visits, the
study doctor will ask health questions and do tests. At each visit, vital signs
and weight will be checked. Each visit approximately 17 ml of blood will be
taken and a urine sample of 40 ml will be collected. Every three months, the
patient undergoes an ECG and an ultrasound to monitor the heart function. Once
a year, the patient will need to have an ophthalmic examination and hearing
tests.

It is possible that in the course of the study additional tests will need to be
performed if the patient has certain heart or liver problems. The study doctor
will decide which tests are necessary. This may include an X-ray of the chest,
a bone marrow examination, an ultrasound of abdomen, a liver biopsy, but also
an additional blood test.

Blood tests may hurt or cause a hematoma. In rare cases, a liver biops may
cause a hemorrhage in the liver, internal bleeding, puncture of the
gallbladder, an infection, an abscess or puncture of a lung. It is also
possible that the blood pressure cuff or inconvenience caused a contusion of
the upper arm.