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Clinical Trials |
1 University of Texas Health Science Center, and 2 South Texas Veterans Health Care System, San Antonio, Texas; 3 University of Michigan Cancer Center, Ann Arbor, Michigan; 4 Arizona Cancer Center, Tucson, Arizona; 5 University of Rochester Medical Center, Rochester, New York; and 6 Human Genome Sciences, Rockville, Maryland
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Forty-two patients received intravenous repifermin (25 µg/kg or 50 µg/kg) or placebo for 3 days before their auto-HSCT conditioning regimen and for up to 10 days after auto-HSCT. Within each dose level, 14 patients were randomized to repifermin and 7 patients to placebo. Clinical evaluations of mucositis were scheduled before auto-HSCT conditioning regimen, on the day of transplant, and three times per week until mucositis resolved.
Results: In general, the incidence of adverse events was similar for patients treated with repifermin and placebo. No clinically meaningful differences were noted among treatment groups for clinical laboratory variables. Treatment groups experienced similar time to engraftment. The frequency of Grade 2 to 4 mucositis was 100% for patients in the placebo group, 64% for patients in the 25 µg/kg group (P = 0.041 versus placebo), and 50% for patients in the 50 µg/kg group (P = 0.006 versus placebo). Results of other endpoints, including pain on swallowing and use of pain medication specifically for mucositis, suggested a better outcome for patients in the 50 µg/kg group compared with the placebo and 25 µg/kg groups.
Conclusions: Repifermin was well tolerated. Repifermin given before and after auto-HSCT seems to be active in reducing mucositis, but a larger trial will be necessary to determine the efficacy of repifermin with this dose schedule.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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40% of patients receiving standard chemotherapy, in 75 to 90% of bone marrow transplant patients receiving high-dose myeloablative therapy, and in almost all of the patients treated with radiotherapy for head and neck malignancies (1, 2, 3, 4, 5)
. Clinical signs of mucositis include inflammation of the oral mucosa (stomatitis) usually followed by focal-to-diffuse ulcerations (6)
. The resulting edema, erythema, and ulceration generally develop within 5 to 7 days after the initiation of chemotherapy. Malnutrition and dehydration are commonly associated with mucositis because of the inhibiting effects of stomatitis on proper intake of food and fluids. Opportunistic pathogens frequently exploit breeches in the epithelial barrier causing infection and sepsis in patients with mucositis. Keratinocyte growth factor-2 (KGF-2), also known as human fibroblast growth factor-10, is a 208 amino acid polypeptide (Mr 19,000) belonging to the fibroblast growth factor (FGF) family of mitogens (7) . Under normal physiologic conditions, KGF-2 is thought to display a paracrine activity on epithelial cell proliferation and differentiation because it is synthesized and secreted by mesenchymal cells adjacent to epithelial cells expressing the FGF receptors FGFR1iiib and FGFR2iiib (8 , 9) . Repifermin is a truncated form of recombinant KGF-2 (140 amino acids; Mr 16,000) that retains the pharmacological and biological activity of full-length KGF-2. The primary pharmacological effects of repifermin are epithelial proliferation and migration, and in some tissues, epithelial differentiation is also induced (10 , 11) . In several animal models including mouse, rat, and monkey, repifermin has been shown to promote the healing of ulcerated oral and intestinal mucosal tissue and reduce the severity of complications stemming from the development and exacerbation of mucositis (10, 11, 12) . In a murine bone marrow transplant model, repifermin administered pre- and post-transplantation significantly delayed conditioning regimen-induced acceleration of graft-versus-host disease mortality relative to placebo control (13) . In addition, repifermin has been shown in vitro and in vivo to specifically target normal epithelial tissue while failing to induce tumor cell proliferation or tumor growth for 26 KGF receptor-positive, human tumor cell lines (14) .
The rationale for repifermin use in chemotherapy-induced mucositis after autologous hematopoietic stem cell transplantation (auto-HSCT) is to promote the repair of the injured mucosal lining by stimulating the proliferation of the epithelial cell component and in turn reduce injury to the gastrointestinal tract. A previous study evaluated the safety and preliminary efficacy of repifermin (1 µg/kg to 50 µg/kg) administered after the hematopoietic stem cell transplant (15) . The study showed that repifermin was well tolerated but not active in reducing the incidence or severity of mucositis. The purpose of the current study was to evaluate the safety of repifermin administered before the auto-HSCT conditioning regimen and after the auto-HSCT.
This report details the results of this Phase I/II study to evaluate the safety of KGF-2 given before and after auto-HSCT. A preliminary analysis of the ability of KGF-2 to prevent mucositis was also done.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients were ineligible for the following reasons: previous hematopoietic stem cell transplantation; visible oral ulcerations at screening; pregnant or nursing; child-bearing potential and not using adequate contraceptive precautions; a history of allergies to Escherichia coli-derived products; a posterior subcapsular cataract identified at the screening ophthalmologic examination; a history of thyroid disease before chemotherapy (except for hypothyroidism adequately controlled with replacement therapy); or a history or clinical evidence of active significant acute or chronic diseases that may have compromised the ability to evaluate or interpret the effects of the study treatment on mucositis. Excluded medications included recombinant interleukin 11, topical steroids, sucralfate, hydrogen peroxide, pilocarpine, misoprostol, oral chlorhexidine rinses, or any agent that would interfere with the ability of the investigator to assess changes in the appearance of the mucositis during the study.
Study Design.
This study was a multicenter, randomized, double-blinded, placebo-controlled, Phase I/II study. The primary objective was to evaluate the safety of repifermin in subjects at risk of developing mucositis secondary to the action of conditioning regimens for auto-HSCT. A secondary objective of the study was to evaluate the effects of repifermin on the incidence and severity of moderate-to-severe mucositis in this setting when given before and after auto-HSCT. Patient cohorts were treated with escalating doses of repifermin. Dose levels of repifermin evaluated in this study were 25 µg/kg and 50 µg/kg. Within each dose level, 14 patients were randomized to treatment with repifermin, and 7 patients were randomized to treatment with placebo.
All of the patients received a daily dose of repifermin or placebo for 3 days before their auto-HSCT conditioning regimen. After patients received their conditioning regimen and auto-HSCT, daily treatments with repifermin or placebo were resumed and continued for up to 10 days. Patients were followed for 28 days after the last dose of placebo or repifermin.
The safety of repifermin was assessed by evaluation of the type, frequency, severity, and duration of adverse events, changes in laboratory parameters, engraftment, ophthalmologic examinations, and immunogenicity of repifermin. Adverse events were collected throughout the dosing period and for 28 days after the last dose. Laboratory parameters were collected before dosing, every other day during dosing, and 14 days after the last dose. A chest X-ray and electrocardiogram were done before dosing and after the last dose. Immunogenicity was assessed by an ELISA method before dosing, at the end of dosing, and 14 days after the last dose.
The efficacy of repifermin was assessed by the incidence of Grade 2 to 4 mucositis measured by the NCI-CTC mucositis toxicity scale for bone marrow transplant studies. In this scale, Grade 2 mucositis is defined as painless ulcers, erythema, or mild soreness in the absence of lesions; Grade 3 mucositis is defined as painful erythema, edema, or ulcers preventing swallowing or requiring hydration, enteral or parenteral nutritional support; and Grade 4 mucositis is defined as severe ulceration requiring prophylactic intubation or resulting in documented aspiration pneumonia. Mucositis was also assessed by the Oral Mucositis Assessment Scale (OMAS) score (16) . The OMAS measures ulceration and erythema in nine areas of the mouth (upper and lower labial mucosa, right and left buccal mucosa, right and left lateral and ventral portions of the tongue, floor of the mouth, soft palate (fauces), and hard palate (gingival). Scores for ulceration were 0 = no lesion; 1 = <1 cm2; 2 = 1 to 3 cm2; and 3 = >3 cm2, whereas scores for erythema were 0 = none; 1 = not severe; and 2 = severe. Thus, the OMAS score could range from 0 (no ulceration, no erythema) to 45 (ulcers >3 cm2 and severe erythema in all nine areas of the mouth evaluated). The NCI-CTC mucositis grade and OMAS score were to be assessed by the same individual throughout the study. Each grader was specifically trained in the assessment and grading of mucositis.
Other efficacy endpoints included the severity and duration of ambient oral and oropharyngeal pain and pain on swallowing, an ability to eat score, narcotic pain medication use, and the frequency, severity, and duration of diarrhea. Ambient oral/oropharyngeal and pain on swallowing was evaluated with a scale ranging from 0 (no pain at all) to 10 ("most severe pain I can imagine; can’t eat and even drinking is difficult"). Ability to eat was evaluated with the following scale: 1 (normal), 2 (limited to only soft solid food), 3 (only liquids), and 4 (no foods or liquids).
Clinical evaluations of mucositis and other endpoint assessments were scheduled before the auto-HSCT conditioning regimen, on the day of the transplant, and then three times per week (typically Monday, Wednesday, and Friday) until the mucositis of the patient resolved.
Statistical Analyses.
Statistical analyses and summaries were provided for the intent-to-treat population, defined as all of the subjects randomized. All analyses were conducted by comparing the repifermin-treated groups with the pooled placebo group from the two cohorts. Fisher’s exact test was used for the categorical endpoints in both the safety and efficacy analysis. ANOVA model was used for the continuous endpoints in the efficacy analysis, except that the Wilcoxon rank-sum test was used for duration of mucositis. Because of the exploratory nature of this study, no adjustments were made to the analyses with respect to multiple testing.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The mean age was 50 years, with 31 men and 11 women treated. Treatment groups were well balanced with regards to all of the baseline characteristics. The most common conditioning regimen consisted of cyclophosphamide, etoposide, and carmustine, and was used for 43%, 50%, and 64% of patients in the placebo, 25 µg/kg, and 50 µg/kg groups, respectively. The majority of other conditioning regimens included melphalan, either as monotherapy or in combination with other agents. Overall, 64% of patients underwent an auto-HSCT for lymphoma, whereas the remainder underwent auto-HSCT for other hematologic malignancies.
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. The adverse events observed were as expected for this patient population. The only adverse events that were significantly different between groups were non-neutropenic fever, anxiety, and weight gain. Non-neutropenic fever was more common in the placebo group than the repifermin groups. Anxiety and weight gain were more common in the repifermin groups than the placebo groups but were not dose related.
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. The only significant difference was for non-neutropenic fever, which occurred more frequently in the placebo group than the 25 µg/kg or 50 µg/kg repifermin groups.
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Efficacy.
As shown in Fig. 1
, all of the patients (14 of 14, 100%) in the placebo group developed Grade 2 or greater mucositis, compared with 64.2% (9 of 14) of patients in the 25 µg/kg group and 50% (7 of 14) of patients in the 50 µg/kg group. Pairwise comparisons showed a significant difference between the 50 µg/kg group and the placebo group (P = 0.006) and a significant difference between the 25 µg/kg group and the placebo group (P = 0.041). The majority of the mucositis was Grade 2, as only 5 patients (1 in the placebo group, 3 in the 25 µg/kg group, and 1 in the 50 µg/kg group) experienced Grade 3 or greater mucositis. The most common conditioning regimen consisted of cyclophosphamide, etoposide, and carmustine. The percentage of patients experiencing Grade 2 to 4 mucositis on this regimen was 100% (6 of 6), 57% (4 of 7), and 56% (5 of 9) for the placebo, 25 µg/kg, and 50 µg/kg treatment groups, respectively.
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Results of other efficacy endpoints, including duration of Grade 2 to 4 mucositis, mouth pain, pain on swallowing, use of pain medication, ability to eat, and mucositis assessed by OMAS are presented in Table 4
. A number of differences were observed that suggested a better outcome for patients in the 50 µg/kg group compared with the placebo and 25 µg/kg groups. The mean duration of Grade 2 to 4 mucositis was 5.5 days, 4.6 days, and 3.2 days for the placebo, 25 µg/kg, and 50 µg/kg groups, respectively. The mean worst pain on swallowing score was 4.6, 4.8, and 2.1 for the placebo, 25 µg/kg, and 50 µg/kg groups, respectively. The difference between the 50 µg/kg and placebo treatment groups was statistically significant (P = 0.044). Days on narcotic pain medication were 5.4, 4.3, and 3.9 days for the placebo, 25 µg/kg, and 50 µg/kg groups, respectively. The difference between groups was more pronounced when comparing groups for the days on narcotic pain medication specifically prescribed for pain associated with mucositis (3.9, 3.1, and 1.6 days for the placebo, 25 µg/kg, and 50 µg/kg groups, respectively; P = 0.06 for the comparison of 50 µg/kg and placebo). There was a trend for a better ability to eat score for the 50 µg/kg than the placebo group (1.8 versus 2.5, P = 0.09). Values for the worst OMAS score were 14.0, 14.1, and 9.6 for the placebo, 25 µg/kg, and 50 µg/kg groups, respectively, but did not attain statistical significance.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The good safety profile of repifermin is additionally supported by the observation that the incidence of laboratory abnormalities including serum electrolyte abnormalities, liver function tests, and amylase was similar between the repifermin and placebo arms. Electrocardiographic and chest X-ray abnormalities were also similar between the repifermin and placebo arms. Time to engraftment was similar in the study and placebo groups. Patients in the repifermin and placebo arms had the same incidence of infections including bacterial infections.
Because the primary objective of the trial was to evaluate the safety and tolerability of repifermin, it was not designed to have sufficient statistical power to identify differences in efficacy between groups. Nonetheless, there was a significant reduction in the incidence of Grade 2 to 3 mucositis in patients who received repifermin. In addition, there were significant differences suggesting that patients treated with 50 µg/kg had less pain on swallowing and were better able to eat compared with the placebo group. There was also a strong trend suggesting that patients receiving repifermin required less pain medication for mucositis compared with the patients who received placebo.
The results of this study suggest that treatment with repifermin before the auto-HSCT conditioning regimen is necessary to achieve efficacy in reducing the incidence of mucositis. All of the patients in this study received 10 post auto-HSCT doses. However, the number of post auto-HSCT doses required is unclear. In a similar patient population, KGF-1 was shown to reduce the incidence and duration of mucositis with 3 pre- and 3 post auto-HSCT doses (17) . Further studies are needed to evaluate the efficacy of repifermin with fewer post auto-HSCT doses.
A shortcoming of this study was that multiple conditioning regimens were allowed. This could have introduced biases into both the safety and efficacy results. However, it is unlikely that this had a major impact on the results, because as shown in Table 1
, treatment groups were well balanced for the use of the different regimens.
Two other studies have failed to show evidence that repifermin is effective in reducing the incidence or severity of mucositis. In one study, 51 patients received either 75 µg/kg repifermin or placebo in a double-blind, placebo-controlled crossover study in patients receiving 200 mg/m2 melphalan conditioning regimen for tandem multiple myeloma transplants. Repifermin, which was administered for 3 days before the melphalan and for up to 7 days after the transplant, was well tolerated but not effective in reducing the incidence or severity of mucositis.7 In another study in the same patient population as the current study, repifermin administered only after the auto-HSCT only showed good tolerability but failed to show any evidence of activity in reducing the incidence or severity of mucositis (15) . Differences in results might be attributable to different patient populations, different conditioning regimens, or different repifermin treatment regimens. A larger trial with a homogenous population of patients treated with a uniform conditioning regimen will be necessary to definitively evaluate the efficacy of repifermin in reducing the incidence and severity of mucositis.
An inclusion criteria for this study stipulated that all of the patients were to receive a conditioning regimen with a high propensity for producing mucositis, defined as an expectation of at least a 50% incidence of NCI-CTC Grade 3 or Grade 4 mucositis with standard mucositis management. However, only 12% (5 of 42) of patients developed Grade 3 mucositis, and no patients had Grade 4 mucositis. The reason for the discrepancy between the expected and observed incidence of Grade 3 to 4 mucositis is unclear. Possible explanations include that the expectations were an overestimate of the actual incidence of Grade 3 to 4 mucositis in this population because most of the patients enrolled in this study did not receive total body irradiation, which is known to cause a higher incidence of mucositis. It is also possible that patients enrolled in this study received better oral care in a clinical study setting, but this is unlikely because there are no efficacious agents in preventing or ameliorating mucositis because of chemotherapy. Ambiguity in differentiating between Grade 2 and Grade 3 mucositis also could have played a role in the underestimation of the severity of the mucositis in this study. A criterion for Grade 3 mucositis is that the patient develops painful erythema in contrast to Grade 2 mucositis where the patient can have mild soreness. Because there is a subjective element in determining the level of pain, and because patients can have different pain thresholds, it might be difficult to differentiate between Grade 2 and 3 mucositis as intended in the NCI-CTC.
It is important to prevent all degrees of mucositis in patients undergoing auto-HSCT. Patients with Grade 2 mucositis can suffer from erythema, oral ulcers, and mouth soreness. These symptoms contribute to decreased oral intake in a population that has increased metabolic demands imposed by the tissue repair necessary after the administration of high-dose chemotherapy and by infection. In addition, the presence of mucositis plays an important part in the well-being of the patient after auto-HSCT. A recent report analyzed the most bothersome side effects during transplantation from the perspective of the patient (18) . In that report, patients identified mouth sores as the most troubling and debilitating side effect during their transplant. In our analysis, patients who received 50 µg/kg of KGF-2 had a lower score of worst pain on swallowing and a lower worst ability to eat score. In addition, there was a trend toward fewer days on narcotic pain medication specifically given for mucositis-related pain.
In conclusion, the results of this study showed that repifermin was well tolerated and seemed to be active in reducing the incidence of mucositis. These results must be confirmed in a larger randomized trial.
Investigators.
Cesar O. Freytes, University of Texas Health Science Center, San Antonio, Texas; Voravit Ratanatharathorn, University of Michigan Cancer Center, Ann Arbor, Michigan; Charles Taylor, Arizona Cancer Center, Tucson, Arizona; Camille Abboud, University of Rochester Medical Center, Rochester, New York; Sonali Smith, University of Chicago, Chicago, Illinois; Everardo Cobos, Southwest Cancer Center, Lubbock, Texas; Luis Pineiro, Baylor University Medical Center, Dallas, Texas; and Steve Goldstein, H. Lee Moffitt Cancer & Research Institute, Tampa, Florida.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Requests for reprints: Cesar O. Freytes, University of Texas Health Science Center at San Antonio, Mail Code 7880, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900. Phone: (210) 617-5268; Fax: (210) 617-5271; E-mail: freytes{at}uthscsa.edu
7 E. Anaissie, personal communication. 
Received 6/ 8/04; revised 8/11/04; accepted 9/16/04.
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REFERENCES |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This article has been cited by other articles:
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  E. Schmidt, N. H. Thoennissen, A. Rudat, R. Bieker, C. Schliemann, R. M. Mesters, M. Zuhlsdorf, C. Muller-Tidow, and W. E. Berdel Use of palifermin for the prevention of high-dose methotrexate-induced oral mucositis Ann. Onc., September 1, 2008; 19(9): 1644 - 1649. [Abstract] [Full Text] [PDF]
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