Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II Supportive care Active 18 and over Other 2006-004432-70 NCT00501098

Trial Description

Summary

• To assess the overall clinical yield - in terms of efficacy and safety endpoints of adding caspofungin as prophylaxis of Invasive Pulmonary Aspergillosis in patients undergoing induction treatment for newly diagnosed acute leukemia

• To investigate the prognostic significance of Ptx3 at diagnosis and during the first chemotherapy cycle with respect to the development of IPA

Further Study Information

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.

Eligibility Criteria

Inclusion Criteria:

• all patients with a diagnosis af acute leukemia who are enrolled in the clinical protocols of NILG for acute leukemia at diagnosis

• age > 18

• written informed consent

Exclusion Criteria:

• presence of signs or symptoms suspected of invasive fungal infection at enrollment

• history of allergy, hypersensitivity, or any serious reaction to echinocandin

• pregnancy or breast-feeding

• acute hepatitis or moderate/severe hepatic insufficiency of any cause;

• concomitant treatment with any systemic antifungal agent

• recent prior use of caspofungin

Trial Contact Information

Trial Lead Organizations/Sponsors

Northern Italy Leukemia Group

Giuseppe Rossi, MD

Principal Investigator

Chiara Cattaneo

Principal Investigator

Simona Monte		Ph: +390872570300 Ext._
		Email: monte@negrisud.it

Marilena Romero		Ph: +390872570300
		Email: romero@negrisud.it

Italy
	Alessandria
	Ospedale SS. Biagio e Arrigo
		Alessandro Levis, MD	Principal Investigator
		Flavia Salvi, MD	Sub-Investigator
		Lorella Depaoli, MD	Sub-Investigator
	Bergamo
	Ospedali Riuniti di Bergamo
		Renato Bassan, MD	Principal Investigator
		Tamara Intermesoli, MD	Sub-Investigator
		Elena Oldani, Dr. Biol Sci	Sub-Investigator
		Federica Delaini, Dr. Biol Sci	Sub-Investigator
		Orietta Spinelli, Dr. Biol Sci	Sub-Investigator
		Vittoria Guerini	Sub-Investigator
	Brescia
	Spedali Civili di Brescia
		Giuseppe Rossi, MD	Principal Investigator
	Mestre
	Ospedale Civile Umberto I
		Chisesi Teodoro, MD	Ph: (+39) 041 2607357
		Chisesi Teodoro, MD	Principal Investigator
	Milano
	Ospedale Maggiore Policlinico
		Giorgio Lambertenghi-Deliliers, MD	Principal Investigator
		Agostino Cortelezzi, MD	Sub-Investigator
		Maria Cristina Pasquini, MD	Sub-Investigator
		Nicola Fracchiolla, MD	Sub-Investigator
		Claudio Annaloro, MD	Sub-Investigator
		Angelo Gardellini, MD	Sub-Investigator
		Kathrin Von Hohenstaufen, MD	Sub-Investigator
	Monza
	Ospedale San Gerardo
		Enrico Pogliani, MD	Principal Investigator
		Elisabetta Terruzzi, MD	Sub-Investigator
		Matteo Parma, MD	Sub-Investigator
		Monica Fumagalli, MD	Sub-Investigator
		Luisa Verga, MD	Sub-Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00501098
Information obtained from ClinicalTrials.gov on July 16, 2008