FDA Approval for Palifermin
- Approved for the treatment of severe oral mucositis
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
On December 15, 2004, the U.S. Food and Drug Administration approved a recombinant protein called palifermin (Kepivance™, a trademark of Amgen, Inc.) to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies who receive high doses of chemotherapy and radiation therapy followed by stem cell rescue. Mucositis - sores and ulcers in the lining of the mouth - is a common side effect of certain cancer treatments.
Palifermin is a nonglycosylated, 16.3 kD protein produced by an E. coli strain that has been genetically modified to contain a truncated version of the genetic sequence for human keratinocyte growth factor (KGF). Endogenous KGF is a paracrine growth factor produced by mesenchymal cells and fibroblasts; binding of KGF to the KGF receptor on adjacent epithelial cell tissues results in proliferation and differentiation.
The KGF receptor is 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 of the eye. The KGF receptor is not present on cells of the hematopoietic lineage.
The following potential mechanisms through which endogenous KGF may protect epithelial cells from injury and/or hasten recovery from injury have been proposed: induction of mitogenesis, tissue thickening and induction of cellular protective mechanisms.
The recommended dose of palifermin is 60 µg/kg/d by intravenous bolus injection for three consecutive days immediately prior to and for three consecutive days, beginning the day of stem cell re-infusion, following the completion of myeloablative conditioning regimen. Palifermin should not be administered less than 24 hours prior to or less than 24 hours following myelotoxic therapy. Palifermin should not be administered through an IV line containing heparin.
Palifermin is recommended for use in patients with hematologic malignancies undergoing hematopoietic stem cell transplantation to reduce the incidence and duration of severe oral mucositis. The safety and effectiveness of palifermin in patients with solid tumors has not been established.
Approval was based primarily on the results of a randomized, placebo-controlled, multicenter trial in 212 patients. This study confirmed the results of a randomized, placebo-controlled, multicenter, schedule-ranging trial. Both trials were conducted in patients with hematologic malignancies undergoing myeloablative chemotherapy and total body irradiation, with hematopoietic stem cell rescue.
In the primary efficacy study, patients were randomized 1:1 (palifermin: placebo). The treatment schedule for both studies was: investigational drug (palifermin/placebo) on Days11, 10, and 9, 1200 cGy total body irradiation in divided doses on Days 8, 7, 6, 5, etoposide 60 mg/kg on Day 4, cyclophosphamide 75-100 mg/kg on Day 2, stem cell re-infusion on Day 0, investigational drug (palifermin/placebo) on Days 0, 1, and 2, and Neupogen pn Days 0 through 21 or until neutrophil engraftment was documented.
In the primary efficacy study, the median duration of WHO grade 3 and 4 mucositis was significantly shorter (three days vs. nine days, p<0.001, CMH test) in patients receiving palifermin. The reduction in median duration of severe mucositis reflects both a reduction in the incidence of severe mucositis (67 percent vs. 98 percent) and a shorter median duration in those who experienced severe mucositis (six days vs. nine days).
There was also a reduction in the incidence of WHO grade 4 mucositis (20 percent vs. 62 percent) and a reduction in the requirement for opioid analgesics from initiation of treatment through post-transplant day 28. Patients used a daily diary to record the amount of mouth and throat soreness. Compared with placebo-treated patients, palifermin-treated patients reported less mouth and throat soreness.
These results confirmed the findings of a phase II study. In that study, as compared with placebo, there was a reduction in median days of WHO Grade 3/4 oral mucositis (four days vs. six days), lower incidence of WHO Grade 3/4 oral mucositis (67 percent vs. 80 percent) and lower incidence of WHO Grade 4 oral mucositis (26 percent vs. 50 percent) among patients receiving palifermin.
The incidence serious adverse events was similar in palifermin and placebo-treated patients; the only serious adverse event attributed to palifermin was skin rash, occurring in <1 percent palifermin-treated patients. The most common adverse reactions attributed to palifermin were skin toxicities (rash, erythema, edema, pruritus), oral toxicities (dysesthesia, tongue discoloration, tongue thickening, alteration of taste), pain, arthralgias, and dysesthesia.
The median time to onset of cutaneous toxicity was six days following the first of three consecutive daily doses of palifermin, with a median duration of five days. In patients receiving palifermin, dysesthesia (including hyperesthesia, hypoesthesia, and paresthesia) was usually localized to the perioral region, whereas in patients receiving placebo dysesthesias were more likely to occur in extremities.
Palifermin-treated patients had an increased incidence of elevated serum amylase (38 percent vs. 31 percent NCI CTC Grade 3/4) and serum lipase (11 percent vs. 5 percent; NCI CTC Grade 3/4) as compared to placebo controls. In phase I studies, modest dose-related increases in blood pressure and in proteinuria were reported; no clear increase in nephrotoxicity or hypertension was reported in the efficacy studies.
Because the KGF receptor is also present on malignant epithelial cells, there is a theoretical risk that palifermin may also stimulate the proliferation of KGF-receptor bearing malignant cells. There is also a theoretical risk of ocular toxicity as a result of KGF stimulation of cells on the lens of the eye. To date, clinical studies have not demonstrated an increase in second cancers or ocular toxicity. Additional nonclinical and clinical studies characterizing the risks of epithelial-derived tumor stimulation and ocular toxicity are ongoing or planned.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.