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This prospective, randomized, double-blind, placebo-controlled study evaluated the efficacy of palifermin to reduce the incidence of severe (grade 3-4) acute GVHD after myeloablation and allo-SCT. Adults who received allo-SCT for hematologic malignancies received placebo or palifermin 60 μg/kg daily on three consecutive days before conditioning and a single dose of 180 μg/kg after conditioning, but often 1 or 2 days before allo-SCT. Subjects received MTX (plus CYA or tacrolimus) on days 1, 3, 6 and 11. Acute GVHD was evaluated once weekly and oral mucositis was evaluated daily. Subjects were randomly assigned to placebo (n=78) or palifermin (n=77). Conditioning included TBI in approximately half of the subjects (48% placebo, 51% palifermin). The primary efficacy end point, subject incidence of grade 3-4 acute GVHD, was similar between treatment groups (17% placebo, 16% palifermin). Grade 3-4 oral mucositis (73% placebo, 81% palifermin) and other secondary efficacy end points were similar between treatment groups. The most commonly reported treatment-related adverse events were skin/s.c. events such as rash, pruritus, and erythema. This exploratory study of acute GVHD after myeloablation and allo-SCT did not provide evidence of a treatment effect with this dosing regimen of palifermin.

Purpose Radiochemotherapy of head and neck cancer causes severe mucositis in most patients. We investigated whether palifermin reduces this debilitating sequela. Methods We conducted a multicenter, double-blind, randomized, placebo-controlled trial in 186 patients with stages II to IVB carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received 60 or 66 Gy after complete (R0) or incomplete resection (R1), respectively, at 2 Gy/fraction and five fractions per week. Cisplatin 100 mg/m2 was administered on days 1 and 22 (and on day 43 with R1). Patients were randomly assigned to receive weekly palifermin 120 μg/kg or placebo from 3 days before and continuing throughout radiochemotherapy. Trained evaluators performed oral assessments twice weekly. The primary end point was the incidence of severe oral mucositis (WHO grades 3 to 4). Overall survival and time to locoregional progression were also assessed. Analysis was by intention to treat. Results Severe oral mucositis was seen in 47 (51%) of 92 patients administered palifermin and 63 (67%) of 94 administered placebo (P = .027). Palifermin decreased the duration (median, 4.5 v 22.0 days) and prolonged the time to develop (median, 45 v 32 days) severe mucositis. Neither patient-reported mouth and throat soreness scores nor treatment breaks differed between treatment arms. After median follow-up of 32.8 months, 23 deaths (25%) had occurred in both treatment arms, and disease had recurred in 25 (27%) and 22 (24%) of palifermin- and placebo-treated patients, respectively. Conclusion Palifermin reduced the occurrence of severe oral mucositis in patients with head and neck cancer undergoing postoperative radiochemotherapy. Additional clinical exploration of palifermin with postoperative radiochemotherapy would be useful.

Purpose Oral mucositis (OM) is a debilitating toxicity of chemoradiotherapy for head and neck cancer (HNC). This randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of palifermin to reduce OM associated with definitive chemoradiotherapy for locally advanced HNC. Patients and Methods Patients receiving conventionally fractionated radiotherapy (2.0 Gy/d, 5 days/wk to 70 Gy) with cisplatin (100 mg/m2 on days 1, 22, and 43) received palifermin (180 μg/kg) or placebo before starting chemoradiotherapy and then once weekly for 7 weeks. The primary end point was the incidence of severe, observable, and functional OM (WHO grade 3 to 4). Results The palifermin (n = 94) and placebo (n = 94) arms were well balanced. The incidence of severe OM was significantly lower for palifermin than for placebo (54% v 69%; P = .041). In the palifermin arm, median time to severe OM was delayed (47 v 35 days), median duration of severe OM was shortened (5 v 26 days), and the incidence of xerostomia grade ≥ 2 was lower (67% v 80%), favoring palifermin; however, the differences were not significant after multiplicity adjustment. Opioid analgesic use, average mouth and throat soreness scores, and chemoradiotherapy compliance were not significantly different between treatment arms. Adverse events were similar between arms (98%, palifermin; 93%, placebo). The most common study drug–related adverse events were rash, flushing, and dysgeusia. After median follow-up of 25.8 months, overall survival and progression-free survival were similar between treatment arms. Conclusion Although palifermin reduced severe functional OM, its role in the management of locally advanced HNC during chemoradiotherapy remains to be elucidated.

Purpose Acute mucositis is a dose-limiting toxicity of concurrent chemoradiotherapy regimens for locally advanced head and neck cancer. Palifermin (a recombinant human keratinocyte growth factor; ΔN23-KGF) stimulates the proliferation and differentiation of mucosal epithelium to reduce mucositis in patients receiving intensive therapy for hematologic cancers. This study assessed the efficacy and safety of palifermin in patients receiving concurrent chemoradiotherapy for advanced head and neck squamous cell carcinoma. Patients and Methods In a phase II trial, standard radiotherapy was delivered in daily 2-Gy fractions to 70 Gy, or hyperfractionated radiotherapy was delivered in 1.25-Gy fractions twice daily to 72 Gy, over 7 weeks. Chemotherapy included cisplatin 20 mg/m2 for 4 days and continuous-infusion fluorouracil 1,000 mg/m2/d for 4 days on weeks 1 and 5 of irradiation. Patients were randomly assigned 2:1 to palifermin 60 μg/kg or placebo once weekly for 10 doses. A follow-up trial evaluated long-term survival. Results Sixty-seven patients received palifermin and 32 received placebo. The median duration of grade ≥ 2 mucositis was 6.5 and 8.1 weeks in the palifermin and placebo groups, respectively (P = .157). Palifermin appeared to reduce mucositis, dysphagia, and xerostomia during hyperfractionated radiotherapy (n = 40) but not standard radiation therapy (n = 59). Adverse events were similar between treatment groups. Palifermin did not alter tumor response or survival. Conclusion Ten once-weekly doses of palifermin at 60 μg/kg were well tolerated. Most patients completed treatment, but palifermin did not reduce the morbidity of concurrent chemotherapy and radiotherapy. Future studies should evaluate higher palifermin doses with longer and more standardized assessment of acute mucositis.

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.

The term 'futility' is used to refer to the inability of a clinical trial to achieve its objectives. In particular, stopping a clinical trial when the interim results suggest that it is unlikely to achieve statistical significance can save resources that could be used on more promising research. There are various approaches that have been proposed to assess futility, including stochastic curtailment, predictive power, predictive probability, and group sequential methods. In this paper, we describe and contrast these approaches, and discuss several issues associated with futility analyses, such as ethical considerations, whether or not type I error can or should be reclaimed, one-sided vs two-sided futility rules, and the impact of futility analyses on power.

Immune thrombocytopenia purpura (ITP) is characterized by destruction of circulating platelets and the presence of antiplatelet antibodies. Many of the current immunomodulatory therapies act by reducing platelet destruction and usually do not have a lasting effect. This prospective, exploratory study characterized patients with ITP by identifying their demographic and comorbid clinical factors, use of treatments, serologic markers of autoimmunity, and possible relationships between platelet counts, concentrations of endogenous thrombopoietin (eTPO), and the presence of circulating anti-TPO antibodies. Data including medical history and laboratory evaluations were collected at a single patient visit on 205 patients (19 children, 186 adults). Reported histories revealed a 5% rate of thrombotic/ischemic events. Autoimmune markers including direct antiglobulin test and antinuclear antibodies were found more frequently than in the normal population; antiplatelet antibody testing was not done. eTPO concentrations were comparable to concentrations found in healthy volunteers. Our study confirmed that no significant inverse correlation occurred between circulating concentrations of eTPO and platelet counts in patients with ITP (Spearman r = -0.15). Two of the 205 patients tested (1%) had neutralizing activity of recombinant human TPO in a biological assay; however, this activity was confirmed to be anti-TPO antibody in only 1 patient.

BACKGROUND Oral mucositis is a complication of intensive chemotherapy and radiotherapy with no effective treatment. We tested the ability ofpalifermin (recombinant human keratinocyte growth factor) to decrease oral mucosal injury induced by cytotoxic therapy. METHODS This double-blind study compared the effect ofpalifermin with that of a placebo on the development of oral mucositis in 212 patients with hematologic cancers; 106 patients received palifermin (60 μg per kilogram ofbody weight per day) and 106 received a placebo intravenously for three consecutive days immediately before the initiation of conditioning therapy (fractionated total-body irradiation plus high-dose chemotherapy) and after autologous hematopoietic stem-cell transplantation. Oral mucositis was evaluated daily for 28 days after transplantation. RESULTS The incidence oforal mucositis of World Health Organization (WHO) grade 3 or 4 was 63 percent in the palifermin group and 98 percent in the placebo group (P

We would like to address questions raised in Dr Haines’ Letter to the Editor published July 1, 2007,1 regarding the study, “Palifermin reduces the incidence of mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy.”2 With respect to the choice of treatment regimen used, the particular fluorouracil / leucovorin (FU/ LV, Mayo) regimen used in this study was widely used both in the United States and Australia at the time the study was designed and conducted. The study commenced in the mid 1990s, with the final patient enrolled onto the treatment phase of the trial in May 2000. Dr Haines cites a study by Wang et al,3 however this was not published until after our study had completed accrual. On the other hand, a much larger study involving 372 patients published in 1994 in this journal,4 suggested that the Mayo schedule as used in this study2 was preferable to the original, weekly Roswell Park regimen of FU and folinic acid, on the basis of similar effectiveness with reduced toxicity.

The substantial placebo response in depression confounds treatment decisions and the assessment of new therapies. Improvement with placebo occurs infrequently in patients with chronic depression and in those with pituitary-adrenocortical hyperfunction, but other consistent predictors of placebo response have not been detected. We divided 241 moderately to severely depressed patients who had received placebo on a double-blind basis for 3 to 6 weeks into responders (greater than or equal to 50% improvement in Hamilton depression score, final Hamilton depression score less than or equal to 10), extreme nonresponders (less than 25% improvement), and partial responders (all others). Improvement with placebo was associated with a relatively short illness, a precipitating event, depression of only moderate global severity, and a good response to previous antidepressant treatment. These observations suggest that depressed patients who do and do not recover with placebo have different conditions that have not yet been fully characterized.

Background: Oral mucositis is an adverse effect of myeloablative therapy which has serious clinical and economic consequences as well as a negative impact upon quality of life. The duration and severity of oral mucositis can be reduced by administering palifermin to patients with hematological malignancies receiving myeloablative therapy and undergoing hematopoietic stem cell transplantation (HSCT). However, we still require additional data on the long-term disease outcomes of patients treated with palifermin. Therefore we present here the long-term, safety data for palifermin-treated HSCT patients followed up for approximately 60 months after the last palifermin dose. Methods: The long-term safety data were collected during the follow-up phase of 4 parent trials where patients had received at least one dose of palifermin or placebo. Study assessments included overall survival (OS), progression-free survival (PFS), and secondary malignancies. Assessments were made at 6-month intervals during year 1 and annually thereafter until death or loss to follow-up. Kaplan-Meier curves for overall survival and PFS were calculated and the treatment groups were compared using stratified log-rank test. Results: Altogether 662 patients were randomized to treatment and received either palifermin or placebo (421 palifermin, 241 placebo); 538 patients entered the follow-up study (342 palifermin, 196 placebo). The median follow-up time for patients alive at last visit was 49.8 months (palifermin N=290) and 49.5 months (placebo N=169). There were 131 (32%) and 72 (30%) deaths in the palifermin and placebo groups, respectively. The overall survival curves were similar for both groups (p=0.717). Disease progression occurred in 167 (41%) palifermin- and 87 (36%) placebo-treated patients; the difference in PFS between the two groups was non-significant (p=0.280). Secondary malignancies were observed in 8% of patients in both groups: the incidence of secondary hematologic malignancies was 4% (palifermin: 14/342) versus 5% (placebo: 10/196) while the incidence of solid tumors was 2% in both groups. Conclusion: The results of this 60-month follow-up study indicate that long-term disease outcomes are not affected by administering palifermin to patients with hematological malignancies who are receiving myeloablative therapy and undergoing HS. There was no difference in OS and PFS between the palifermin and placebo groups. Furthermore there was no difference in the incidence of secondary malignancies between the two patient groups. The incidence of secondary hematologic malignancies and solid tumors was low, comparable between groups, and within the expected range for this patient population.