A Study to Determine the Safety Profile and Maximum Tolerated Dose Of

Home , Micafungin

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 therefore of interest, andcaspofungin was recently approvedfor Introduction treatment of invasive aspergillosis refractory to or intolerant 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. investigator as being possibly related to the study drug. The overall incidence of hepatic adverse events, irrespective of causality, was similar across dosage groups and showed no Safety and tolerability dose trend. There were no marked changes over time in Overall the nature and incidence of adverse events were average SGOT, SGPT or gamma-GT values in any dosage as expectedfor patients who hadjust undergoneHSCT group (Table 4). Average serum bilirubin values increased (Table 3). The most common adverse events, irrespective of during the ﬁrst few days of treatment to a similar extent in causality, were thrombocytopaenia, hypokalaemia, muco- all dosage groups. sitis, anaemia, hyperglycaemia, diarrhoea, fever and No adverse event related to kidney function was assessed nausea. by investigators as having a relationship to the study drug. Adverse events that were assessed by the investigator as The incidence of kidney function adverse events, irrespec- having at least a possible relationship to micafungin tive of causality, was higher in the 6.0 mg/kg/day group comprisedphlebitis (three patients), fever anddiarrhoea than in the other three dosage groups, and average (two patients each) andinjection-site reaction, abdominal creatinine andurea values increasedover time in this pain, asthenia, hypertension, dyspepsia, nausea, vomiting, group (Table 4). Five of the eight patients in the 6.0 mg/kg/ albuminuria, bilirubinaemia, hypervolaemia, hypercalcae- day group had increased creatinine and/or urea. Four of mia, maculopapular rash, rash andpruritus (one patient the ﬁve patients receivedan allogeneic transplant andwere each). All of these adverse events were rated as mild or maintainedon immunosuppressive therapy with cyclospor- moderate in severity. ine. The remaining patient underwent an autologous

Table 2 Duration andinitial doseof Micafungin

Micafungin dosage group Total

3.0 mg/kg/day 4.0 mg/kg/day 6.0 mg/kg/day 8.0 mg/kg/day

Number of patients 10 10 8 8 36

Duration (no. of days) Mean7s.d. 17.174.8 19.376.9 22.374.6 19.875.5 19.475.6 Median 16.5 18.5 22.5 20.0 18.0 Range 13–28 8–28 17–28 14–28 8–28

Initial dose (mg/day) Mean7s.d. 234.3732.3 284.8763.3 453.2798.9 599.97154.4 — Median 244.7 294.0 420.0 578.0 — Range 171–264 180–366 358–671 442–896 —

Table 3 Most frequent adverse eventsa regardless of relationship to study drug; number of patients (%)

Adverse event Micafungin dosage group Total (n ¼ 36)

3.0 mg/kg/day (n ¼ 10) 4.0 mg/kg/day (n ¼ 10) 6.0 mg/kg/day (n ¼ 8) 8.0 mg/kg/day (n ¼ 8)

Fever 10 (100) 9 (90.0) 7 (87.5) 6 (75.0) 32 (88.9) Tachycardia 3 (30.0) 4 (40.0) 6 (75.0) 2 (25.0) 15 (41.7) Diarrhoea 8 (80.0) 10 (100) 8 (100) 7 (87.5) 33 (91.7) Nausea 5 (50.0) 8 (80.0) 7 (87.5) 5 (62.5) 25 (69.4) Mucositis 4 (40.0) 7 (70.0) 6 (75.0) 7 (87.5) 24 (66.7) Vomiting 7 (70.0) 5 (50.0) 3 (37.5) 4 (50.0) 19 (52.8) Thrombocytopaenia 5 (50.0) 8 (80.0) 8 (100) 5 (62.5) 26 (72.2) Anaemia 6 (60.0) 7 (70.0) 7 (87.5) 4 (50.0) 24 (66.7) Hypokalaemia 6 (60.0) 10 (100) 8 (100) 3 (37.5) 27 (75.0) Hyperglycaemia 5 (50.0) 8 (80.0) 7 (87.5) 3 (37.5) 23 (63.9) Hypervolaemia 3 (30.0) 5 (50.0) 6 (75.0) 5 (62.5) 19 (52.8) Bilirubinaemia 3 (30.0) 4 (40.0) 6 (75.0) 5 (62.5) 18 (50.0) Dehydration 2 (20.0) 7 (70.0) 6 (75.0) 2 (25.0) 17 (47.2) Rash 6 (60.0) 7 (70.0) 4 (50.0) 2 (25.0) 19 (52.8) Hypoproteinaemia 1 (10.0) 4 (40.0) 6 (75.0) 4 (50.0) 15 (41.7) Hyponatraemia 0 (0.0) 0 (0.0) 6 (75.0) 3 (37.5) 9 (25.0) aMost frequent adverse events: in at least 70% of patients in any dosage group (i.e. seven out of ten patients or six out of eight patients).

Bone Marrow Transplantation Maximum tolerated dose of micafungin B Sirohi et al 50 Table 4 Mean laboratory values (standard error) at baseline and end of therapy by treatment group

Laboratory parameter Micafungin dosage group

Visita 3.0 mg/kg/day (n ¼ 10) 4.0 mg/kg/day (n ¼ 10) 6.0 mg/kg/day (n ¼ 8) 8.0 mg/kg/day (n ¼ 8)

Creatinine (mmol/l) Baseline 86 (20.1) 76 (14.0) 71 (18.7) 86 (12.3) EOT 81 (22.0) 85 (18.2) 101 (37.5) 80 (18.7)

SGPT (U/L) Baseline 40.9 (43.86) 30.0 (17.36) 29.3 (22.89) 28.6 (22.14) EOT 37.0 (23.67) 28.8 (17.84) 24.0 (18.63) 29.6 (15.65)

aEOT, endof therapy. Changes between baseline andEOT were not statistically signiﬁcant.

transplantation andthe post transplantation course was range of doses that are well tolerated suggests an advantage complicatedby bacterial sepsis. with regardto flexibility in dosing. Rash andpruritus (potential histamine-relatedadverse As all patients completedat least 8 daysof therapy, this events) were assessedby the investigator as causally related study fulfilled the minimum treatment duration for for two patients; both were in the 8 mg/kg/day dosage discerning any drug-related toxicity. The study protocol group andwere gradedashaving mildseverity. No statedthat patients shouldcomplete a minimum of 7 days systemic infusion-related adverse events were reported. of treatment. The average duration of treatment was An injection-site reaction was reportedfor one patient in similar across treatment groups, which is consistent with the 3.0 mg/kg/day group and one in the 4.0 mg/kg/day an absence of dose-related toxicity. group, andphlebitis was reportedfor one patient in the All the adverse events noted in the present study 3.0 mg/kg/day group, two in the 4.0 mg/kg/day group and generally reflectedcomplications associatedwith HSCT, one in the 6.0 mg/kg/day group. These were mild or andnone showeda clear increase in incidencewith moderate in all patients. One of the cases of injection-site increasing dose. The slightly higher incidence of adverse reaction andthree of the cases of phlebitis were assessedby events, irrespective of causality to study drug, in the 6 mg/ the investigator as causally related to the study drug. kg/group may be due to the higher proportion of allogeneic transplant recipients receiving their concomitant immunosuppressive medication but the number of patients per Discussion group is too small to draw firm conclusions. Micafungin showedminimal evidenceof histamine-like reactions or As reliable diagnosis of invasive fungal infections is difficult systemic infusion-relatedreactions. Injection-site reactions andearly intervention is critical in patients at risk for fungal including phlebitis were seldom. infections, prophylaxis against fungal infections is desirable. Laboratory parameters for liver function were assessed The ideal antifungal agent for prophylaxis would provide in detail in the current study, and showed minimal evidence protection against a wide range of fungal pathogens with of dose-related hepatotoxicity. There was an increase in minimal toxicity. In order to achieve effective prophylaxis creatinine in the 6.0 mg/kg/day group (though the mean with an acceptable safety profile, it is crucial to determine was within normal limits andnot clinically significant, doses associated with a minimal risk of toxicity.11 Table 4), this might be due to the higher number of Micafungin, recently approvedin Japan andUSA, is a allogeneic recipients who receivedcyclosporine as immu- new echinocandin lipopeptide synthesized through the nosuppressive therapy. However, the number of patients chemical modification of a fermentation product from receiving cyclosporine in each dosage group is too low to Coleophoma empetri.12 In vitro, the minimum concentration draw any conclusion about this potential interaction with of micafungin requiredto inhibit the growth of 90% of higher doses. Formal pharmacokinetic interaction studies

isolates (MIC90) for yeast-like organisms was lower than were performedon concomitant cyclosporine andmica- that for fluconazole, itraconazole or amphotericin B.13 fungin andon concomitant tacrolimus andmicafungin in Preclinical studies have shown micafungin to have a broad healthy volunteers. Cyclosporine andtacrolimus hadno spectrum of activity against Candida and Aspergillus effect on the pharmacokinetics of micafungin (Herbert species.14–16 et al.18,19; data on file, Astellas). In addition micafungin had Micafungin has been assessedin HIV-positive patients no effect on the pharmacokinetics of tacrolimus (Herbert with oesophageal candidiasis and was well tolerated at fixed et al.19; data on file, Astellas Pharma). The study published daily doses of 50, 100 and 150 mg, with daily doses of 100 by Herbert et al.18 showedthat micafungin appears to and150 mg being more effective than 50 mg. 17 decrease the apparent oral clearance of a single dose of An earlier study of micafungin in neutropaenic patients cyclosporine. However, a previously performedstudy demonstrated that doses up to 200 mg/day (equivalent to a revealedthat co-administrationof micafungin hadno dose of 3 mg/kg per day in a 65 kg patient) were well effect on the pharmacokinetics of steady-state cyclosporine tolerated.9 The current study shows that daily doses of up (data on file, Astellas Pharma). to 8 mg/kg (mean dose of 600 mg) were well tolerated. The Assessment of efficacy was not a main objective of this criteria for the MTD were not met in either study. The wide study. However, findings on the incidence of fungal

Bone Marrow Transplantation Maximum tolerated dose of micafungin B Sirohi et al 51 infection suggest that micafungin is effective in the 8 Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, prophylaxis of fungal infection. No confirmedcase of Dmoszynska A et al. Caspofungin versus liposomal ampho- systemic fungal infection was reported. The recently tericin B for empirical antifungal therapy in patients with reportedPhase III trial comparing Micafungin 50 mg/day persistent fever andneutropenia. N Engl J Med 2004; 30: 1391– with 400 mg of fluconazole showedthat the overall efficacy 1402. of micafungin was superior to that of fluconazole as 9 Hiemenz J, Gagnoni P, Simpson D, Devine S, Chao N, Keirns J et al. Pharmacokinetic andmaximum tolerateddose antifungal prophylaxis during the neutropaenic phase after study of micafungin in combination with fluconazole versus HSCT (80.0% in the micafungin arm vs 73.5% in the fluconazole alone for the prophylaxis of fungal infections 20 fluconazole arm). in adult patients undergoing a bone marrow or peripheral In conclusion, the criteria for MTD was not met in our stem cell transplant. Antimicrob Agents Chemother 2005; 49: study and thus can be inferred to be 8 mg/kg/day or higher. 1331–1336. The excellent safety profile of this novel 1,3-b-D-glucan 10 Green S, Weiss GR. Southwest oncology group standard synthetase inhibitor, andthe supportive efficacy findings response criteria, endpoint definitions and toxicity criteria. show promise for antifungal prophylaxis in this high-risk Invest New Drugs 1992; 10: 239–253. patient group. 11 Guiot HFL, Fibbe WL, van’t Wout JW. 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