Abstract

Mucositis is a frequent and debilitating complication experienced by patients receiving high-dose chemotherapy and/or radiotherapy significantly impacting patient-reported outcomes (Spielberger et al, ASCO 2003) and healthcare resources (Emmanouilides, ASH 2003) for its management. Palifermin has been shown in hematological cancer patients to reduce the duration, incidence, and severity of mucositis and its related clinical sequelae following 3-consecutive daily doses of 60 mcg/kg before and after TBI and chemotherapy with HSCT (Spielberger et al, ASCO 2003). In this phase 1, randomized, double-blind, placebo-controlled, dose escalation study, the PK and PD of palifermin were evaluated in healthy subjects. A single IV bolus of palifermin or placebo was administered at 6 dose levels ranging from 60 to 250 mcg/kg. Blood samples for PK assessments were collected through 120 hours post administration, and PK analysis was conducted using noncompartmental methods. PD measurements (using Ki67 staining on buccal mucosa biopsies) assessing the proliferation of buccal mucosal epithelium were performed on all subjects at baseline and 48 or 72 hours following administration of palifermin or placebo. Seventy-nine subjects received study drug (n=16 placebo and n=63 palifermin). Most subjects were white (76%) and men (96%). The mean age was 25.8 years (range 18 to 53). A sharp decrease in palifermin concentrations occurred during the first 1 to 1.5 hours postdose, followed by a slight increase and then a subsequent decay phase. Exposure to palifermin increased approximately proportional to dose (3-fold increase in C0 and AUC for a 4-fold increase in dose).

Table 1. Mean (SD) PK Data

Dose (mcg/kg)nC0AUC0-∞ (ng*hr/mL)t1/2,z (hr)CL (mL/hr/kg)
60 16 891 (661) 134 (40.5) 4.50 (0.580) 494 (171) 
90 15 1020 (823) 170 (54.8) 4.92 (0.460) 590 (212) 
120 1530 (1190) 253 (85.7) 5.22 (0.412) 528 (185) 
160 1590 (1100) 257 (69.2) 4.89 (0.274) 661 (162) 
210 1700 (1560) 322 (96.5) 5.89 (0.975) 714 (245) 
250 2720 (2150) 412 (110) 6.09 (1.20) 645 (172) 
Dose (mcg/kg)nC0AUC0-∞ (ng*hr/mL)t1/2,z (hr)CL (mL/hr/kg)
60 16 891 (661) 134 (40.5) 4.50 (0.580) 494 (171) 
90 15 1020 (823) 170 (54.8) 4.92 (0.460) 590 (212) 
120 1530 (1190) 253 (85.7) 5.22 (0.412) 528 (185) 
160 1590 (1100) 257 (69.2) 4.89 (0.274) 661 (162) 
210 1700 (1560) 322 (96.5) 5.89 (0.975) 714 (245) 
250 2720 (2150) 412 (110) 6.09 (1.20) 645 (172) 

The PD response also increased with increasing doses of palifermin up to the dose of 160 mcg/kg at which near maximal effect appeared to have been reached. A greater response for Ki67 staining was observed at 48 hours compared with 72 hours. Transient asymptomatic increases in amylase (primarily of salivary origin) and lipase were noted 1 to 3 days postdosing at all palifermin doses. Upper torso, arm, and facial skin erythema and injection site reactions were more frequently noted at the highest doses. In this study, palifermin was safe and generally well tolerated in the dose range examined. In summary, for the dose range examined, exposure to palifermin increased approximately dose-proportionally and an increased PD response was observed with increased dose with a flattening of the dose response relationship at higher doses. Based on the safety and PD profile of palifermin in this study and the results of a phase 3 study (Spielberger et al, ASCO 2003), future trials in oncology patients will be conducted using a single 180 mcg/kg dose in lieu of 3 doses at 60 mcg/kg.

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