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© 2003 American Society for Clinical Oncology Randomized Phase I Trial of Recombinant Human Keratinocyte Growth Factor Plus Chemotherapy: Potential Role as Mucosal Protectant
From the Fox Chase Cancer Center, Philadelphia, PA; Sidney Kimmel Cancer Center, San Diego; Amgen Inc, Thousand Oaks; and Jonsson Cancer Center, University of California at Los Angeles, Los Angeles, CA; Cleveland Clinic Foundation, Cleveland, OH; Arizona Clinical Research Center, Tucson, AZ; Cancer Therapy and Research Center Institute for Drug Development, San Antonio, TX; and Vanderbilt-Ingram Cancer Center, Nashville, TN. Address reprint requests to Neal J. Meropol, MD, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111; email: nj_meropol{at}fccc.edu.
Purpose: To evaluate the safety of recombinant human keratinocyte growth factor (KGF) when administered with fluorouracil (FU) in patients with metastatic colorectal cancer. Patients and Methods: Patients (N = 81) received KGF by intravenous (IV) bolus on days 1 to 3, followed by FU 425 mg/m2/d IV bolus plus leucovorin 20 mg/m2/d IV on days 4 to 8. KGF dose levels were 1, 10, 20, 40, 60, and 80 µg/kg/d. A randomized, placebo-controlled design was employed (2:1 randomization of KGF to placebo). Oral mucositis was assessed by examination on days 1, 4, 8, 15, and 28. In addition, patients provided daily assessments of oral symptoms using a self-administered questionnaire. Results: Skin and oral events occurred in 13 of 18 patients (eight patients, grade 1; four patients, grade 2; and one patient, grade 3) treated with 60 and 80 µg/kg of KGF and three of 11 patients treated with 40 µg/kg (grade 1). These symptoms were dose limiting in three cases (ie, in two of 10 patients treated with 80 µg/kg and in one of eight patients treated with 60 µg/kg). The frequency of grade 2 to 4 mucositis was 43% in patients treated with KGF, compared with 67% in patients treated with placebo (P = .06). Patient self-assessments of oral pain and clinical assessments of mucositis showed good correlation (Kendall’s tau = 0.75). Conclusion: KGF is generally well tolerated when administered IV at doses up to 40 µg/kg/d for 3 days before a 5-day course of FU plus leucovorin. A clinically meaningful biologic effect was also suggested in that patients treated with the epithelial growth factor KGF had a lower rate of grade 2 to 4 mucositis than did patients treated with placebo.
MUCOSITIS IS the clinical manifestation of damage to gastrointestinal epithelium caused by cancer treatment.1 Upper and lower gastrointestinal mucosal injury is common with many chemotherapeutic agents and radiation therapy. The pathogenesis of oral mucositis is multifactorial and may involve damage to the epithelium and underlying stroma, with increased vascular permeability, edema, inflammatory cell infiltration, and fibrosis. Salivary gland damage, with loss of saliva barrier function, and bone marrow suppression, with resultant immunocompromise, can lead to symptomatic oral superinfection.1 The clinical presentation of mucositis can include painful oral ulceration. Oral mucositis is a significant dose-limiting toxicity (DLT) associated with fluorouracil (FU), particularly when modulated by leucovorin.2 In one large study involving FU plus leucovorin given for 5 consecutive days, the overall incidence of oral mucositis was 80%; in 28% of patients, oral mucositis interfered with eating solids or resulted in dehydration.2 Attempts to prevent and treat oral mucositis induced by chemotherapy or radiation have included oral cryotherapy,3 allopurinol mouth rinses,4,5 oral anesthetics, and cytokines.6–9 Oral mucositis frequently leads to dose reductions and postponement of scheduled treatments. A therapy that could reduce the incidence, duration, or severity of chemotherapy-induced mucositis could potentially contribute to maintenance of dose intensity, improve quality of life, and reduce the costs associated with cancer care. Keratinocyte growth factor (KGF) is a member of the heparin-binding family of fibroblast growth factor 7 (FGF-7).10–12 KGF stimulates the growth of epithelial cells from a wide variety of tissues, but it has no direct effect on other cell types. The apparent specificity of KGF is caused by the restricted expression the keratinocyte growth factor receptor (KGFR). Epithelial cells in a variety of tissues, including the epidermis, pancreas, liver, lung, and urothelium, express KGFR. KGF is produced by mesenchymal cells located adjacent to the epithelium of many organs, such as the epidermis, oral and lower gastrointestinal epithelium, pancreas, liver, lung, urothelium, prostate epithelium, and other tissues.13–17 It is produced by dermal fibroblasts within the skin and by lamina propria cells of the intestines. The widespread expression of KGF in normal tissues indicates a role in tissue homeostasis. The level of KGF messenger mRNA (mRNA) within dermal wounds is 160-fold greater than the level found in intact skin,18 and it is also elevated in the intestines of patients with inflammatory bowel disease.19 These observations indicate that increased production of KGF is a normal response to epithelial injury and that it may represent a component of damage repair. Recombinant human KGF significantly ameliorates radiation- and chemotherapy-induced injury of oral and lower gastrointestinal tract epithelium in animal models. Administration of KGF causes epithelial thickening in the nonkeratinized layers of oral epithelium in mice and reverses epithelial atrophy in the mouse oral cavity caused by irradiation.20 Prophylactic administration of KGF reduces the incidence of oral mucosal ulceration after a single radiation dose in mice.21 Intravenous (IV) administration of KGF also decreases acute intestinal injury and promotes healing of small intestinal ulcerations produced by nonsteroidal anti-inflammatory agents in rats.22 Protection of normal mucosa can result in improved survival following treatment-induced injury. In murine model systems, KGF increases survival when given as a pretreatment before chemotherapy (FU)-induced or radiation-induced gastrointestinal injury.23 Furthermore, KGF does not alter tumor growth rate or the tumor growth-inhibiting effect of FU in colorectal xenograft models.23 As an initial step in the clinical development of KGF as a mucosal protectant, we undertook a phase I study to determine the toxicity profile and maximum tolerated dose of KGF when administered with FU plus leucovorin. A prior phase I study of healthy adult volunteers determined the dose range and safety and explored the biologic activity of KGF.24 In an effort to distinguish toxicities associated with KGF from those secondary to FU, a placebo-controlled design was employed in the current study. This report details the results of this phase I study, including preliminary evidence that KGF may affect the incidence of oral mucositis associated with FU.
Patient Eligibility Subjects were aged 18 years or older with measurable metastatic colon or rectal adenocarcinoma and were scheduled to receive palliative FU and leucovorin chemotherapy. An Eastern Cooperative Oncology Group performance status of 0 to 2 (ambulatory at least 50% of waking hours) and a life expectancy of at least 4 months was required. Prior chemotherapy was permitted, including previous treatment with FU. Subjects had normal baseline oral examinations (ie, no pre-existing lesion) and no recent history (as defined as 30 days before the day of the eligibility examination) of oral ulceration, herpes simplex, oral candidiasis, severe gingivitis, or the presence of active or chronic mucositis, xerostomia, or diarrhea. Baseline organ function requirements included absolute neutrophil count  1.5 x 109/L, platelet count 100 x 109/L, serum creatinine  2.0 mg/dL, serum bilirubin 2.0 mg/dL, serum aspartate amino transferase less than five times the upper limit of normal, and absence of other serious concurrent medical illness. Patients were ineligible if they received chemotherapy, radiotherapy, or other investigational drugs within 4 weeks of enrollment (<6 weeks for chemotherapy with mitomycin or nitrosoureas), had any unresolved adverse event from previous therapy, had major surgery within 2 weeks before study entry, had a history of insulin-dependent diabetes mellitus, were pregnant or breast feeding, were of child-bearing potential and not using adequate contraceptive precautions, or had a previous hypersensitivity reaction to leucovorin calcium or Escherichia coli-derived material. Written informed consent was required of all patients, and the institutional review boards of all participating centers approved the study.
Study Design All patients received leucovorin 20 mg/m2 by rapid IV injection, followed immediately by FU 425 mg/m2 by rapid IV injection for 5 consecutive days on days 4 to 8 of each 28-day cycle. This regimen was chosen on the basis of its frequent use in metastatic colorectal cancer and its high incidence of oral mucositis. Recombinant human KGF, supplied as a lyophilized white powder with matching placebo (Amgen, Thousand Oaks, CA), was administered by IV injection on days 1 to 3 of each cycle. Patient cohorts were treated with escalating doses of KGF. Dose levels were 1, 10, 20, 40, 60, and 80 µg/kg/d. Randomization between KGF and placebo was 1:1 for the initial cohort receiving 1 µg/kg/d and 2:1 for the five subsequent cohorts. Twelve subjects were planned for each cohort, with allowance for additional patient enrollment in the event of early drop-out or to better characterize toxicities at a given dose level. Patients were informed of clinical data regarding the use of oral cryotherapy,3 but this intervention as prophylaxis was not permitted during the study.
DLT was defined as any World Health Organization (WHO) grade 3 or greater adverse event or a WHO grade 2 adverse event that the subject found to be intolerable.25 Dose escalation took place if
Assessment of Oral Mucositis
Statistical Considerations Statistical analyses and summaries were provided for the intent-to-treat population, defined as all subjects who were randomly assigned to treatment and who received at least one dose of study drug. The incidence of adverse events and changes in laboratory parameters were summarized by treatment group. Comparisons of all placebo subjects and all KGF subjects were performed using Fisher’s exact test for incidence of oral mucositis and the Wilcoxon rank sum test for duration of mucositis. Correlations between patient and physician assessments of mucositis were described by the Spearman rank correlation coefficient, based on area under the curve (AUC) measures (mucositis intensity v time), and by Kendall’s tau, based on assessments on a single day when peak mucositis was expected.
Eighty-one patients were enrolled in this study from 10 study sites. Demographic characteristics of the 81 patients are outlined in Table 2  . The median age was 63 years, with 47 men and 34 women participating. Forty-five patients (56%) had a history of tobacco use (a possible influence on mucositis), and 12% of patients were current smokers. Forty-six patients (57%) had received previous therapy with FU (76% adjuvant only, 24% for metastatic disease).
Treatment toxicities for which there was a 10% difference in frequency between pooled placebo patients and any KGF group are listed in Table 3. Common adverse events in the control group treated with FU plus leucovorin alone were diarrhea (74%), nausea (33%), fatigue (26%), and oral toxicities (83%). As shown in Table 4, oral events were the most commonly observed grade 3 to 4 side effects of therapy, consistent with the known toxicity pattern of FU. Twenty-six percent of patients in the placebo groups had grade 3 to 4 oral toxicities, compared with 17% of patients treated with KGF. The only other grade 3 to 4 toxicity that occurred in more than 10% of patients in the placebo group was granulocytopenia (11%). Nineteen percent of patients treated with KGF had grade 3 to 4 granulocytopenia, and this did not seem to be dose dependent, indicating that the KGF was not contributory.
Although the predefined frequency of DLTs attributable to KGF was not reached with KGF doses between 1 and 80 µg/kg/d, there were three adverse reactions involving the skin that required discontinuation of KGF in the 18 patients treated with 60 or 80 µg/kg (Table 5 ). Overall, skin and oral adverse events (rash, flushing, pruritis, edema, hypoesthesia, paresthesia, tongue disorder [thickening], and alteration in taste sensation) attributed to KGF occurred in 13 of 18 patients treated with 60 and 80 µg/kg of KGF (eight patients, grade 1; four patients, grade 2; and one patient, grade 3) and in three of 11 patients treated with 40 µg/kg (all grade 1). These events were reported in 16 of 39 patients (41%) dosed with KGF at 20 µg/kg/d, whereas these symptoms were reported in only two of 21 subjects (10%) treated with placebo. The skin and oral toxicities associated with KGF were generally mild to moderate in severity, with onset approximately 36 hours after the first dose of KGF and resolution 7 to 10 days thereafter.
Asymptomatic elevations in amylase and lipase were noted in patients treated with KGF at doses 20 µg/kg/d (Fig 1). Serum measurements were obtained on days 1 and 4 of the first cycle of treatment. The mean percentage increases in amylase and lipase values in the placebo group (n = 27) were 12% and 5%, respectively. Forty-eight of 54 patients treated with KGF had an increase in amylase, with a mean increase of 69% above baseline. Fifty of 54 patients treated with KGF had an increase in lipase, with a mean increase of 171%. The increases were more pronounced at the higher dose levels. In the 60 and 80 µg/kg/d cohorts combined, the mean percentage increases for amylase and lipase were 108% and 241%, respectively. Five of 11 patients in the 40 µg/kg/d cohort had increases in serum amylase and lipase levels. No patients experienced clinical manifestations of pancreatitis (ie, abdominal pain).
Although the formal definition of maximum tolerated dose was not met, dose escalation beyond 80 µg/kg of KGF was halted, given the frequency of dose-dependent adverse events at dose levels that demonstrated evidence of biologic activity (vida infra).
On the basis of the assessments of oral mucositis by trained observers, 18 of the 27 patients (67%) who received placebo showed WHO grade 2 or greater oral mucositis, compared with 23 of 54 patients (43%) who were treated with KGF (P = .06). A decrease in WHO grades 2 to 4 mucositis was suggested in all cohorts receiving at least 10 µg/kg/d of KGF. This decrease in incidence between the placebo and KGF groups was -12%, -35%, -35%, -25%, and -30% for KGF cohorts 10, 20, 40, 60, and 80 µg/kg/d, respectively (Fig 2
Results of the daily questionnaire indicate that there was a relationship between the patient assessments of mouth/throat pain and the clinical assessment of mucositis (Fig 4 ). On the basis of AUC measures, Spearman’s correlation for WHO criteria and the 5-point self-administered item is 0.72, and for WHO criteria and the 0-to-10-point self-administered item, it is 0.68. In addition, at peak mucositis (the day 15 WHO assessment), Kendall’s tau is 0.75 for WHO and the 5-point measure. Figure 5 shows patient assessments of mouth soreness (11-point scale) in placebo (mean ± SE, AUC = 35.9 ± 7.6) and KGF (mean ± SE, AUC = 30.3 ± 4.8) groups, based on daily questionnaires.
The data presented show that KGF is relatively well tolerated at doses up to 80 µg/kg/d when administered intravenously for 3 days before a 5-day course of FU and leucovorin in cancer patients with metastatic colorectal cancer. A prior study of KGF in healthy subjects showed increased Ki67 expression in skin biopsies at KGF doses of 5 to 20 µg/kg/d for 3 consecutive days, thus providing evidence that the doses used in this study are biologically active.24 Although oral and cutaneous toxicities were common at doses 60 µg/kg/d, the specified definition of maximum tolerated dose was not reached with KGF doses between 1 and 80 µg/kg/d. Three patients had cutaneous dose-limiting toxicities related to KGF (one of which was grade 3 and two of which were grade 2 events) that were considered intolerable by the patients. We feel that the frequency and nature of these symptoms was sufficient to warrant discontinuation of further dose escalation. Given that KGF is being administered as a supportive care measure, we believe that patients should not be exposed to a potential level of adverse events that one would tolerate in the case of a cytotoxic agent. On the basis of these considerations and the evidence presented that indicates biologic activity at the dose levels tested, we propose a KGF dose of 40 µg/kg/d for further study.
Asymptomatic elevations in amylase and lipase were common at KGF doses
This phase I study was not designed to specifically demonstrate protection against oral mucositis. However, exploratory analyses showed a trend toward decreased grades 2 to 4 mucositis in patients treated with doses of KGF We recognize that inclusion of a placebo arm in a phase I study is unusual. However, we anticipated difficulty in distinguishing between toxicities attributable to FU and those related to KGF. A concurrent control group permitted this interpretation. In conclusion, KGF is generally well tolerated when administered IV at biologically active doses, with the most common side effects being rash, flushing, edema, and asymptomatic elevations in amylase and lipase. Furthermore, this phase I study provides the first clinical evidence that a growth factor with epithelial specificity may affect the development of chemotherapy-induced mucositis. The potential activity of KGF as a mucosal toxicity protectant requires further evaluation in studies designed primarily to address this end point. Specific evaluation of KGF in the prevention of mucositis is currently underway in the contexts of standard dose chemotherapy,26 high-dose chemotherapy,27,30 and head and neck radiation.31,32
The following is a list of Principal Investigators who participated in this study. Gerald H. Clamon, MD, University of Iowa Hospitals and Clinics, Iowa City, IA; Cynthia Gail Leichman, MD, Roswell Park Cancer Institute, Buffalo, NY; Neal J. Meropol, MD, Fox Chase Cancer Center, Philadelphia, PA; Eric Rowinsky, MD, Institute for Drug Development, San Antonio, TX; Mace L. Rothenberg, MD, Vanderbilt University Medical Center, Nashville, TN; Alan P. Venook, MD, University of California at San Francisco, San Francisco, CA; Robert J. Pelley, MD, Cleveland Clinic Foundation, Cleveland, OH; Manuel R. Modiano, MD, Arizona Clinical Research Center, Tucson, AZ; John Gutheil, MD, Vical Inc, San Diego, CA; Robyn R. Young, MD, Scott and White Hospital Cancer Center, Temple, TX; Lee S. Rosen, MD, UCLA School of Medicine, Los Angeles, CA; and Heinz Josef Lenz, MD, USC Norris Cancer Center, Los Angeles, CA.
Supported by a grant from Amgen, Inc. Presented in part at the Nineteenth Annual Meeting of the American Society of Clinical Oncology, May 20–23, 2000, New Orleans, LA.
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7. Meropol NJ, Miller LL, Korn EL, et al: Severe myelosuppression resulting from concurrent administration of granulocyte colony stimulating factor and cytotoxic chemotherapy. J Natl Cancer Inst 84:1201–1203, 1992 8. Crawford J, Tomita DK, Mazanet R, et al: Reduction of oral mucositis by filgrastim (r-metHuG-CSF) in patients receiving chemotherapy. Cytokines Cell Mol Ther 5:187–193, 1999[Medline] 9. Meropol NJ, Rustum YM, Creaven PJ, et al: Phase I and pharmacokinetic study of weekly 5-fluorouracil administered with granulocyte-macrophage colony-stimulating factor and high-dose leucovorin: A potential role for growth factor as mucosal protectant. Cancer Invest 17:1–9, 1999[Medline]
10. Rubin JS, Osada H, Finch PW, et al: Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci U S A 86:802–806, 1989 11. Rubin JS, Bottaro DB, Chedid M, et al: Keratinocyte growth factor. Cell Biol Int 19:399–411, 1995[CrossRef][Medline]
12. Finch PW, Rubin JS, Miki T, et al: Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science 245:752–755, 1989 13. Housley RM, Morris CF, Boyle W, et al: Keratinocyte growth factor induced proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract. J Clin Invest 94:1764–1777, 1994[Medline] 14. Yi ES, Yin S, Songmei Y, et al: Keratinocyte growth factor induces pancreatic ductal epithelial proliferation. Am J Pathol 145:80–85, 1994[Abstract]
15. Pierce GF, Yanagihara D, Klopchin K, et al: Stimulation of all epithelial elements during skin regeneration by keratinocyte growth factor. J Exp Med 179:831–840, 1994 16. Yi ES, Shabaik AS, Lacey DL, et al: Keratinocyte growth factor causes proliferation of urothelium in vivo. J Urol 154:1566–1570, 1995[CrossRef][Medline] 17. Ulich TR, Yi ES, Longmuir K, et al: Keratinocyte growth factor is a growth factor in type II pneumocytes in vivo. J Clin Invest 93:1298–1306, 1994[Medline]
18. Werner S, Peters KG, Longaker MT, et al: Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci U S A 89:6896–6900, 1992 19. Finch PW, Pricolo V, Wu A, et al: Increased expression of keratinocyte growth factor mRNA associated with inflammatory bowel disease. Gastroenterology 110:441–451, 1996[CrossRef][Medline] 20. Farrell CL, Rex KL, Kaufman SA, et al: Effects of keratinocyte growth factor in the squamous epithelium of the upper aerodigestive tract of normal and irradiated mice. Int J Radiat Biol 75:609–620, 1999[CrossRef][Medline] 21. Dorr W, Noack R, Spekl K, et al: Modification of oral mucositis by keratinocyte growth factor: Single radiation exposure. Int J Rad Biol 77:341–347, 2001
22. Han DS, Li F, Holt L, et al: Keratinocyte growth factor-2 promotes healing of experimental small intestinal ulceration in rats. Am J Physiol Gastrointest Liver Physiol 279:G1011–G1022, 2000
23. Farrell CL, Bready JV, Rex KL, et al: Keratinocyte growth factor protects mice from chemotherapy and radiation induced gastrointestinal injury and mortality. Cancer Res 58:933–939, 1998 24. Serdar CM, Heard R, Prathikanti R, et al: Safety, pharmacokinetics and biologic activity of rHuKGF in normal volunteers: Results of a placebo-controlled randomized double blind phase I study. Blood 90:172a, 1997 (suppl 1, abstr 761) 25. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207–214, 1981[CrossRef][Medline] 26. Clarke SJ, Abdi A, Davis ID, et al: Recombinant human keratinocyte growth factor (rHuKGF) prevents chemotherapy-induced mucositis in patients with advanced colorectal cancer: A randomized phase II trial. Proc Am Soc Clin Oncol 20:383a, 2001 (abstr 1529) 27. Spielberger RT, Stiff P, Emmanouilides C, et al: Efficacy of recombinant human keratinocyte growth factor (rHuKGF) in reducing mucositis in patients with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation (auto-PBPCT) after radiation-based conditioning—Results of a phase 2 trial. Proc Am Soc Clin Oncol 20:7a, 2001 (abstr 25) 28. Parulekar W, Mackenzie R, Bjarnason G, et al: Scoring oral mucositis. Oral Oncol 34:63–71, 1998[CrossRef][Medline] 29. Sonis ST, Eilers JP, Epstein JB, et al: Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Group. Cancer 85:2103–2113, 1999[CrossRef][Medline] 30. Durrant S, Pico JL, Schmitz N, et al: A phase I study of recombinant human keratinocyte growth factor (rHuKGF) in lymphoma patients receiving high-dose chemotherapy (HDC) with autologous peripheral blood progenitor cell transplantation (AutoPBPCT). Blood 94:708a, 1999 (suppl 1, abstr 3130) 31. Brizel DM, Herman T, Goffinet D, et al: A phase I/II trial of escalating doses of recombinant human keratinocyte growth factor (rHuKGF) in head & neck cancer (HNC) patients receiving radiotherapy (RT) with concurrent chemotherapy (CCT). Int J Radiat Oncol Biol Phys 51:40, 2001 (suppl 1, abstr 67)[CrossRef] 32. Brizel DM, Le QT, Rosenthal D, et al: Phase II study of recombinant human keratinocyte growth factor (rHuKGF) in head & neck cancer treated with standard (SRT) or hyperfractionated irradiation (HRT) & concurrent chemotherapy (CT). Int J Rad Biol Phys 54:285, 2002 (suppl, abstr 2128)[CrossRef] Submitted October 15, 2002; accepted January 21, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
