Trial Information

A Multicenter Phase II Study to Evaluate the Safety, Tolerability and Efficacy of Caspofungin as Prophylactic Treatment of Invasive Fungal Infections in Patients With Acute Leukemia Undergoing Induction Chemotherapy

Invasive aspergillosis (IA), and particularly invasive pulmonary aspergillosis (IPA), is an
important cause of morbidity and mortality in patients who are receiving chemotherapy for
acute leukemia (AL), being the the most common invasive mycosis which develops in these
patients. Proven invasive aspergillosis has been reported in 6,5% of patients with acute
leukemia in a retrospective multicenter study (Pagano, Haematologica 2001) but that
frequency may be underestimated, since definite diagnosis is difficult to obtain,
particularly in leukemic patients.

When the recently developed, internationally recognized IFIGC/MSG/EORTC diagnostic criteria
were retrospectively applied to a consecutive series of acute leukemia patients, the overall
frequency of IPA was 25,3% (proven/probable 8,5%; possible 16,9%). Criteria for a diagnosis
of IPA were fulfilled in 62,8% of pulmonary infiltrates developing in AL patients
(proven/probable 17,1%; possible 45,7%). IPA developed both in AML and in ALL patients.
Proven/probable IPA developed in 83% of cases during the first induction cycle (Borlenghi,
EHA 2003). It may be estimated that such figures would be higher when patients would be
followed prospectively and strictly monitored, particularly with GM antigenemia.

The mechanisms by which common colonizing agents like Aspergillus spp. can become invasive
pathogens and cause severe tissue damage are only partially known. Recent experimental data
in animal models raised the hypothesis that the long pentraxin Ptx3 may play an important
role in resistance to selected microbial agents, in particular to Aspergillus fumigatus
(Garlanda, Nature 2002).

Caspofungin is an echinocandin with potent antifungal activity against Aspergillus species.
Its mechanism of action differs from that of the antifungal agents used so far, like
amphotericin and azoles. It has proven effective and well tolerated and its use is therefore
currently approved as salvage treatment in patients with invasive aspergillosis refractory
to amphotericin, as well as for the empiric treatment of febrile neutropenia. Indeed it has
been recently evaluated as empirical treatment in neutropenic patients with persistent fever
of unknown origin and proved equally effective and better tolerated than liposomal
amphotericin.

There are as yet no data on the use of caspofungin as primary prophylaxis in patients with
acute leukaemia, a setting in which the lack of effective preventive treatments together
with the generally favourable safety profile and efficacy of caspofungin makes it
particularly attractive for investigation.

It can be hypothesized from the above data that the administration of caspofungin as
prophylactic treatment of invasive aspergillosis should be safe and well tolerated by
patient undergoing chemotherapy for acute leukemia at diagnosis.

It may reduce the high incidence of invasive pulmonary aspergillosis which
characteristically develops during the first course of induction treatment, avoiding the
direct morbidity and mortality of IPA and its negative impact on the treatment and prognosis
of AL as well as the costs for IPA diagnosis and treatment.

The serum levels of the long pentraxin Ptx3 may have interpatient variability and may
correlate with the subsequent development of invasive aspergillosis.

These facts led to the present multicenter, phase II, single arm, open study, performed by
the Northern Italy Leukemia Group. There will be approximately 12 participating centers,
which will enroll a total of 100 patients. Patients will receive caspofungin, starting from
the first day of induction chemotherapy for leukemia, as a single daily dose intravenously
at the dosage of 70 mg q.d. and followed by 50 mg q.d. thereafter until documentation of
complete hematologic remission after the first induction cycle or of leukemia persistence
after one cycle of induction and one cycle of salvage chemotherapy.

No stratification is planned. Patients will concurrently receive all the medications needed
for the treatment of acute leukemia,according to the ongoing protocols of NILG for acute
leukemia at diagnosis. The study period continues

The treatment will be stopped in the presence of any of the following conditions:

- Development of a severe adverse event or of any grade 3-4 toxicity attributable to
caspofungin

- Development of proven/probable IPA No caspofungin dose reduction is planned. The dose
of caspofungin will be adjusted when patients weight is over 80 kgs and in patients
taking rifampin or other liver enzymes-inducing drugs.