Originally published as JCO Early Release 10.1200/JCO.2005.04.1152 on October 30 2006

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Palifermin Reduces the Incidence of Oral Mucositis in Patients With Metastatic Colorectal Cancer Treated With Fluorouracil-Based Chemotherapy

Lee S. Rosen, Ehtesham Abdi, Ian D. Davis, John Gutheil, Frederick M. Schnell, John Zalcberg, Alessandra Cesano, Urte Gayko, Mon-Gy Chen, Stephen Clarke

From Premiere Oncology, John Wayne Cancer Institute, St John's Health Center, Santa Monica; Sharp HealthCare, Sidney Kimmel Cancer Center, San Diego; Amgen Inc, Thousand Oaks, CA; Bendigo Health Care Group, Bendigo; Department of Medical Oncology, Austin Health, Heidelberg; Peter MacCallum Cancer Institute, Melbourne, Victoria; Medical Oncology Department, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; and Central Georgia Hematology Oncology, Macon, GA

Address reprint requests to Lee S. Rosen, MD, Premiere Oncology, John Wayne Cancer Institute, 2020 Santa Monica Blvd, Ste 510, Santa Monica, CA 90404; e-mail: lrosen{at}premiereoncology.com

	ABSTRACT

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Purpose: To characterize the efficacy and safety of palifermin in reducing the incidence of oral mucositis (OM) and diarrhea when administered to patients with metastatic colorectal cancer (CRC) receiving fluorouracil/leucovorin (FU/LV) chemotherapy.

Patients and Methods: Patients (N = 64) were randomly assigned to receive either placebo or palifermin (40 µg/kg for 3 consecutive days) before each of two consecutive cycles of chemotherapy with FU/LV. The incidence of OM and diarrhea, safety, disease progression, and survival were evaluated.

Results: Thirty-six patients received placebo and 28 patients received palifermin. The incidence of WHO grade 2 or higher OM was lower in patients who received palifermin compared with placebo (29% v 61% in cycle 1; 11% v 47% in cycle 2). FU dose reductions in the second chemotherapy cycle were more frequent in the placebo group (31%) than in the palifermin group (14%). Investigators reported lower mucositis scores and patients reported less severe symptoms with palifermin. There were no statistically significant differences in the incidence or severity of diarrhea or in overall survival between the groups. Overall, palifermin was safe and well tolerated.

Conclusion: Palifermin administered at the indicated dosing regimen (40 µg/kg for 3 consecutive days) before chemotherapy was well tolerated and resulted in a statistically significant and clinically meaningful reduction in the incidence of WHO grade 2 or higher OM in patients with metastatic CRC.

	INTRODUCTION

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Approximately 30% of patients with colorectal cancer (CRC) have metastases at diagnosis, and 50% of patients with early stage CRC eventually develop metastatic disease.¹ Most chemotherapy regimens include fluorouracil (FU), commonly administered with leucovorin (LV), which increases the affinity of FU for thymidylate synthase.^2,3 When this study was conducted (1990s), FU/LV was the standard of care in the adjuvant and metastatic setting.⁴ Fluoropyrimidines remain a mainstay of therapy, and are now often combined with newer agents such as oxaliplatin, irinotecan, and bevacizumab.

FU is associated with a high incidence of GI toxicities, including mucositis and diarrhea, which often result in treatment delay or dose reduction for subsequent courses. Mucositis can be clinically debilitating, requiring the use of narcotic analgesics to control pain, and can significantly decrease quality of life. Dose reductions have unknown effects on treatment outcomes.⁵

Until recently, there has been no approved pharmacologic agent in any setting to reduce the incidence and duration of mucositis.^6,7 Cryotherapy is sometimes used for mucositis, as recommended by Multinational Association of Supportive Care in Cancer (MASCC) guidelines, based on three clinical trials showing that cryotherapy treatment before FU administration reduced the incidence of mucositis.^8-11

Palifermin (Kepivance; Amgen Inc, Thousand Oaks, CA) is a truncated, recombinant form of human keratinocyte growth factor (KGF) approved to decrease the incidence and duration of severe mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support. The safety and efficacy of palifermin have not been established in other settings. Discovered in 1989, KGF is a 28-kd member of the fibroblast growth factor family with epithelial cell proliferative properties.¹² Preclinical models demonstrated that palifermin markedly reduced chemotherapy- and radiation-induced injury to the oral cavity and lower GI mucosal linings.^13,14 A placebo-controlled, double-blind, phase III study demonstrated the efficacy of palifermin in reducing the incidence and duration of severe mucositis in the hematopoietic transplantation setting.¹⁵

The findings reported here are from a phase I/II randomized, double-blind, placebo-controlled study conducted in patients with metastatic CRC receiving FU/LV chemotherapy. The first part of the study provided information on the safety of palifermin when administered intravenously (IV) for 3 consecutives days (in sequentially escalating doses up to 80 µg/kg) before one chemotherapy cycle. These published results demonstrated that palifermin was generally well tolerated when administered for 3 consecutive days before a 5-day course of chemotherapy. In addition, no safety stopping criteria were observed at doses up to 80 µg/kg.¹⁶ Here we report results from the second part of the study, in which the ability of palifermin to ameliorate chemotherapy-induced mucositis and diarrhea (when administered at 40 µg/kg for 3 consecutive days) was examined during two consecutive cycles of chemotherapy.

	PATIENTS AND METHODS

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Patient Eligibility
Institutional review board or ethics committee approval and patients' written informed consents were obtained before any study-related procedures. Eligible patients were at least 18 years old, had advanced (Dukes' D) colon or rectal adenocarcinoma, and were scheduled to receive bolus FU and low-dose LV on the Mayo regimen as first-line or subsequent therapy. Patients were required to have a normal oral cavity examination (no oral ulceration, herpes simplex, oral candidiasis, or severe gingivitis); an Eastern Cooperative Oncology Group (ECOG) score 2; a life expectancy of 4 months; absolute neutrophil count 1.5 x 10⁹/L; platelet count 100 x 10⁹/L; and normal renal and hepatic function.

Patients were ineligible if they had received previous radiotherapy or chemotherapy 4 weeks or major surgery 2 weeks of study day 1; had insulin-dependent diabetes; or had a known allergy to LV or known hypersensitivity to Escherichia coli–derived material. Because this study was conducted before publication of the MASCC guidelines on mucositis, cryotherapy was not used as a treatment for mucositis.

Study Design
The study design is shown in Figure 1. Patients were randomly assigned (by center and prior chemotherapy) in a 1:1 ratio to receive palifermin or placebo. Palifermin 40 µg/kg, supplied as a lyophilized white powder, or matching placebo, was administered IV on 3 consecutive study days before each of two consecutive cycles of chemotherapy.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Study design. FU, fluorouracil; IV, intravenous.

Properly trained site staff rated mucositis severity using the 5-point WHO toxicity grading scale (where grade 0 = none and grade 4 = mucositis to the extent that alimentation was not possible).¹⁷ Diarrhea was graded using the National Cancer Institute Common Toxicity Criteria (CTC) system (where grade 0 = none and grade 4 = increase of more than 10 stools/d, grossly bloody diarrhea, or need of parenteral support). Assessments occurred at baseline, on study days 1, 4, 8, 12, 15, and at the end of both cycles 1 and 2 (study day 28).

Patients also provided self-assessments (from study days 1 to 27 of each chemotherapy cycle) of oral and diarrhea symptoms using a self-administered questionnaire (Oral Mucositis Daily Questionnaire) composed of 10 questions in three categories: overall health, mouth and throat soreness (MTS), and diarrhea.

Efficacy
Palifermin activity as a mucosal protectant was evaluated through comparisons of the incidence, duration, and severity of mucositis (WHO grades 2 to 4) and diarrhea (CTC grades) between patients in the two study arms. Patient-reported outcome end points were evaluated as area under the curve throughout the duration of the study.

Safety
Safety evaluations included adverse events (AEs) and changes in clinical laboratory values. Serum samples were collected during each chemotherapy cycle for evaluation of antipalifermin antibody development using both radioimmunoassay and enzyme-linked immunosorbent assay. Positive samples were tested further for neutralizing activity in a cell-based bioassay.

After completion of the second part of this study, patients were enrolled onto a long-term follow-up study to monitor the effects of palifermin on disease outcome and patient survival.

Statistical Considerations
Efficacy analyses were done by chemotherapy cycle, with primary focus on the first cycle. The efficacy population included all patients who were randomly assigned and who received at least one dose of palifermin or placebo in that cycle. The incidences of mucositis and diarrhea were estimated along with a 95% CI. The same population was used for safety and efficacy analyses. Categoric variables were summarized by the frequency and percentage in each category. Continuous variables were summarized by mean, standard deviation, median, quartiles, and range. Severity was measured by the worst toxicity grade observed for a patient in each cycle. Treatment comparison was performed using the Wilcoxon-Mann-Whitney test (stratified by center) for the incidence of WHO grade 2 or higher mucositis and MTS scores. Overall survival was examined using the log-rank test (stratified by center), and survival time was calculated from the date of randomization.

In these analyses, study centers enrolling less than six patients were pooled into one center. P values were calculated using both asymptotic ² approximation and exact distribution methods. A logistical regression model was used to assess the effect of palifermin on the incidence of WHO grade 2 or higher mucositis, adjusting for important baseline prognostic factors including ECOG scores, carcinoembryonic antigen (CEA) concentration (a measure of tumor burden), and prior chemotherapy.

	RESULTS

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Patients
Sixty-five patients were randomly assigned and 64 received study drug at 15 centers (placebo, n = 36; palifermin, n = 28). Baseline demographics and clinical characteristics are listed in Table 1. The palifermin group had a higher proportion of patients with an ECOG score of 2 (14%) and a higher proportion of patients who had prior radiotherapy (21%). The mean baseline CEA concentration was also more than two-fold higher for patients receiving palifermin, as was the proportion of patients with CEA concentrations more than 500 µg/L. Most patients receiving palifermin completed the study (93%). Eight patients receiving placebo and two patients receiving palifermin did not complete the study due to protocol violations, withdrawn consents, disease progression, or other reasons.

Incidence and Severity of Mucositis
During the first chemotherapy cycle, the incidence of WHO grade 2 or higher mucositis in the palifermin group was approximately half that observed in the placebo group (29%; 95% CI, 13% to 49% v 61%; 95% CI, 43% to 77%, respectively; P = .016 and P = .023, Fisher’s exact test; Fig 2A). Analyses using a logistic regression model where adjustments for baseline ECOG scores, CEA concentrations, and prior chemotherapy still yielded significant differences (P = .002) between the two groups in the incidence of WHO grade 2 or higher mucositis. During the second chemotherapy cycle, the mucositis incidence decreased in both groups, with the palifermin group continuing to demonstrate a lower incidence of WHO grade 2 or higher mucositis and an observed four-fold difference between those receiving palifermin and placebo (11%; 95% CI, 2% to 29% v 47%; 95% CI, 29% to 65%, respectively; P = .003 and P = .004, Fisher’s exact test; Fig 2B). The proportion of patients who had no mucositis manifestations was higher in patients receiving palifermin than in those receiving placebo (46% v 17% in cycle 1 and 63% v 31% in cycle 2, respectively). No patient experienced grade 4 mucositis. Fewer patients receiving palifermin required a chemotherapy dose reduction of 10% during cycle 2 than patients receiving placebo (14% v 31%, respectively).

View larger version (25K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Incidence and severity of oral mucositis during chemotherapy in colorectal patients.

Patient-Reported Outcomes of MTS and Diarrhea
Patients completed an Oral Mucositis Daily Questionnaire (baseline to study day 27 of each chemotherapy cycle) and MTS results were calculated in terms of area under the curve (with a lower number indicating less MTS). Average compliance rates for all patient-reported outcome questions were consistently above 80%. Self-reported MTS scores were greater in patients receiving placebo. In cycle 1, the MTS scores were statistically significantly different between the two groups (mean ± standard deviation, 22.6 ± 19.9 placebo v 9.2 ± 14.3 grade-days palifermin; P = .005). In cycle 2, there was a two-fold difference in MTS score favoring palifermin over placebo.

The results of the diarrhea questions were comparable between the two treatment groups, showing no significant differences throughout both cycles 1 and 2.

Safety
AEs. All patients experienced at least one AE during cycle 1. During cycle 2, 96% of patients receiving palifermin and 97% of patients receiving placebo experienced at least one AE. Overall, the incidences of specific AEs were similar between chemotherapy cycles 1 and 2 (Table 2).

Laboratory Assessments
Palifermin was associated with transient and asymptomatic increases in serum amylase and lipase levels during both cycles, with the absolute increases tending to be lower during the second cycle (Table 3). Importantly, no correlation between abdominal pain or other clinical symptoms and increases in amylase or lipase was observed. Increases were typically grades 1 to 3 on the CTC scale. No palifermin patient had a grade 4 increase in serum amylase, but three patients did have grade 4 increases from baseline in serum lipase. Increases were observed on study day 4 and normalized by study day 27 of each cycle. Over both chemotherapy cycles, the incidences of increases in serum amylase and lipase were similar. Median values at the end-of-study assessments were similar to the baseline values.

More patients receiving placebo (47%) experienced grade 3 and 4 neutropenia than patients receiving palifermin (32%). No other clinically significant changes in laboratory values were observed.

Antibody Assessments
Of the sera samples from 63 patients tested by an electrochemiluminescence immunoassay, only one patient in each group tested positive at one or more postdose time points for antipalifermin antibodies; all titers were below the quantitation limit of the assay. There was no evidence of neutralizing antibody activity against palifermin.

Disease Outcomes
Long-term follow-up data for disease outcomes are available for the 64 patients in this report. The median follow-up duration was 14.5 months (placebo, 15.5 months; palifermin, 14.5 months). The Kaplan-Meier estimate curves for overall survival time (Fig 3), time to disease progression, and progression-free survival were all superimposable between the two groups, supporting the conclusion that palifermin has no effect on the underlying disease itself in this clinical setting.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier estimated survival curve for colorectal patients in the cyclic chemotherapy setting.

	DISCUSSION

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This study was the first clinical trial conducted to assess the effectiveness of palifermin at ameliorating the manifestations of chemotherapy-induced GI mucotoxicity. The choice of this clinical setting was based on the observation of high mucosal toxicities associated with some FU regimens. This FU/LV regimen was chosen based on its relatively high incidences (70%) of grade more than 2 upper and lower GI toxicities.

Our results confirmed the high mucositis incidence associated with FU/LV chemotherapy and showed the incidence of mucositis of grade 2 or higher was significantly reduced in patients receiving palifermin (40 µg/kg for 3 consecutive days before chemotherapy) compared with patients receiving placebo (50% and 80% lower in cycles 1 and 2, respectively). Importantly, palifermin administration appeared to reduce the need for a chemotherapy dose reduction (secondary to chemotoxicity, which was the reason for dose reductions) in cycle 2; dose reduction was necessary three times more often for the placebo group (31%) than the palifermin group (11%). This lower exposure to chemotherapy for patients receiving placebo most likely led to a lower level of chemotherapy-induced mucositis and an underestimation of the beneficial effect of palifermin in the second chemotherapy cycle. Notably, the patient-reported outcomes of MTS were similar to clinicians' assessments of mucositis, supporting the use of this patient-based methodology. Clinicians may want to investigate this tool for assessing mucositis because it allows for a daily patient self-assessment, eliminating the need for office visits for mucositis assessments by caregivers.

In this multicycle chemotherapy setting, palifermin was generally well tolerated, with no cumulative AEs observed. Although palifermin was associated with a higher incidence of individual skin-related AEs such as erythema and pruritus, the overall incidence of skin-related AEs was similar between the two groups (palifermin, 43%; placebo, 56% in cycle 1; palifermin, 52%; placebo, 50% in cycle 2). As expected, palifermin was associated with a higher incidence of oral-related AEs such as a white coating on the surface of the tongue and taste disorders. These AEs are consistent with the known pharmacologic effects of palifermin, tended to be mild or moderate in severity, were reversible, and rarely resulted in drug discontinuation.

Palifermin was associated with a transient, asymptomatic increase in amylase and lipase that peaked by 4 days after the first palifermin dose in each cycle and had no clinical consequence (pancreatitis). The effects of palifermin on amylase and lipase levels have been reported previously and may be related to the KGF receptor's expression on salivary glands and pancreatic ductal cells. There were differences between the two groups in the incidences of grades 3 or 4 neutropenia; although the reasons for these differences in absolute neutrophil counts were unclear but may include small sample sizes, lack of standardization in AE reporting, or indirect effects of palifermin on myelopoiesis (hematopoietic cells do not express the KGF receptor). Long-term follow-up studies are needed to evaluate these findings further. Given the similarity of palifermin to the endogenous molecule, there was no evidence of neutralizing antibodies against palifermin.

Because palifermin is an epithelial growth factor and some epithelial tumors may express the KGF receptor, theoretically it is possible that palifermin administration to these patients may interfere with disease outcomes, either through direct stimulation of tumor growth or interference with the tumor response to cytotoxic treatment. Thus, it was important to collect long-term data on disease progression and overall survival. These results suggest that palifermin did not affect disease outcomes in these patients. There were no differences in the long-term survival between the two groups. These results with a small patient sample cannot be considered conclusive and additional studies are needed to evaluate fully the long-term safety of palifermin in the solid tumor setting.

In summary, we demonstrated that palifermin can be administered safely in the multicycle chemotherapy setting in patients with metastatic CRC and is effective at the dose tested (40 µg/kg for 3 consecutive days before chemotherapy) in reducing the incidence and severity of mucositis. The palifermin safety profile from part A of this study resulted in the chosen dose for part B. Though the treatment of CRC often includes agents in addition to FU and LV, these drugs remain the recommended standard of care for CRC in many countries. Palifermin is a novel therapeutic that may help reduce the incidence and duration of FU-induced mucositis, potentially allowing for uninterrupted full-dose treatment in patients receiving these chemotherapy regimens. To date, only cryotherapy has been shown to have some benefit in reducing mucositis (although it has no effect for diarrhea) in patients undergoing FU chemotherapy.^9-11 Currently, palifermin is the only pharmacologic agent approved for the reduction of the incidence and severity of mucositis in patients with hematologic malignancies receiving high-dose chemoradiotherapy and stem-cell transplantation. Additional investigations with other chemotherapeutic agents known to cause significant mucositis should be conducted to evaluate fully the benefits of palifermin in preventing this severely debilitating adverse effect.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Lee S. Rosen Amgen Inc Amgen Inc Frederick M. Schnell Amgen Inc Amgen Inc John Zalcberg Amgen Inc Amgen Inc Amgen Inc Alessandra Cesano Amgen Inc Amgen Inc Urte Gayko Amgen Inc Amgen Inc Mon-Gy Chen Amgen Inc Amgen Inc Stephen Clarke Amgen Inc

	Author Contributions

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Conception and design: Lee S. Rosen, Ian D. Davis, John Gutheil, Frederick M. Schnell, John Zalcberg Financial support: Lee S. Rosen Administrative support: Lee S. Rosen Provision of study materials or patients: Lee S. Rosen, Ehtesham Abdi, John Gutheil, Frederick M. Schnell, John Zalcberg, Stephen Clarke Collection and assembly of data: Lee S. Rosen, Ehtesham A. Abdi, John Gutheil, Frederick M. Schnell, Urte Gayko, Stephen Clarke Data analysis and interpretation: Lee S. Rosen, Ian D. Davis, Frederick M. Schnell, John Zalcberg, Alessandra Cesano, Urte Gayko, Mon-Gy Chen Manuscript writing: Lee S. Rosen, Ehtesham Abdi, Ian D. Davis, John Gutheil, Frederick M. Schnell, John Zalcberg, Alessandra Cesano, Urte Gayko, Mon-Gy Chen, Stephen Clarke Final approval of manuscript: Lee S. Rosen, Ehtesham Abdi, Ian D. Davis, John Gutheil, Frederick M. Schnell, John Zalcberg, Alessandra Cesano, Urte Gayko, Mon-Gy Chen, Stephen Clarke

 

	ACKNOWLEDGMENTS

 
We thank Cuneyt Serdar, Chin-Yu Lin, John Isitt, Carol Brannan, Helen Wei, and Elizabeth L. Pham for assistance with the conduct of the study, preparation of the analysis, and editorial assistance; and the patients who participated in this study, their families, and all the physicians, nurses, and study coordinators who cared for the patients.

	NOTES

 
published online ahead of print at www.jco.org on October 30, 2006.

Supported by Amgen Inc, Thousand Oaks, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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14. Farrell CL, Rex KL, Kaufman SA, et al: Effects of keratinocyte growth factor in the squamous epithelium of the upper aerogastrointestinal tract of normal and irradiated mice. J Radiat Biol 75 : 609 -620, 1999[CrossRef]

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Submitted September 4, 2005; accepted September 15, 2006.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rosen, L. S. Articles by Clarke, S. Search for Related Content PubMed PubMed Citation Articles by Rosen, L. S. Articles by Clarke, S. Related Articles Related Correspondence