Cancidas (Caspofungin Acetate) - Description and Clinical Pharmacology

DESCRIPTION

CANCIDAS is a sterile, lyophilized product for intravenous (IV) infusion that contains a semisynthetic lipopeptide (echinocandin) compound synthesized from a fermentation product of Glarea lozoyensis. CANCIDAS is an echinocandin that inhibits the synthesis of β (1,3)-D-glucan, an integral component of the fungal cell wall.

CANCIDAS (caspofungin acetate) is 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N² -(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin B₀ diacetate (salt). CANCIDAS 50 mg also contains: 39 mg sucrose, 26 mg mannitol, glacial acetic acid, and sodium hydroxide. CANCIDAS 70 mg also contains 54 mg sucrose, 36 mg mannitol, glacial acetic acid, and sodium hydroxide. Caspofungin acetate is a hygroscopic, white to off-white powder. It is freely soluble in water and methanol, and slightly soluble in ethanol. The pH of a saturated aqueous solution of caspofungin acetate is approximately 6.6. The empirical formula is C₅₂H₈₈N₁₀O₁₅•2C₂H₄O₂ and the formula weight is 1213.42. The structural formula is:

CLINICAL PHARMACOLOGY

Mechanism of Action

Caspofungin is an antifungal drug [see Clinical Pharmacology].

Pharmacokinetics

Adult and pediatric pharmacokinetic parameters are presented in Table 8.

Distribution

Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour IV infusions. A short α-phase occurs immediately postinfusion, followed by a β-phase (half-life of 9 to 11 hours) that characterizes much of the profile and exhibits clear log-linear behavior from 6 to 48 hours postdose during which the plasma concentration decreases 10-fold. An additional, longer half-life phase, γ-phase, (half-life of 40-50 hours), also occurs. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance. Caspofungin is extensively bound to albumin (~97%), and distribution into red blood cells is minimal. Mass balance results showed that approximately 92% of the administered radioactivity was distributed to tissues by 36 to 48 hours after a single 70-mg dose of [³H] caspofungin acetate. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration.

Metabolism

Caspofungin is slowly metabolized by hydrolysis and N-acetylation. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L-747969. At later time points (≥5 days postdose), there is a low level (≤7 picomoles/mg protein, or ≤1.3% of administered dose) of covalent binding of radiolabel in plasma following single-dose administration of [³H] caspofungin acetate, which may be due to two reactive intermediates formed during the chemical degradation of caspofungin to L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their degradates, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. These two tyrosine derivatives are found only in urine, suggesting rapid clearance of these derivatives by the kidneys.

Excretion

Two single-dose radiolabeled pharmacokinetic studies were conducted. In one study, plasma, urine, and feces were collected over 27 days, and in the second study plasma was collected over 6 months. Plasma concentrations of radioactivity and of caspofungin were similar during the first 24 to 48 hours postdose; thereafter drug levels fell more rapidly. In plasma, caspofungin concentrations fell below the limit of quantitation after 6 to 8 days postdose, while radiolabel fell below the limit of quantitation at 22.3 weeks postdose. After single intravenous administration of [³H] caspofungin acetate, excretion of caspofungin and its metabolites in humans was 35% of dose in feces and 41% of dose in urine. A small amount of caspofungin is excreted unchanged in urine (~1.4% of dose). Renal clearance of parent drug is low (~0.15 mL/min) and total clearance of caspofungin is 12 mL/min.

Special Populations

Renal Impairment

In a clinical study of single 70-mg doses, caspofungin pharmacokinetics were similar in healthy adult volunteers with mild renal impairment (creatinine clearance 50 to 80 mL/min) and control subjects. Moderate (creatinine clearance 31 to 49 mL/min), severe (creatinine clearance 5 to 30 mL/min), and end-stage (creatinine clearance <10 mL/min and dialysis dependent) renal impairment moderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49% for AUC). However, in adult patients with invasive aspergillosis, candidemia, or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections) who received multiple daily doses of CANCIDAS 50 mg, there was no significant effect of mild to end-stage renal impairment on caspofungin concentrations. No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialyzable, thus supplementary dosing is not required following hemodialysis.

Hepatic Impairment

Plasma concentrations of caspofungin after a single 70-mg dose in adult patients with mild hepatic impairment (Child-Pugh score 5 to 6) were increased by approximately 55% in AUC compared to healthy control subjects. In a 14-day multiple-dose study (70 mg on Day 1 followed by 50 mg daily thereafter), plasma concentrations in adult patients with mild hepatic impairment were increased modestly (19 to 25% in AUC) on Days 7 and 14 relative to healthy control subjects. No dosage adjustment is recommended for patients with mild hepatic impairment.

Adult patients with moderate hepatic impairment (Child-Pugh score 7 to 9) who received a single 70-mg dose of CANCIDAS had an average plasma caspofungin increase of 76% in AUC compared to control subjects. A dosage reduction is recommended for adult patients with moderate hepatic impairment based upon these pharmacokinetic data [see Dosage and Administration].

There is no clinical experience in adult patients with severe hepatic impairment (Child-Pugh score >9) or in pediatric patients with any degree of hepatic impairment.

Gender

Plasma concentrations of caspofungin in healthy adult men and women were similar following a single 70-mg dose. After 13 daily 50-mg doses, caspofungin plasma concentrations in women were elevated slightly (approximately 22% in area under the curve [AUC]) relative to men. No dosage adjustment is necessary based on gender.

Race

Regression analyses of patient pharmacokinetic data indicated that no clinically significant differences in the pharmacokinetics of caspofungin were seen among Caucasians, Blacks, and Hispanics. No dosage adjustment is necessary on the basis of race.

Geriatric Patients

Plasma concentrations of caspofungin in healthy older men and women (≥65 years of age) were increased slightly (approximately 28% AUC) compared to young healthy men after a single 70-mg dose of caspofungin. In patients who were treated empirically or who had candidemia or other Candida infections (intra-abdominal abscesses, peritonitis, or pleural space infections), a similar modest effect of age was seen in older patients relative to younger patients. No dosage adjustment is necessary for the elderly [see Use in Specific Populations].

Pediatric Patients

CANCIDAS has been studied in five prospective studies involving pediatric patients under 18 years of age, including three pediatric pharmacokinetic studies [initial study in adolescents (12-17 years of age) and children (2-11 years of age) followed by a study in younger patients (3-23 months of age) and then followed by a study in neonates and infants (<3 months)] [see Use in Specific Populations].

Pharmacokinetic parameters following multiple doses of CANCIDAS in pediatric and adult patients are presented in Table 8.

Table 8: Pharmacokinetic Parameters Following Multiple Doses of CANCIDAS in Pediatric (3 months to 17 years) and Adult Patients

Population	N	Daily Dose	Pharmacokinetic Parameters (Mean ± Standard Deviation)
			AUC0-24hr (μg∙hr/mL)	C1hr (μg/mL)	C24hr (μg/mL)	t1/2 (hr)Harmonic Mean ± jackknife standard deviation	CI (mL/min)
PEDIATRIC PATIENTS
Adolescents, Aged 12-17 years	8	50 mg/m2	124.9 ± 50.4	14.0 ± 6.9	2.4 ± 1.0	11.2 ± 1.7	12.6 ± 5.5
Children, Aged 2-11 years	9	50 mg/m2	120.0 ± 33.4	16.1 ± 4.2	1.7 ± 0.8	8.2 ± 2.4	6.4 ± 2.6
Young Children, Aged 3-23 months	8	50 mg/m2	131.2 ± 17.7	17.6 ± 3.9	1.7 ± 0.7	8.8 ± 2.1	3.2 ± 0.4
ADULT PATIENTS
Adults with Esophageal Candidiasis	6N=5 for C1hr and AUC0-24hr; N=6 for C24hr	50 mg	87.3 ± 30.0	8.7 ± 2.1	1.7 ± 0.7	13.0 ± 1.9	10.6 ± 3.8
Adults receiving Empirical Therapy	119N=117 for C24hr; N=119 for C1hr	50 mgFollowing an initial 70-mg loading dose on day 1	--	8.0 ± 3.4	1.6 ± 0.7	--	--

Drug Interactions [see Drug Interactions (7) ]

Studies in vitro show that caspofungin acetate is not an inhibitor of any enzyme in the cytochrome P450 (CYP) system. In clinical studies, caspofungin did not induce the CYP3A4 metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes.

Clinical studies in adult healthy volunteers show that the pharmacokinetics of CANCIDAS are not altered by itraconazole, amphotericin B, mycophenolate, nelfinavir, or tacrolimus. CANCIDAS has no effect on the pharmacokinetics of itraconazole, amphotericin B, or the active metabolite of mycophenolate.

Cyclosporine: In two adult clinical studies, cyclosporine (one 4 mg/kg dose or two 3 mg/kg doses) increased the AUC of caspofungin by approximately 35%. CANCIDAS did not increase the plasma levels of cyclosporine. There were transient increases in liver ALT and AST when CANCIDAS and cyclosporine were co-administered [see Warnings and Precautions].

Tacrolimus: CANCIDAS reduced the blood AUC_0-12 of tacrolimus (FK-506, Prograf^®) by approximately 20%, peak blood concentration (C_max) by 16%, and 12-hour blood concentration (C_12hr) by 26% in healthy adult subjects when tacrolimus (2 doses of 0.1 mg/kg 12 hours apart) was administered on the 10th day of CANCIDAS 70 mg daily, as compared to results from a control period in which tacrolimus was administered alone. For patients receiving both therapies, standard monitoring of tacrolimus blood concentrations and appropriate tacrolimus dosage adjustments are recommended.

Rifampin: A drug-drug interaction study with rifampin in adult healthy volunteers has shown a 30% decrease in caspofungin trough concentrations. Adult patients on rifampin should receive 70 mg of CANCIDAS daily.

Other inducers of drug clearance

Adults: In addition, results from regression analyses of adult patient pharmacokinetic data suggest that co-administration of other inducers of drug clearance (efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine) with CANCIDAS may result in clinically meaningful reductions in caspofungin concentrations. It is not known which drug clearance mechanism involved in caspofungin disposition may be inducible. When CANCIDAS is co-administered to adult patients with inducers of drug clearance, such as efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, use of a daily dose of 70 mg of CANCIDAS should be considered.

Pediatric patients: In pediatric patients, results from regression analyses of pharmacokinetic data suggest that co-administration of dexamethasone with CANCIDAS may result in clinically meaningful reductions in caspofungin trough concentrations. This finding may indicate that pediatric patients will have similar reductions with inducers as seen in adults. When CANCIDAS is co-administered to pediatric patients with inducers of drug clearance, such as rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine, a CANCIDAS dose of 70 mg/m² daily (not to exceed an actual daily dose of 70 mg) should be considered.

Microbiology

Mechanism of Action

Caspofungin, an echinocandin, inhibits the synthesis of beta (1,3)-D-glucan, an essential component of the cell wall of susceptible Aspergillus species and Candida species. Beta (1,3)-D-glucan is not present in mammalian cells. Caspofungin has shown activity against Candida species and in regions of active cell growth of the hyphae of Aspergillus fumigatus.

Drug Resistance

There have been reports of clinical failures in patients receiving caspofungin therapy due to the development of drug resistance. Some of these reports have identified specific mutations in the Fks subunits of the glucan synthase enzyme. These mutations are associated with higher MICs and breakthrough infection. Candida species that exhibit reduced susceptibility to caspofungin as a result of an increase in the chitin content of the fungal cell wall have also been identified, although the significance of this phenomenon in vivo is not well known.

Drug Interactions

Studies in vitro and in vivo of caspofungin, in combination with amphotericin B, suggest no antagonism of antifungal activity against either A. fumigatus or C. albicans. The clinical significance of these results is unknown.

Activity in Vitro and in Clinical Infections

Caspofungin has been shown to be active both in vitro and in clinical infections against most strains of the following microorganisms:

Aspergillus fumigatus
Aspergillus flavus
Aspergillus terreus
Candida albicans
Candida glabrata
Candida guilliermondii
Candida krusei
Candida parapsilosis
Candida tropicalis

Susceptibility Testing Methods

The interpretive standards for caspofungin against Candida species are applicable only to tests performed using Clinical Laboratory and Standards Institute (CLSI) microbroth dilution reference methods^2,3 for MIC (partial inhibition endpoint) read at 24 hours. No interpretive criteria have been established for Aspergillus species or other filamentous fungi.

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of pathogens. These reports should aid the physician in selecting an antifungal drug product for treatment. The techniques for Broth Microdilution are described below.

Broth Microdilution Techniques

Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure at 24 hours^2,3. Standardized procedures are based on a microdilution method (broth) with standardized inoculum concentrations and standardized concentrations of caspofungin powder. The MIC values should be interpreted according to the criteria provided in Table 9.

Table 9: Susceptibility Interpretive Criteria for Caspofungin

Pathogen	Broth Microdilution MICA report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. (mcg/mL) at 24 hours
	Susceptible (S)	Non-Susceptible (NS)
Candida species	≤2	>2

Quality Control

Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standard caspofungin powder should provide the following range of values noted in Table 10³. Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.

Table 10: Acceptable Quality Control Ranges for caspofungin to be used in Validation of Susceptibility Test Results

QC Strain	Broth Microdilution (MIC in mcg/mL) at 24 hoursThe MIC for caspofungin is the lowest concentration at which a score of 2 (prominent decrease in turbidity [> 50% inhibition of growth as compared to the growth control]; see CLSI document M27-A32, Section 7.6.3) is observed after 24 hours of incubation.
Candida parapsilosis ATCC 22019	0.25 – 1.0
Candida krusei ATCC 6258	0.12 – 1.0

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to evaluate the carcinogenic potential of caspofungin.

Caspofungin did not show evidence of mutagenic or genotoxic potential when evaluated in the following in vitro assays: bacterial (Ames) and mammalian cell (V79 Chinese hamster lung fibroblasts) mutagenesis assays, the alkaline elution/rat hepatocyte DNA strand break test, and the chromosome aberration assay in Chinese hamster ovary cells. Caspofungin was not genotoxic when assessed in the mouse bone marrow chromosomal test at doses up to 12.5 mg/kg (equivalent to a human dose of 1 mg/kg based on body surface area comparisons), administered intravenously.

Fertility and reproductive performance were not affected by the intravenous administration of caspofungin to rats at doses up to 5 mg/kg. At 5 mg/kg exposures were similar to those seen in patients treated with the 70-mg dose.

Animal Toxicology and/or Pharmacology

In one 5-week study in monkeys at doses which produced exposures approximately 4 to 6 times those seen in adult patients treated with a 70-mg dose, scattered small foci of subcapsular necrosis were observed microscopically in the livers of some animals (2/8 monkeys at 5 mg/kg and 4/8 monkeys at 8 mg/kg); however, this histopathological finding was not seen in another study of 27 weeks duration at similar doses.

No treatment-related findings were seen in a 5-week study in infant monkeys at doses which produced exposures approximately 3 times those achieved in pediatric patients receiving a maintenance dose of 50 mg/m² daily.

CLINICAL STUDIES

The results of the adult clinical studies are presented by indications in Section 14.1 to 14.4. Results of pediatric clinical trials are in Section 14.5.

Empirical Therapy in Febrile, Neutropenic Patients

A double-blind study enrolled 1111 febrile, neutropenic (<500 cells/mm³) patients who were randomized to treatment with daily doses of CANCIDAS (50 mg/day following a 70-mg loading dose on Day 1) or AmBisome (3 mg/kg/day). Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia) and on receipt of prior antifungal prophylaxis. Twenty-four percent of patients were high risk and 56% had received prior antifungal prophylaxis. Patients who remained febrile or clinically deteriorated following 5 days of therapy could receive 70 mg/day of CANCIDAS or 5 mg/kg/day of AmBisome. Treatment was continued to resolution of neutropenia (but not beyond 28 days unless a fungal infection was documented).

An overall favorable response required meeting each of the following criteria: no documented breakthrough fungal infections up to 7 days after completion of treatment, survival for 7 days after completion of study therapy, no discontinuation of the study drug because of drug-related toxicity or lack of efficacy, resolution of fever during the period of neutropenia, and successful treatment of any documented baseline fungal infection.

Based on the composite response rates, CANCIDAS was as effective as AmBisome in empirical therapy of persistent febrile neutropenia (see Table 11).

Table 11: Favorable Response of Patients with Persistent Fever and Neutropenia

	CANCIDAS 1	AmBisome	% Difference (Confidence Interval) 2
Number of Patients 3	556	539
Overall Favorable Response	190 (33.9%)	181 (33.7%)	0.2 (-5.6, 6.0)
No documented breakthrough fungal infection	527 (94.8%)	515 (95.5%)	-0.8
Survival 7 days after end of treatment	515 (92.6%)	481 (89.2%)	3.4
No discontinuation due to toxicity or lack of efficacy	499 (89.7%)	461 (85.5%)	4.2
Resolution of fever during neutropenia	229 (41.2%)	223 (41.4%)	-0.2

The rate of successful treatment of documented baseline infections, a component of the primary endpoint, was not statistically different between treatment groups.

The response rates did not differ between treatment groups based on either of the stratification variables: risk category or prior antifungal prophylaxis.

Candidemia and the Following other Candida Infections: Intra-Abdominal Abscesses, Peritonitis and Pleural Space Infections

In a randomized, double-blind study, patients with a proven diagnosis of invasive candidiasis received daily doses of CANCIDAS (50 mg/day following a 70-mg loading dose on Day 1) or amphotericin B deoxycholate (0.6 to 0.7 mg/kg/day for non-neutropenic patients and 0.7 to 1 mg/kg/day for neutropenic patients). Patients were stratified by both neutropenic status and APACHE II score. Patients with Candida endocarditis, meningitis, or osteomyelitis were excluded from this study.

Patients who met the entry criteria and received one or more doses of IV study therapy were included in the modified intention-to-treat [MITT] analysis of response at the end of IV study therapy. A favorable response at this time point required both symptom/sign resolution/improvement and microbiological clearance of the Candida infection.

Two hundred thirty-nine patients were enrolled. Patient disposition is shown in Table 12.

Table 12: Disposition in Candidemia and Other Candida Infections (Intra-abdominal abscesses, peritonitis, and pleural space infections)

	CANCIDAS 1	Amphotericin B
Randomized patients	114	125
Patients completing study 2	63 (55.3%)	69 (55.2%)
DISCONTINUATIONS OF STUDY
All Study Discontinuations	51 (44.7%)	56 (44.8%)
Study Discontinuations due to clinical adverse events	39 (34.2%)	43 (34.4%)
Study Discontinuations due to laboratory adverse events	0 (0%)	1 (0.8%)
DISCONTINUATIONS OF STUDY THERAPY
All Study Therapy Discontinuations	48 (42.1%)	58 (46.4%)
Study Therapy Discontinuations due to clinical adverse events	30 (26.3%)	37 (29.6%)
Study Therapy Discontinuations due to laboratory adverse events	1 (0.9%)	7 (5.6%)
Study Therapy Discontinuations due to all drug-related 3 adverse events	3 (2.6%)	29 (23.2%)

Of the 239 patients enrolled, 224 met the criteria for inclusion in the MITT population (109 treated with CANCIDAS and 115 treated with amphotericin B). Of these 224 patients, 186 patients had candidemia (92 treated with CANCIDAS and 94 treated with amphotericin B). The majority of the patients with candidemia were non-neutropenic (87%) and had an APACHE II score less than or equal to 20 (77%) in both arms. Most candidemia infections were caused by C. albicans (39%), followed by C. parapsilosis (20%), C. tropicalis (17%), C. glabrata (8%), and C. krusei (3%).

At the end of IV study therapy, CANCIDAS was comparable to amphotericin B in the treatment of candidemia in the MITT population. For the other efficacy time points (Day 10 of IV study therapy, end of all antifungal therapy, 2-week post-therapy follow-up, and 6- to 8-week post-therapy follow-up), CANCIDAS was as effective as amphotericin B.

Outcome, relapse and mortality data are shown in Table 13.

Table 13: Outcomes, Relapse, & Mortality in Candidemia and Other Candida Infections (Intra-abdominal abscesses, peritonitis, and pleural space infections)

	CANCIDAS 1	Amphotericin B	% Difference 2 after adjusting for strata (Confidence Interval) 3
Number of MITT 4 patients	109	115
FAVORABLE OUTCOMES (MITT) AT THE END OF IV STUDY THERAPY
All MITT patients	81/109 (74.3%)	78/115 (67.8%)	7.5 (-5.4, 20.3)
Candidemia     Neutropenic     Non-neutropenic	67/92 (72.8%) 6/14 (43%) 61/78 (78%)	63/94 (67.0%) 5/10 (50%) 58/84 (69%)	7.0 (-7.0, 21.1)
Endophthalmitis	0/1	2/3
Multiple Sites     Blood / Pleural     Blood / Peritoneal     Blood / Urine     Peritoneal / Pleural     Abdominal / Peritoneal     Subphrenic / Peritoneal	4/5 1/1 1/1 - 1/2 - 1/1	4/4 1/1 1/1 1/1 - 1/1 -
DISSEMINATED INFECTIONS, RELAPSES AND MORTALITY
Disseminated Infections in neutropenic patients	4/14 (28.6%)	3/10 (30.0%)
All relapses 5	7/81 (8.6%)	8/78 (10.3%)
Culture-confirmed relapse	5/81 (6%)	2/78 (3%)
Overall study 6 mortality in MITT     Mortality during study therapy     Mortality attributed to Candida	36/109 (33.0%) 18/109 (17%) 4/109 (4%)	35/115 (30.4%) 13/115 (11%) 7/115 (6%)

In this study, the efficacy of CANCIDAS in patients with intra-abdominal abscesses, peritonitis and pleural space Candida infections was evaluated in 19 non-neutropenic patients. Two of these patients had concurrent candidemia. Candida was part of a polymicrobial infection that required adjunctive surgical drainage in 11 of these 19 patients. A favorable response was seen in 9 of 9 patients with peritonitis, 3 of 4 with abscesses (liver, parasplenic, and urinary bladder abscesses), 2 of 2 with pleural space infections, 1 of 2 with mixed peritoneal and pleural infection, 1 of 1 with mixed abdominal abscess and peritonitis, and 0 of 1 with Candida pneumonia.

Overall, across all sites of infection included in the study, the efficacy of CANCIDAS was comparable to that of amphotericin B for the primary endpoint.

In this study, the efficacy data for CANCIDAS in neutropenic patients with candidemia were limited. In a separate compassionate use study, 4 patients with hepatosplenic candidiasis received prolonged therapy with CANCIDAS following other long-term antifungal therapy; three of these patients had a favorable response.

In a second randomized, double-blind study, 197 patients with proven invasive candidiasis received CANCIDAS 50 mg/day (following a 70-mg loading dose on Day 1) or CANCIDAS 150 mg/day. The diagnostic criteria, evaluation time points, and efficacy endpoints were similar to those employed in the prior study. Patients with Candida endocarditis, meningitis, or osteomyelitis were excluded. Although this study was designed to compare the safety of the two doses, it was not large enough to detect differences in rare or unexpected adverse events [see Adverse Reactions]. A significant improvement in efficacy with the 150-mg daily dose was not seen when compared to the 50-mg dose.

Esophageal Candidiasis (and information on oropharyngeal candidiasis)

The safety and efficacy of CANCIDAS in the treatment of esophageal candidiasis was evaluated in one large, controlled, noninferiority, clinical trial and two smaller dose-response studies.

In all 3 studies, patients were required to have symptoms and microbiological documentation of esophageal candidiasis; most patients had advanced AIDS (with CD4 counts <50/mm³).

Of the 166 patients in the large study who had culture-confirmed esophageal candidiasis at baseline, 120 had Candida albicans and 2 had Candida tropicalis as the sole baseline pathogen whereas 44 had mixed baseline cultures containing C. albicans and one or more additional Candida species.

In the large, randomized, double-blind study comparing CANCIDAS 50 mg/day versus intravenous fluconazole 200 mg/day for the treatment of esophageal candidiasis, patients were treated for an average of 9 days (range 7-21 days). Favorable overall response at 5 to 7 days following discontinuation of study therapy required both complete resolution of symptoms and significant endoscopic improvement. The definition of endoscopic response was based on severity of disease at baseline using a 4-grade scale and required at least a two-grade reduction from baseline endoscopic score or reduction to grade 0 for patients with a baseline score of 2 or less.

The proportion of patients with a favorable overall response was comparable for CANCIDAS and fluconazole as shown in Table 14.

Table 14: Favorable Response Rates for Patients with Esophageal Candidiasis ¹

	CANCIDAS	Fluconazole	% Difference 2 (95% CI)
Day 5-7 post-treatment	66/81 (81.5%)	80/94 (85.1%)	-3.6 (-14.7, 7.5)

The proportion of patients with a favorable symptom response was also comparable (90.1% and 89.4% for CANCIDAS and fluconazole, respectively). In addition, the proportion of patients with a favorable endoscopic response was comparable (85.2% and 86.2% for CANCIDAS and fluconazole, respectively).

As shown in Table 15, the esophageal candidiasis relapse rates at the Day 14 post-treatment visit were similar for the two groups. At the Day 28 post-treatment visit, the group treated with CANCIDAS had a numerically higher incidence of relapse; however, the difference was not statistically significant.

Table 15: Relapse Rates at 14 and 28 Days Post-Therapy in Patients with Esophageal Candidiasis at Baseline

	CANCIDAS	Fluconazole	% Difference 1 (95% CI)
Day 14 post-treatment Day 28 post-treatment	7/66 (10.6%) 18/64 (28.1%)	6/76 (7.9%) 12/72 (16.7%)	2.7 (-6.9, 12.3) 11.5 (-2.5, 25.4)

In this trial, which was designed to establish noninferiority of CANCIDAS to fluconazole for the treatment of esophageal candidiasis, 122 (70%) patients also had oropharyngeal candidiasis. A favorable response was defined as complete resolution of all symptoms of oropharyngeal disease and all visible oropharyngeal lesions. The proportion of patients with a favorable oropharyngeal response at the 5- to 7-day post-treatment visit was numerically lower for CANCIDAS; however, the difference was not statistically significant. Oropharyngeal candidiasis relapse rates at Day 14 and Day 28 post-treatment visits were statistically significantly higher for CANCIDAS than for fluconazole. The results are shown in Table 16.

Table 16: Oropharyngeal Candidiasis Response Rates at 5 to 7 Days Post-Therapy and Relapse Rates at 14 and 28 Days Post-Therapy in Patients with Oropharyngeal and Esophageal Candidiasis at Baseline

	CANCIDAS	Fluconazole	% Difference 1 (95% CI)
Response Rate Day 5-7 post-treatment	40/56 (71.4%)	55/66 (83.3%)	-11.9 (-26.8, 3.0)
Relapse Rate Day 14 post-treatment	17/40 (42.5%)	7/53 (13.2%)	29.3 (11.5, 47.1)
Relapse Rate Day 28 post-treatment	23/39 (59.0%)	18/51 (35.3%)	23.7 (3.4, 43.9)

The results from the two smaller dose-ranging studies corroborate the efficacy of CANCIDAS for esophageal candidiasis that was demonstrated in the larger study.

CANCIDAS was associated with favorable outcomes in 7 of 10 esophageal C. albicans infections refractory to at least 200 mg of fluconazole given for 7 days, although the in vitro susceptibility of the infecting isolates to fluconazole was not known.

Invasive Aspergillosis

Sixty-nine patients between the ages of 18 and 80 with invasive aspergillosis were enrolled in an open-label, noncomparative study to evaluate the safety, tolerability, and efficacy of CANCIDAS. Enrolled patients had previously been refractory to or intolerant of other antifungal therapy(ies). Refractory patients were classified as those who had disease progression or failed to improve despite therapy for at least 7 days with amphotericin B, lipid formulations of amphotericin B, itraconazole, or an investigational azole with reported activity against Aspergillus. Intolerance to previous therapy was defined as a doubling of creatinine (or creatinine ≥2.5 mg/dL while on therapy), other acute reactions, or infusion-related toxicity. To be included in the study, patients with pulmonary disease must have had definite (positive tissue histopathology or positive culture from tissue obtained by an invasive procedure) or probable (positive radiographic or computed tomography evidence with supporting culture from bronchoalveolar lavage or sputum, galactomannan enzyme-linked immunosorbent assay, and/or polymerase chain reaction) invasive aspergillosis. Patients with extrapulmonary disease had to have definite invasive aspergillosis. The definitions were modeled after the Mycoses Study Group Criteria [see References]. Patients were administered a single 70-mg loading dose of CANCIDAS and subsequently dosed with 50 mg daily. The mean duration of therapy was 33.7 days, with a range of 1 to 162 days.

An independent expert panel evaluated patient data, including diagnosis of invasive aspergillosis, response and tolerability to previous antifungal therapy, treatment course on CANCIDAS, and clinical outcome.

A favorable response was defined as either complete resolution (complete response) or clinically meaningful improvement (partial response) of all signs and symptoms and attributable radiographic findings. Stable, nonprogressive disease was considered to be an unfavorable response.

Among the 69 patients enrolled in the study, 63 met entry diagnostic criteria and had outcome data; and of these, 52 patients received treatment for >7 days. Fifty-three (84%) were refractory to previous antifungal therapy and 10 (16%) were intolerant. Forty-five patients had pulmonary disease and 18 had extrapulmonary disease. Underlying conditions were hematologic malignancy (N=24), allogeneic bone marrow transplant or stem cell transplant (N=18), organ transplant (N=8), solid tumor (N=3), or other conditions (N=10). All patients in the study received concomitant therapies for their other underlying conditions. Eighteen patients received tacrolimus and CANCIDAS concomitantly, of whom 8 also received mycophenolate mofetil.

Overall, the expert panel determined that 41% (26/63) of patients receiving at least one dose of CANCIDAS had a favorable response. For those patients who received >7 days of therapy with CANCIDAS, 50% (26/52) had a favorable response. The favorable response rates for patients who were either refractory to or intolerant of previous therapies were 36% (19/53) and 70% (7/10), respectively. The response rates among patients with pulmonary disease and extrapulmonary disease were 47% (21/45) and 28% (5/18), respectively. Among patients with extrapulmonary disease, 2 of 8 patients who also had definite, probable, or possible CNS involvement had a favorable response. Two of these 8 patients had progression of disease and manifested CNS involvement while on therapy.

CANCIDAS is effective for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of itraconazole, amphotericin B, and/or lipid formulations of amphotericin B. However, the efficacy of CANCIDAS for initial treatment of invasive aspergillosis has not been evaluated in comparator-controlled clinical studies.

Pediatric Patients

The safety and efficacy of CANCIDAS were evaluated in pediatric patients 3 months to 17 years of age in two prospective, multicenter clinical trials.

The first study, which enrolled 82 patients between 2 to 17 years of age, was a randomized, double-blind study comparing CANCIDAS (50 mg/m² IV once daily following a 70-mg/m² loading dose on Day 1 [not to exceed 70 mg daily]) to AmBisome (3 mg/kg IV daily) in a 2:1 treatment fashion (56 on caspofungin, 26 on AmBisome) as empirical therapy in pediatric patients with persistent fever and neutropenia. The study design and criteria for efficacy assessment were similar to the study in adult patients [see Clinical Studies]. Patients were stratified based on risk category (high-risk patients had undergone allogeneic stem cell transplantation or had relapsed acute leukemia). Twenty-seven percent of patients in both treatment groups were high risk. Favorable overall response rates of pediatric patients with persistent fever and neutropenia are presented in Table 17.

Table 17: Favorable Overall Response Rates of Pediatric Patients with Persistent Fever and Neutropenia

	CANCIDAS	AmBisome 1
Number of Patients	56	25
Overall Favorable Response	26/56 (46.4%)	8/25 (32.0%)
High risk	9/15 (60.0%)	0/7 (0.0%)
Low risk	17/41 (41.5%)	8/18 (44.4%)

The second study was a prospective, open-label, non-comparative study estimating the safety and efficacy of caspofungin in pediatric patients (ages 3 months to 17 years) with candidemia and other Candida infections, esophageal candidiasis, and invasive aspergillosis (as salvage therapy). The study employed diagnostic criteria which were based on established EORTC/MSG criteria of proven or probable infection; these criteria were similar to those criteria employed in the adult studies for these various indications. Similarly, the efficacy time points and endpoints used in this study were similar to those employed in the corresponding adult studies [see Clinical Studies (14.2, 14.3, and 14.4) ]. All patients received CANCIDAS at 50 mg/m² IV once daily following a 70-mg/m² loading dose on Day 1 (not to exceed 70 mg daily). Among the 49 enrolled patients who received CANCIDAS, 48 were included in the efficacy analysis (one patient excluded due to not having a baseline Aspergillus or Candida infection). Of these 48 patients, 37 had candidemia or other Candida infections, 10 had invasive aspergillosis, and 1 patient had esophageal candidiasis. Most candidemia and other Candida infections were caused by C. albicans (35%), followed by C. parapsilosis (22%), C. tropicalis (14%), and C. glabrata (11%). The favorable response rate, by indication, at the end of caspofungin therapy was as follows: 30/37 (81%) in candidemia or other Candida infections, 5/10 (50%) in invasive aspergillosis, and 1/1 in esophageal candidiasis.