Kepivance (Page 3 of 4)

12.2 Pharmacodynamics

Epithelial cell proliferation was assessed by Ki67 immunohistochemical staining in healthy subjects. A 3-fold or greater increase in Ki67 staining was observed in buccal biopsies from 3 of 6 healthy subjects given Kepivance at 40 mcg/kg/day intravenously for 3 days, when measured 24 hours after the third dose. Dose-dependent epithelial cell proliferation was observed in healthy subjects given single intravenous doses of 120 to 250 mcg/kg 48 hours post-dosing.

12.3 Pharmacokinetics

The pharmacokinetics of Kepivance were studied in healthy subjects and patients with hematologic malignancies. After single intravenous doses of 20 to 250 mcg/kg in healthy subjects and 60 mcg/kg in cancer patients, Kepivance concentrations declined over 95% in the first 30 minutes post-dose. A slight increase or plateau in concentration occurred at approximately 1 to 4 hours, followed by a terminal decline phase. Kepivance exhibited linear pharmacokinetics with extravascular distribution. In cancer patients compared with healthy subjects, after a 60 mcg/kg single dose of Kepivance the average total body clearance (CL) was 2- to 4-fold higher, and volume of distribution at steady state (Vss) was 2-fold higher. The elimination half-life was similar between healthy subjects and cancer patients (average 4.5 hours with a range of 3.3 to 5.7 hours). No accumulation of Kepivance occurred after 3 consecutive daily doses of 20 and 40 mcg/kg in healthy subjects or 60 mcg/kg in cancer patients. Age (1 to 16 years) did not affect the pharmacokinetics of palifermin over the dose range of 40 to 80 mcg/kg [see Use in Specific Populations ( 8.4)].

Drug Interactions

Co-administration with Heparin

The potential pharmacokinetic interaction between palifermin and heparin was evaluated in a single-dose study in 27 healthy subjects receiving palifermin (60 mcg/kg) co-administered with and without therapeutic levels of unfractionated heparin. This co-administration resulted in a 5-fold increase in palifermin AUC and an 80% decrease in the mean CL. There was no significant effect of palifermin on heparin activity with respect to activated partial thromboplastin time (aPTT). A second study was conducted in 31 evaluable healthy subjects receiving palifermin (40 mcg/kg/day for 3 days) co-administered with and without therapeutic levels of unfractionated heparin. In this study, coadministration of heparin and palifermin resulted in a 425% increase in palifermin AUC and a 76.5, 73.1, and 38.8% decrease in palifermin CL, volume of distribution, and half-life, respectively. These changes in palifermin PK did not have a noticeable effect on Ki67 expression in buccal biopsies, used as a marker of epithelial cell proliferation.

Pharmacokinetics in Specific Populations

Renal Impairment

Results from a pharmacokinetics study in 24 subjects with varying degrees of renal impairment demonstrated that renal impairment has little or no influence on Kepivance pharmacokinetics.

Hepatic Impairment

The pharmacokinetic profile of patients with hepatic insufficiency has not been assessed.

Elderly

In a single-dose study, subjects received a 180-mcg/kg or 90-mcg/kg dose of palifermin administered by intravenous bolus injection. Subjects over the age of 65 (n=8) had an approximately 30% lower rate of CL on average than those 65 and younger (n=19). No dose adjustment is recommended for the geriatric population [see Use in Specific Populations ( 8.5)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Palifermin was not carcinogenic in a 26-week study in rasH2 transgenic mice at intravenous doses of 0.1, 1, or 10 mg/kg/dose.

Palifermin was not genotoxic in the reverse mutation bacterial (Ames) test, cytogenic test, or rat micronucleus assay.

In a fertility and early embryonic development study, palifermin was administered intravenously to male and female rats at doses of 100, 300 or 1000 μg/kg/day. Males were dosed 28 days prior to mating through cohabitation and females were dosed 14 days prior to mating through gestation Day 7. Decreased epididymal sperm counts, and increased post-implantation losses were observed at doses ≥ 300 μg/kg/day (5 fold the recommended human dose, on a body weight basis). Increased pre-implantation loss and decreased fertility index, were observed at a palifermin dose of 1000 μg/kg/day.

14 CLINICAL STUDIES

14.1 Autologous transplantation preparative regimens that include total body irradiation

The safety and efficacy of Kepivance in decreasing the incidence and duration of severe oral mucositis in patients with hematologic malignancies (NHL, Hodgkin’s disease, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, or multiple myeloma) receiving myelotoxic therapy requiring hematopoietic stem cell support, were established in a randomized placebo-controlled clinical trial of 212 patients (Study 1) and a randomized, schedule-ranging, placebo-controlled clinical trial of 169 patients (Study 2).

In Study 1, patients received high-dose cytotoxic therapy consisting of fractionated total-body irradiation (TBI) (12 Gy total dose), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide (100 mg/kg) followed by hematopoietic stem cell support. Patients were randomized to receive either Kepivance (n = 106) or placebo (n = 106). Kepivance 60 mcg/kg was administered as a daily intravenous injection for 3 consecutive days prior to initiation of cytotoxic therapy and for 3 consecutive days following infusion of hematopoietic stem cells. The major efficacy outcome was the number of days during which patients experienced severe oral mucositis (Grade 3/4 on the WHO [World Health Organization] scale) 1. Other analyses included the incidence, duration, and severity of oral mucositis and the use of opioid analgesia. There was no evidence of a delay in time to hematopoietic recovery in patients who received Kepivance as compared to patients who received placebo. The results of Study 1 are presented in Table 2 and Figure 1.

Table 2: Study 1 Efficacy Outcomes

* P < 0.001 compared to placebo, using Generalized Cochran-Mantel-Haenszel (CMH) test stratified for study center.

Efficacy Variable Kepivance (60 mcg/kg/day) (n = 106) Placebo (n = 106)
Median (25 th , 75 th percentile) Days of WHO Grade 3/4 Oral Mucositis* 3 (0, 6) 9 (6, 13)
Incidence of WHO Grade 3/4 Oral Mucositis 63% (67/106) 98% (104/106)
Median (25 th , 75 th percentile) Days of WHO Grade 3/4 Oral Mucositis in Affected Patients 6 (3, 8) (n = 67) 9 (6, 13) (n = 104)
Incidence of WHO Grade 4 Oral Mucositis 20% 62%
Median (25 th , 75 th percentile) Cumulative Opiod Dose (morphine mg equivalents) 212 (3, 558) 535 (269, 1429)

Figure 1: Study 1 Incidence of Oral Mucositis by Maximum Grade WHO Oral Mucositis Scale

Figure 1
(click image for full-size original)

Study 2 was a randomized, multi-center, placebo-controlled trial comparing varying schedules of Kepivance. All patients received high-dose cytotoxic therapy consisting of fractionated TBI (12cGy total dose), high-dose etoposide (60 mg/kg), and high-dose cyclophosphamide (75-100 mg/kg) followed by hematopoietic stem cell support. The results for Study 1 were supported by results observed in the subset of patients in Study 2 who received the same dose and schedule of Kepivance administered in Study 1. One arm of Study 2 that included patients who received Kepivance for 3 consecutive days prior to initiation of cytotoxic therapy, a dose given on the last day of TBI prior to etoposide, and for 3 consecutive days following infusion of hematopoietic stem cells was prematurely closed by the Safety Committee for lack of efficacy and a trend towards increased severity and duration of oral mucositis as compared to placebo-treated patients. The Safety Committee attributed the safety finding to Kepivance having been administered within 24 hours of chemotherapy, which resulted in an increased sensitivity of the rapidly dividing epithelial cells in the immediate post-chemotherapy period [see Dosage and Administration ( 2.1) and Drug Interactions ( 7)].

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