June 26, 2016
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Kepivance

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Kepivance




CLINICAL PHARMACOLOGY

Mechanism Of Action

KGF is an endogenous protein in the fibroblast growth factor (FGF) family that binds to the KGF receptor. Binding of KGF to its receptor has been reported to result in proliferation, differentiation, and migration o f epithelial cells. The KGF receptor, one o f four receptors in the FGF family, has been reported to be present on epithelial cells in many tissues examined including the tongue, buccal mucosa, esophagus, stomach, intestine, salivary gland, lung, liver, pancreas, kidney, bladder, mammary gland, skin (hair follicles and sebaceous gland), and the lens o f the eye. The KGF receptor has been reported to not be present on cells o f the hematopoietic lineage. Endogenous KGF is produced by mesenchymal cells and is upregulated in response to epithelial tissue injury.

In mice and rats, Kepivance enhanced proliferation o f epithelial cells (as measured by Ki67 immunohistochemical staining and BrDU uptake) and demonstrated an increase in tissue thickness o f the tongue, buccal mucosa, and gastrointestinal tract. Kepivance has been studied in murine models o f chemotherapy and radiationinduced gastrointestinal injury. In such models, administration o f Kepivance prior to and/or after the cytotoxic insult improved survival and reduced weight loss compared to control animals.

Kepivance has been shown to enhance the growth o f human epithelial tumor cell lines in vitro at concentrations ≥ 10 mcg/mL ( > 15-fold higher than average therapeutic concentrations in humans). In nude mouse xenograft models, three consecutive daily treatments o f Kepivance at doses o f 1,500 and 4,000 mcg/kg (25- and 67-fold higher than the recommended human dose, respectively) repeated weekly for 4 to 6 weeks were associated with a dose-dependent increase in the growth rate of 1 of 7 KGF receptor-expressing human tumor cell lines.

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 o f 120 to 250 mcg/kg 48 hours post-dosing.

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 o f Kepivance the average total body clearance (CL) was 2- to 4-fold higher, and volume o f 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 o f Kepivance occurred after 3 consecutive daily doses o f 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 o f palifermin over the dose range o f 40 to 80 mcg/kg [see Use in Specific Populations].

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 o f 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 o f 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 o f 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 o f epithelial cell proliferation.

Pharmacokinetics In Specific Populations

Renal Impairment

Results from a pharmacokinetics study in 24 subjects with varying degrees o f renal impairment demonstrated that renal impairment has little or no influence on Kepivance pharmacokinetics [ see Use in Specific Populations]

Elderly

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

Reproductive And Developmental Toxicology

In animal reproductive toxicity studies, palifermin is embryotoxic at doses that are 2.5 times (rabbits) and 5 to > 8 times (rats) the MRHD, based on body weight (mcg/kg). Pregnant rabbits received intravenous palifermin during organogenesis at doses equivalent to 1.0 and 2.5 times the MRHD, based on body weight (mcg/kg). Increased post-implantation loss and decreased fetal body weights occurred along with maternal toxicity (clinical signs and reductions in body weight gain/food consumption) at doses 2.5 times the MRHD.

In pregnant rats, animals received intravenous palifermin during organogenesis at doses o f 5 to > 8 times the MRHD based on body weight (mcg/kg). Increased post-implantation loss, decreased fetal body weight, and/or increased skeletal variations occurred in the presence o f maternal toxicity at doses > 8 times the MRHD.

Clinical Studies

Autologous Transplantation Preparative Regimens That Include Total Body Irradiation

The safety and efficacy o f Kepivance in decreasing the incidence and duration o f 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 o f 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 o f cytotoxic therapy and for 3 consecutive days following infusion o f hematopoietic stem cells. The major efficacy outcome was the number o f 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 o f oral mucositis and the use of opioid analgesia. There was no evidence o f a delay in time to hematopoietic recovery in patients who received Kepivance as compared to patients who received placebo. The results o f Study 1 are presented in Table 2 and Figure 1.

Table 2: Study 1 Efficacy Outcomes

Efficacy Variable Kepivance (60 mcg/kg/day)
(n = 106)
Placebo
(n = 106)
Median (25th, 75th 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 (25th, 75th 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 (25th, 75th 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

Incidence of Oral Mucositis by Maximum Grade WHO Oral Mucositis Scale - Illustration

1 WHO Oral Mucositis Scale: Grade 1 = soreness/erythema; Grade 2 = erythema, ulcers, can eat solids; Grade 3 = ulcers, requires liquid diet only; Grade 4 = alimentation not possible.

Study 2 was a randomized, multi-center, placebo-controlled trial comparing varying schedules o f 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 o f Kepivance administered in Study 1. One arm o f Study 2 that included patients who received Kepivance for 3 consecutive days prior to initiation o f cytotoxic therapy, a dose given on the last day of TBI prior to etoposide, and for 3 consecutive days following infusion o f hematopoietic stem cells was prematurely closed by the Safety Committee for lack of efficacy and a trend towards increased severity and duration o f oral mucositis as compared to placebo-treated patients. The Safety Committee attributed the safety finding to Kepivance having been administered within 24 hours o f chemotherapy, which resulted in an increased sensitivity of the rapidly dividing epithelial cells in the immediate post-chemotherapy period [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Lack Of Efficacy: Autologous Transplantation Preparative Regimen Using High Dose Melphalan

In a post approval study, Study 3, designed to determine the efficacy of Kepivance with a high dose melphalan preparative regimen, patients with multiple myeloma were evaluated in a multicenter, randomized, double-blind, placebo-controlled trial. The conditioning regimen was melphalan (200 mg/m²) on day -2 followed by autologous hematopoietic stem cell support. A total o f 281 patients were randomized to 3 arms: Kepivance before melphalan on days -6, -5, -4 and after melphalan on days 0, 1, and 2 (pre-post) (n=115); Kepivance before melphalan on days -6, -5, -4 (pre) (n=109); or placebo (n=57).

The main outcome o f the study was maximum severity o f WHO oral mucositis. The median age o f enrolled patients was 57 years (range 32-69), and 55% were male. The results are presented in Figure 2. The prespecified primary analysis was a comparison between the Kepivance pre-post and pre arms to placebo. The incidence o f WHO Grade 3 and 4 in the Kepivance pre-post arm was 38%, compared to 37% in the placebo arm. There were no significant differences between either of the Kepivance regimens and the placebo arm in the incidence o f severe oral mucositis.

Figure 2: Incidence of Oral Mucositis by Maximum Grade WHO Oral Mucositis Scale in High Dose Melphalan Study

Incidence of Oral Mucositis by Maximum Grade WHO Oral Mucositis Scale in High Dose Melphalan Study - Illustration

A subset o f subjects enrolled in the multiple myeloma study were included in an evaluation for the risk of cataract development in patients receiving Kepivance treatment. Ophthalmologic examinations were performed on 101 patients enrolled in a double-blind, randomized, placebo-controlled study o f two different schedules of Kepivance (pre and post chemotherapy and pre chemotherapy only) for reduction in severity o f oral mucositis in subjects with multiple myeloma receiving high dose melphalan followed by autologous peripheral blood stem cell transplantation. For the primary cataract endpoint o f incidence o f cataract development or cataract progression at Month 12, there was a greater proportion of subjects that experienced cataract development in the Kepivance group: 48% (25/52) compared with the placebo group: 29% (4/14) (difference o f 17 [95% CI: -11, 46]) [see ADVERSE REACTIONS - Clinical Trial Experience].

Last reviewed on RxList: 4/19/2016
This monograph has been modified to include the generic and brand name in many instances.

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