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A Study to Determine the Safety Profile and Maximum Tolerated Dose Of Bone Marrow Transplantation (2006) 38, 47–51 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 www.nature.com/bmt ORIGINAL ARTICLE A study to determine the safety profile and maximum tolerated dose of micafungin (FK463) in patients undergoing haematopoietic stem cell transplantation B Sirohi1, RL Powles1, R Chopra2, N Russell3, JL Byrne3, HG Prentice4, M Potter4 andS Koblinger 5 1Leukaemia and Myeloma Unit, Royal Marsden Hospital, Sutton, Surrey, UK; 2Department of Haematological Oncology, Christie Hospital NHS Trust, Manchester, UK; 3Department of Clinical Haematology, Nottingham City Hospital, Nottingham, UK; 4Department of Haematology, Royal Free Hospital, London, UK and 5Astellas Pharma GmbH, Munich, Germany This open-label, dose-escalation study assessed the max- neutropaenic fever that has not responded to broad spectrum imum tolerated dose (MTD) of the new antifungal antibiotics.1 The treatment usually consists of intravenous micafungin in patients undergoing haematopoietic stem cell amphotericin B or fluconazole for suspected Candida transplantation (HSCT). Participants received 3, 4, 6 or infections andlipidassociative formulations of amphotericin 8 mg/kg/day micafungin intravenously from 7 days to a B if there is a dose-escalation required to cover Aspergillus. maximum of 28 days or until neutropaenia resolved. The Sometimes itraconazole is used, and more recently vorico- MTD was defined as the highest dose not causing the same nazole has received a product license and has the advantage Grade 3 or 4 adverse event in three or more patients. All 36 of both intravenous andoral administration. 2,3 participants received X8 days treatment for a median of 18 As diagnosis is difficult, early intervention is critical and days (range: 8–28); 1 patient withdrew consent and a further so attempts have been made at prophylaxis against fungal 11 discontinued to receive another systemic antifungal agent infections, particularly in patients who have hadprevious for a suspected infection. No case of confirmed invasive known problems with Aspergillus. To this end, itraconazole fungal infection occurred. Adverse events were those has been usedwidely.A previously publishedmeta-analysis expected for patients undergoing HSCT and showed no of 38 trials showedno benefit of prophylaxis seen in evidence of dose-related toxicity. Criteria for MTD were invasive aspergillosis or in overall mortality, as the majority not met; no patient had a Grade 3 or 4 adverse event of trials utilizedagents with no activity against Aspergillus considered causally related to micafungin. Thus, the MTD species (fluconazole, ketoconazole).4 Recently, a meta- of micafungin can be inferred to be 8 mg/kg/day or higher. analysis with itraconazole shows that it effectively prevents Bone Marrow Transplantation (2006) 38, 47–51. proven invasive fungal infections andalso reducesmortal- doi:10.1038/sj.bmt.1705398; published online 22 May ity from these infections.5 Drugs presently available are 2006 toxic, which prevents their long-term prophylactic use in Keywords: antifungal; prophylaxis; micafungin (FK463); high-risk patients undergoing a HSCT. echinocandin; HSCT There is therefore a demand for newer agents with broad spectrums of activity that will be active by themselves or in combination. The echinocandin antifungal drugs are there- fore of interest, andcaspofungin was recently approvedfor Introduction treatment of invasive aspergillosis refractory to or intoler- ant of standard antifungal therapy, for invasive candidiasis 6–8 Invasive or systemic fungal infections are a frequent cause andfor empiric therapy. of morbidity and mortality in haemato-oncology patients In a previous Phase I study in adult haemato-oncology undergoing intensive chemotherapy or haematopoietic patients doses of micafungin up to 3 mg/kg per day (daily stem cell transplantation (HSCT), with prolongedneutro- fixed doses of 12.5–200 mg) were well tolerated by adult paenia as the most important risk factor. The most patients, andthe maximum tolerateddose(MTD) was not 9 common pathogens are Aspergillus and Candida species. reached. The aim of the present study was to investigate There is great difficulty in diagnosing fungal infections and further the MTD of micafungin in allogeneic and most patients receive antifungal therapy in a setting of autologous HSCT patients for doses up to 8 mg/kg per day. Patients and methods Correspondence: Professor RL Powles, Parkside Cancer Center, 49 Parkside, Wimbledon SW19 5NB, UK. E-mail: [email protected] Conduct of study Received1 November 2005; revised7 March 2006; accepted17 April The study protocol and amendments were reviewed and 2006; publishedonline 22 May 2006 approvedby the Ethics Committee of participating institu- Maximum tolerated dose of micafungin B Sirohi et al 48 tions. The study was conducted in accordance with the to be at least possibly relatedto micafungin in at least three Declaration of Helsinki andInternational Conference on different patients in the same dosage group. Harmonization for GoodClinical Practice (ICH-GCP) guidelines. Before inclusion into the study, the study was explainedto each patient andhe or she gave written Results informedconsent. Characteristics of study population Patient selection Thirty-six patients were enrolledin the studyandreceived Adult patients scheduled to undergo HSCT at four centres at least one dose of micafungin. They ranged in age from 19 in the UnitedKingdomwere eligible to take part in the to 62 years, with a median age of 47.5 years; 13 of the study. Female patients of child-bearing age had to have a participants were female. Other patient characteristics are negative pregnancy test andbe using a reliable form of shown in Table 1. The four groups were similar except that contraception. Patients with evidence of liver disease the proportion of allogeneic transplants was higher in the (defined as SGOT/AST or SGPT/ALT or total bilirubin 6.0 mg/kg/day group (62.5%) than in the other groups 42.5 times the upper limit of normal), renal impairment (25.0–30.0%). The most common underlying illnesses were (serum creatinine 42.0 mg/dl), evidence of a systemic multiple myeloma, acute myeloidleukaemia, chronic fungal infection or with known hypersensitivity to echino- myeloidleukaemia andacute lymphoblastic leukaemia. candin antifungal agents or structurally related compounds One patient (in the 3.0 mg/kg/day group) withdrew were excluded from the study. Before study enrolment all consent after 22 days in the study, and a further 11 patients patients gave written, informedconsent for their participa- were withdrawn because they received another systemic tion. The study was approved by the relevant ethics antifungal agent for a suspectedinfection (after 9–26 days, committees. median 17 days). Invasive fungal infection was not confirmedfor any patient. Study design Dosing and duration The study had an open-label, sequential dose-escalation As shown in Table 2, the median treatment period was design and proceeded to the next dose level only if the similar (16.5–22.5 days) for all dosage groups. The highest safety review panel (consisting of internal andexternal dose given was 900 mg (in the 8.0 mg/kg/day group). All experts) determined that the previous dose was safe based patients receivedmicafungin for at least 8 days,thus on the definition of the MTD. At least eight evaluable fulfilling the minimum of 7 days of therapy as stipulated in patients were requiredto complete each dosagegroup. the study protocol. Half of the patients completed at least Participants were screened72 h before the first adminis- 18 days of micafungin therapy. tration of study drug. If they met the entry criteria they receivedeither 3.0, 4.0, 6.0 or 8.0 mg/kg/daymicafungin administered intravenously as a 1-hour infusion. Micafun- Maximum tolerated dose gin was suppliedby Astellas Pharma Inc., Tokyo, Japan. No patient, in the 3.0, 4.0, 6.0 or 8.0 mg/kg dosage group, Daily treatment began 2 to 3 days before transplantation had a Grade 3 or 4 adverse event that was assessed by the andlastedfor a minimum of 7 to a maximum of 28 days; investigator as causally related. Thus, the pre-defined treatment was to stop when neutropaenia resolved (X500 cells/ml). Administration of micafungin was to discontinue if the patient experienced an adverse event, Table 1 Patient characteristics which was considered intolerable by either the investigator or patient, or if the patient requiredanother systemic Micafungin dosage group antifungal agent for a suspectedinfection. 3.0 mg/ 4.0 mg/ 6.0 mg/ 8.0 mg/ Routine clinical laboratory assessments of haematology kg/day kg/day kg/day kg/day andserum biochemistry were performedat baseline (the time of patient screening) andon days1, 3, 5, 7, 10, 14, 17, Number of patients 10 10 8 8 21, 24 and28 of treatment. Patients were assessedfor Type of transplant fungal infection at baseline andon days3, 5, 7, 14, 21 and Autologous HSCT 7 7 3 6 28. Monitoring of adverse events was done on an on-going Allogeneic HSCT 3 3 5 2 basis. Reason for transplant Multiple myeloma 4 4 3 1 AML2313 Primary objective CML1230 The primary objective of this study was to determine the ALL 2 1 0 1 safety profile andthe MTD of micafungin administeredto CLL 0 0 1 1 patients undergoing HSCT. Adverse events were graded Other disease 1 0 0 2 from 1 to 4 (least to most severe) using the Southwest Oncology Group Toxicity Criteria.10 The MTD was defined Abbreviations: HSCT ¼ haematopoietic stem cell transplantation; AML ¼ acute myelogenous leukaemia; CML ¼ chronic myelogenous as the highest dose administered without the occurrence of leukaemia; ALL ¼ acute lymphoblastic leukaemia; CLL ¼ chronic lympho- a Grade 3 or 4 adverse event considered by the investigator cytic leukaemia. Bone Marrow Transplantation Maximum tolerated dose of micafungin B Sirohi et al 49 criterion for MTD (i.e. the occurrence of the same, Grade 3 One hepatic adverse event (a patient with mild bilirubi- or 4, causally relatedadverseevent in at least three patients naemia in the 8.0 mg/kg/day group) was assessed by the in the same dosage group) was not met.
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