Prevention Of Severe Oral Mucositis Research Articles

Palifermin Compared to Supersaturated Calcium Phosphate Rinse in Prevention of Severe Oral Mucositis after Stem Cell Transplantation in Patients Receiving Radiotherapy-Based Myeloablative Conditioning

Purpose: Oral mucositis (OM) is a common, debilitating complication of conditioning regimens for hematopoietic stem cell transplantation (HSCT). Supersaturated calcium phosphate rinse (SCPR) and palifermin have shown efficacy in preventing severe OM. However, whether their efficacy differs is unknown. We aimed to compare the efficacy of SCPR and palifermin in HSCT patients receiving myeloablative conditioning. Methods: A comprehensive review of our institutional database was performed to identify patients who received myeloablative-conditioning therapy over 5 years. All HSCT patients who received radiotherapy-based myeloablative conditioning and received either palifermin or SCPR within the study period were included. Most patients received Fludarabine, Busulfan, and total body irradiation (FBT). Patients were divided into two groups based on the OM prophylactic agent received. The primary outcome is prevalence of severe OM (WHO Grade 3 and 4). The secondary outcomes are a prevalence of all-grade OM and WHO Grade 4 OM. These outcomes were compared between the two groups. Results: We identified 26 patients who received SCPR and 122 patients who received palifermin for OM prophylaxis. The prevalence of World Health Organization (WHO) Grade 3 or 4 OM was significantly lower in the palifermin group (57% vs. 100%, p = 0.01). In addition, the palifermin group had lower WHO Grade 4 OM (22% vs. 62%, p = 0.0006). The overall prevalence of OM was not significantly different between the two groups (86% for palifermin group vs. 100% for SCPR arm, p = 0.15). Subgroup analyses demonstrated improved outcomes with palifermin, regardless of age, sex, disease status, donor type, and primary diagnosis. Conclusion: When compared to SCPR, the use of palifermin is associated reduced severity of OM in HSCT patients receiving radiotherapy-based myeloablative conditioning.

Phase 2 pilot trial of RRx-001 as an anti-mucositis agent in patients with head and neck cancer treated with chemoradiation (PREVLAR).

6078 Background: Severe oral mucositis (SOM) is a dose limiting toxicity during radiotherapy and cisplatin for head and neck cancers. The aim of this 4-arm randomized controlled pilot trial was to evaluate the efficacy of different schedules of a novel radioprotectant, RRx-001 versus standard-of-care (SOC), to reduce duration, time to onset and incidence of SOM in patients received cisplatin-based chemoradiotherapy (CRT) for oral cavity or oropharyngeal cancer (OCC). Methods: Patients with locally advanced OCC treated with definitive or postoperative CRT were randomized to receive RRx-001 by 15-minute intravenous infusion in one of three different schedules versus none. The days and severity of mucositis were prospectively evaluated. Oral mucositis was assessed weekly during and after CRT as well as 28 days after completion. The pre-specified efficacy endpoints were duration of grade 3-4 SOM, resolution of SOM, time to onset of SOM and incidence of SOM. Results: A total of 53 patients were enrolled between June 2018 and July 2019 across 11 institutions. Forty-five (out of 53) patients received study drug and were efficacy evaluable. RRx-001 were well tolerated with no associated serious adverse events. All RRx-001 arms numerically outperformed SOC on the pre-specified efficacy measures, and the greatest effect estimate was observed on Arm 1 (RRx-001 pretreatment only + CRT). The following endpoints favored treatment with RRx-001. Median SOM duration by treatment was 22 and 40 days for Arm 1 and SOC respectively. Time to onset of SOM was by 38 days (Arm 1) vs. 26 days (SOC). On Arm 1, 83% of patients had SOM resolution vs 60% on SOC). Gastrostomy requirement was reduced by 45%. No patients on Arm 1 developed grade 4 mucositis vs 30% developed grade 4 mucositis on the SOC arm. Furthermore, the incidence of oropharyngeal dysphagia, which can substantially impair nutrition, was reduced by treatment with RRx-001, occurring at 50% vs 70% for Arm 1 vs SOC respectively. Treatment with RRx-001 resulted in highly significant decrease in the duration of SOM through 60 Gy with a median SOM of 1 day vs 17 days for Arm 1 vs SOC respectively (Wilcoxon rank-sum test p < 0.001). Median cumulative cisplatin dose was significantly greater for RRx-001 Arm 1 than SOC (557.4 mg vs. 438 mg, Wilcoxon p = 0.025). Conclusions: Compared with SOC, SOM among RRx-001-treated patients given 3 different treatment schedules was less severe, of shorter duration, demonstrated delayed time to onset and resolved earlier. Overall, the incidence, duration and severity of SOM and dysphagia was reduced. The safety profile of RRx-001 was similar to SOC. These results will inform the design of a Phase 3 pivotal study of RRx-001 in the prevention of SOM in at-risk cancer patients. Clinical trial information: NCT03515538.

The Self-Management Process for Prevention of Severe Oral Mucositis of Head and Neck Cancer Patients Undergoing Radiotherapy

The Self-Management Process for Prevention of Severe Oral Mucositis of Head and Neck Cancer Patients Undergoing Radiotherapy

Benefits of immunonutrition in patients with head and neck cancer receiving chemoradiation: A phase II randomized, double-blind study

The benefits of immunonutrition in patients with head and neck cancer (HNC), especially for those undergoing definitive concurrent chemoradiation (CCRT), remain unclear. We evaluated the benefits of immunonutrition regarding the prevention of severe oral mucositis. Secondary objectives included assessments of other treatment-related toxicities, changes of nutritional and inflammatory marker levels, treatment tolerance, and survival. In total, 110 patients with HNC undergoing definitive CCRT including 3-week cycles of cisplatin were enrolled in our double-blind phase II study. Patients were randomly assigned to receive an immunonutrient formula containing omega-3-fatty acids, arginine, dietary nucleotides, and soluble fiber (n=55) or an isocaloric isonitrogenous control (n=55). All patients received the assigned product 5 consecutive days before each chemotherapy session. The proportion of patients with severe oral mucositis was compared between the immunonutrients and control groups. The rates of nasopharyngeal cancer (NPC) were 67% and 51% in the immunonutrients and control groups, respectively. All patients had 100% compliance to the assigned product. There was no difference of the proportion of patients with grade 3-4 oral mucositis between the two groups (62% vs. 67%, p=0.690). At the time of analyses, survival tended to be better in the immunonutrients group. The 3-year progression-free survival rates were 69% (95% confidence interval [CI]=55%-80%) and 44% (95% CI=30%-57%) in the immunonutrients and control groups, respectively (p=0.056), whereas the 3-year overall survival rates in these groups were 69% (95% CI=54%-80%) and 50% (95% CI=36%-66%; p=0.065), respectively. In subgroup analyses according to the primary tumor location, the survival benefits were apparently maintained in patients with NPC. Although our study did not demonstrate a reduced risk of severe oral mucositis, we found that immunonutrition might improve survival. Larger studies are needed to determine the optimal dose and schedule of immunonutrition to prevent oral mucositis. In addition, randomized phase III trials evaluating the survival benefits of immunonutrition in patients with cancer are required, and NPC might be a primary malignancy of interest. ClinicalTrials.gov ID NCT05101889.

1729TiP Rationale and design of the phase IIb/III VOICE trial of clonidine MBT for the prevention of severe oral mucositis in patients with OPC receiving chemoradiotherapy

Clonidine MBT (Validive®) is an orally delivered prophylactic treatment for chemoradiotherapy (CRT)-induced severe oral mucositis (SOM) in patients with oropharyngeal cancer (OPC). Clonidine MBT is a novel, extended release formulation designed to adhere to the gums and dissolve slowly, releasing clonidine in the oral cavity over many hours. OPC occurs in the macrophages-rich regions at the back of the tongue and throat. CRT is used 1st line in OPC but tumor radiation also irradiates neighboring macrophages, inducing local expression of pro-inflammatory cytokines.

A Phase 1 Single Dose Escalation Study of Palifermin Administered Pre-Transplant Conditioning in Subjects Undergoing Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation

Background: Early initiation of graft-versus-host disease (GvHD) is driven by donor alloreactive T-lymphocytes directed against recipient's histocompatibility antigens often overexposed during damage to tissues during the conditioning chemotherapy. Palifermin is a truncated form of human recombinant keratinocyte growth factor (KGF, also known as FGF7) that binds to FGF receptor 2b expressed in many epithelia including the epithelium of the epidermis, oral and GI mucosa, urothelium, and thymus, in which it exerts cytoprotective and regenerative effects. Palifermin also has immunomodulatory effects manifested as improvements in thymic function and downregulation of pro-inflammatory cytokines. Palifermin was FDA approved in 2004 at a dose of 60 mcg/kg/day (x3 consecutive days) for prevention of severe oral mucositis in hematologic malignancy patients receiving autologous hematopoietic stem cell transplant (HSCT). A single dose of 180 mcg/kg/day appears to have similar effects. In animal models, palifermin showed efficacy in controlling acute and chronic GvHD. However, subsequent clinical studies did not confirm efficacy for prevention of GvHD or for stimulation of functional thymus recovery using a dose/schedule based on the one that had been approved for autologous HSCT. We conducted a phase 1 study (NCT02356159) to determine the maximal safe single dose level of palifermin administered prior to starting transplant conditioning. Methods: This was an open-label, dose escalation study with standard 3+3 design. Four different dose levels of palifermin (180, 360, 540 and 720 µg/kg) were administered as a single dose on day -7 pretransplant. The reduced-intensity conditioning regimen (cyclophosphamide 1200 mg/m2/day IV and fludarabine 30 mg/m2/day IV), was given on days -6 to -3. Sirolimus, tacrolimus and low-dose post-HSCT methotrexate were used for GvHD prophylaxis. On day 0 all subjects received a peripheral blood stem cell (PBSC) graft from an unrelated donor (MUD) matched at least at HLA-A, -B, -C, -DRB1. Prior to transplant, subjects received one or two cycles of disease-specific lymphodepleting induction chemotherapy (EPOCH-F/R or FLAG). Subjects must have been ≥18 years old with a high-risk hematologic malignancy, Karnofsky performance status ≥60%, and acceptable organ function. The primary objective was to assess safety of palifermin and to recommend the phase 2 study dose. DLT was defined as non-relapse mortality before day 30 post-HSCT regardless of attribution to palifermin and non-hematologic grade ≥4 adverse events (AEs) occurring within 14 days after administration. AEs were recorded according to CTCAEv4. Results: From Oct 2015 to Mar 2019, 18 subjects were enrolled (NHL=7, AML/MDS=5, ALL/LBL=2, CML=2, MPN=1 and MM=1). Kahl's relapse risk was high, standard, and low in 15, 2, and 1 subject, respectively. Median HCT-CI score was 1 (0-4) with median age 47 years (21-66); 14 (78%) were males. Six subjects received dose level 1 (subject #3 was diagnosed with achalasia and grade 4 elevated lipase without radiological signs of pancreatitis, still attributed as DLT possibly related to palifermin). No DLTs occurred afterwards. Three subjects were enrolled onto each of dose levels 2, 3 and 4, with expansion of dose level 4 to 3 more subjects for additional safety exploration. Skin rash and Increased serum amylase or lipase were the most frequent AEs (Table 1A). Grade 3 increased serum amylase and grade 3 possible pancreatitis in subject #3 were the only SAEs attributed to study drug. All subjects engrafted successfully. Day 14 median CD3 and myeloid chimerism was 97% (36-100) and 99% (82-100), respectively, with the median time to 100% CD3 chimerism of 44 days (14-181). Table 1B lists occurrence of GvHD prior to any malignancy relapse. Four subjects had relapsed malignancy, for which 3 received DLI. After a median follow up of 28 months (2-55), 5 subjects have died, 2 malignancy relapses and 3 non-relapse related causes. Conclusion: Palifermin administered at dose four-times higher than previously given in humans is safe to use in patients undergoing MUD peripheral blood HSCT. MTD was not reached. Recommended phase 2 dose for examining efficacy in prevention of GvHD is 720 µg/kg. Disclosures Rubin: NIH/NCI: Ended employment in the past 24 months, Patents & Royalties; KGF/palifermin: Patents & Royalties; Paradigm Shift Therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Palifermin was FDA approved at a dose of 60 mcg/kg/day (x3 consecutive days) for prevention of severe oral mucositis in hematologic malignancy patients receiving autologous hematopoietic stem cell transplant (HSCT).

Cost-effectiveness randomized clinical trial on the effect of photobiomodulation therapy for prevention of radiotherapy-induced severe oral mucositis in a Brazilian cancer hospital setting.

This study aimed to assess the cost-effectiveness of photobiomodulation therapy (PBMT) in association with a Preventive Oral Care Program (POCP) compared with POCP alone in the treatment of radiotherapy (RT)-induced oral mucositis (OM). The cost-effectiveness was evaluated from the health provider perspective and conducted alongside a randomized, double-blind clinical trial. Participants were randomly assigned to either PBMT (n = 25) or control (n = 23) group. The PBMT group participants received PBMT associated with POCP. In the control group, patients were submitted to POCP alone. Costs were identified, quantified, and valued through observation and consultation of the hospital's financial sector database and estimated in Brazilian real and converted to international dollars using the purchasing power parity exchange rate. The incremental cost-effectiveness ratio (ICER) was estimated by considering the prevention of severe OM, interruption of RT, and oral health-related quality of life (OHRQoL) scores, measured by the OHIP-14 and patient-reported OM symptoms scale (PROMS). The incremental cost of PBMT was $857.35, and the cost per session was $25.69. The ICER was $ 2867.39 to avoid one case of severe OM and $ 2756.75 to prevent one interruption in RT due to OM. ICER to reduce 1 point in OHIP-14 and PROMS scores were $170.79 and $31.75, respectively. PBMT is more cost-effective than POCP alone in preventing severe OM, worsening of the OHRQoL, and RT interruptions. PBMT is a promising therapy, especially to avoid interruptions in oncological treatment. ReBEC-RBR-5h4y4n.

A suggested protocol may not be effective in preventing severe oral mucositis, but not enough participants were recruited to be confident in these results

Kawashita Y, Koyama Y, Kurita H, et al. Effectiveness of a comprehensive oral management protocol for the prevention of severe oral mucositis in patients receiving radiotherapy with or without chemotherapy for oral cancer: a multicentre, phase II, randomized controlled trial [published online ahead of print January 2, 2019]. Int J Oral Maxillofac Surg. https://doi.org/10.1016/j.ijom.2018.10.010.

Effectiveness of a comprehensive oral management protocol for the prevention of severe oral mucositis in patients receiving radiotherapy with or without chemotherapy for oral cancer: a multicentre, phase II, randomized controlled trial

The aim of this phase II, multicentre, randomized controlled trial was to evaluate the effectiveness of a comprehensive oral management protocol for the prevention of severe oral mucositis in patients with oral cancer receiving radiotherapy alone or chemoradiotherapy. In total, 124 patients with oral cancer were enrolled from five institutions. Of these, 37 patients undergoing radiotherapy were randomly divided into an intervention group (n=18) and a control group (n=19). The remaining 87 patients, who were undergoing chemoradiotherapy, were also randomized into an intervention group (n=42) and a control group (n=45). During radiotherapy, patients in the control group received only oral care, while those in the intervention group additionally received spacers to cover the entire dentition, pilocarpine hydrochloride, and topical dexamethasone ointment for oral mucositis. The primary endpoint was the incidence of severe oral mucositis. The intervention was significantly associated with a decreased incidence of severe oral mucositis in patients receiving radiotherapy alone (P=0.046), but not in those receiving chemoradiotherapy (P=0.815). These findings suggest that an oral management protocol can prevent severe oral mucositis in patients with oral cancer undergoing radiotherapy without concurrent chemotherapy.

A retrospective study of factors associated with the development of oral candidiasis in patients receiving radiotherapy for head and neck cancer: Is topical steroid therapy a risk factor for oral candidiasis?

The aims of this study were to investigate the incidence and risk factors for oral candidiasis in patients receiving radiotherapy for head and neck cancer, and to determine the influence of topical steroid therapy on the development of oral candidiasis.We conducted a retrospective study of 300 patients receiving radiotherapy to the head and neck region. The primary endpoint was the incidence of oral candidiasis during radiotherapy. Associations between the incidence of oral candidiasis and various clinical factors were investigated. The cumulative incidence rate of oral candidiasis was calculated using the Kaplan–Meier method and analyzed by the log-rank test and Cox regression. Propensity score-matched analysis was used to assess the influence of topical steroid therapy on the development of oral candidiasis.Oral candidiasis occurred in 75 (25.0%) of the 300 patients. Multivariate analysis identified minimum lymphocyte count and severity of oral mucositis during radiotherapy as independent risk factors for the development of oral candidiasis. Topical steroid therapy for oral mucositis was not associated with the incidence of oral candidiasis according to multivariate and propensity score matching analyses.Oral candidiasis was associated with the suppression of the host's immunity and severe oral mucositis, but not topical steroid therapy. Proper oral health care during radiotherapy and the prevention of severe oral mucositis may reduce the incidence of oral candidiasis.

Oral Cryotherapy for Preventing Oral Mucositis in Patients Receiving Cancer Treatment.

In patients receiving treatment for cancer, does oral cryotherapy prevent oral mucositis? Oral cryotherapy is effective for the prevention of oral mucositis in adults receiving fluorouracil-based chemotherapy for solid cancers, and for the prevention of severe oral mucositis in adults receiving high-dose melphalan-based chemotherapy before hematopoietic stem cell transplantation (HSCT).

Low-level laser therapy prevents severe oral mucositis in patients submitted to hematopoietic stem cell transplantation: a randomized clinical trial.

The purpose of this study is to evaluate the effectiveness of low-level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation. This is a randomized, parallel, superiority trial including 35 patients divided into the following: laser (n = 17) and sham (n = 18). The variables assessed were oral mucositis (grade 2 of the World Health Organization oral toxicity scale), severe oral mucositis (grade 3 or 4), and pain (according to a visual analogue scale). In the laser group, a InGaAlP laser, wavelength of 650 nm, power 100 mW, energy per point of 2 J, time 20 s by point, extremity fiber optic 0.028 cm(2), and energy density 70 J/cm(2), was used, applied the first day of conditioning until D + 5, while the sham group received simulated laser over the same period. No statistically significant difference was found in the incidence of oral mucositis (p = 0.146). Severe mucositis was found in 40% of the patients (14/35), 3 in the intervention group (17.65%) and 11 in the sham group (61.11%) (p = 0.015). The cumulative probability of survival with respect to the development of severe oral mucositis was >0.6 for the intervention group and 0 for the control group (p = 0.0397). On the day on which pain was considered the worst, patients in the sham group were more likely to classify their pain as severe compared to those in the laser group (p = 0.041). Low-level laser therapy proved effective for the prevention of severe oral mucositis and intense oral pain in patients submitted to hematopoietic stem cell transplantation.

Clinical applications of palifermin: amelioration of oral mucositis and other potential indications.

Mucositis is one of the most significant toxicities in cancer patients undergoing cytotoxic treatment. It can have a negative impact on both quality of life and health economics. Severe oral mucositis can contribute to hospitalization, need for narcotic analgesics, total parentral nutrition, suboptimal delivery of anti-neoplastic treatment, and morbidity and mortality. Palifermin, a recombinant derivative of human keratinocyte growth factor, is the first active agent approved by the FDA for the prevention of severe oral mucositis in patients undergoing haematopoietic stem cell transplantation (HSCT). Several studies have also shown significant reduction in the incidence, severity and/or duration of oral mucositis in other high-risk settings such as concurrent chemoradiotherapy (CT/RT) for patients with head and neck cancer, and use of mucotoxic chemotherapeutic agents such as doxorubicin in sarcoma and fluorouracil for the treatment of colorectal cancer. The reduction in mucositis has translated into amelioration of symptoms and improvement in daily functioning as measured by patient-reported outcome in multiple studies. The clinical response to palifermin appears to be related in part to epithelial proliferation and mucosal thickening. Palifermin also has other potential clinical applications including the acceleration of immune reconstitution and inhibition of graft-versus-host disease in patients undergoing HSCT, and mitigation of dysphagia in lung cancer patients treated with concurrent CT/RT. Palifermin is generally well tolerated with mild-to-moderate skin and oral adverse events. Future studies may expand the use of palifermin into other areas that would benefit from its cytoprotective and regenerative effects.

Palifermin in high dose chemotherapy and autologous stem cell transplantation reduces infection rate

Palifermin has been demonstrated in a controlled randomized study to have a beneficial effect on the prevention of severe oral mucositis that is associated SUMMARY We performed a retrospective cohort study in patients affected by hematological malignancies and who underwent high dose chemotherapy and autologous stem cell transplant. Forty patients were treated with palifermin while 80 were matched controls. Patients treated with palifermin displayed a lower rate of fever of unknown origin (P=0.02) and of infections not related to central venous catheter (not-CVC infections), (P=0.01). This effect of palifermin on not-CVC infections remained significant also after adjusting for potential confounders (P=0.03). The odds ratio of severe mucositis was 30% lower in palifermin treated patients than in controls (odds ratio: 0.70, 95% confidence interval: 0.33-1.51) but this difference was not significant. Palifermin treated patients had reduced rate of severe gastrointestinal toxicity (P<0.001), reduced morphine utilization (P<0.001), reduced need for total parental nutrition (P<0.001) and lower blood products transfusions requirement (P=0.04). Economical costs related to resources consumption were lower in palifermin treated patients and fully compensated for the cost of this drug. Palifermin in high dose chemotherapy and autologous stem cell transplantation reduces infection rate

A Randomized Placebo Controlled Phase II Trial of Prevention of Severe Oral Mucositis Using Single Dose Velafermin in Patients Receiving Myeloablative Therapy and Autologous Hematopoietic Stem Cell Transplant (AHSCT).

Oral mucositis (OM) is a commonly occurring side effect in patients (pts) undergoing AHSCT. Velafermin, recombinant human fibroblast growth factor-20, is under investigation for the prevention of severe OM. Previous studies demonstrated that velafermin at 30 mcg/kg was well tolerated and was effective in reducing the incidence of severe mucositis. The primary objective of this multicenter, randomized, double-blind, placebo controlled study was to confirm safety and efficacy of 30 mcg/kg velafermin for prevention of severe OM incidence (grade 3/4 OM based on the WHO grading system). The secondary objective was to evaluate safety and efficacy of 10 and 60 mcg/kg doses to better define the therapeutic range. Pts were randomized to receive placebo or velafermin at 30, 10 or 60 mcg/kg in a 3:3:1:1 ratio 24–36 hrs after stem cell infusion. Randomization was stratified by study center and OM risk factors identified from the previous placebo controlled study in a similar population including conditioning regimen and body mass index (BMI ≥30). Pts with multiple myeloma or lymphoma (≥18 y.o.) receiving ≥2X106 /kg CD34+ cells following chemotherapy with or without Total Body Irradiation (TBI) were eligible. OM status and safety data were collected for 30 days post treatment while mortality and disease progression were followed for 1 yr. An interim analysis by a data monitoring committee (DMC) was planned to assess safety and efficacy after 50% of pts completed the 30 day treatment period. A total of 390 pts who received melphalan (200 mg/m2) (n=239), BEAM (n=129), TBI (n=15), or other (n=7) were randomized and 384 pts were treated. The study drug was well tolerated in general and no pts discontinued study due to drug-related adverse events. There were 93 serious adverse events (SAEs) in 78 (20%) pts and no drug-related death was reported. Five infusion-related SAEs were reported including vasovagal episode (2), syncope (2), and anaphylactoid reaction (1). All 5 episodes occurred on the day of study drug infusion and resolved on the same day with no sequelae. Based on review of the results from the interim analysis, which included safety and efficacy data from 200 pts, the DMC recommended that the study continue to completion as planned. The last pt has completed the 30 day study period. The un-blinded results of the OM efficacy endpoints from velafermin treated groups or placebo as well as 30-day safety information from all pts will be reported.

Cryotherapy in the prevention of oral mucositis in patients receiving low-dose methotrexate following myeloablative allogeneic stem cell transplantation: a prospective randomized study of the Gruppo Italiano Trapianto di Midollo Osseo nurses group

Severe oral mucositis is a major cause of morbidity following allogeneic hematopoietic stem cell transplantation (AHSCT). Cryotherapy, that is, the application of ice chips on the mucosa of the oral cavity during the administration of antineoplastic agents, may reduce the incidence and severity of chemotherapy-related oral mucositis. In this multicenter randomized study, we addressed whether cryotherapy during MTX administration is effective in the prevention of severe oral mucositis in patients undergoing myeloablative AHSCT. One hundred and thirty patients undergoing myeloablative AHSCT and MTX-containing GVHD prophylaxis were enrolled and randomized to receive or not receive cryotherapy during MTX administration. The incidence of severe (grade 3-4) oral mucositis, the primary end point of the study, was comparable in patients receiving or not cryotherapy. Moreover, no difference was observed in the incidence of oral mucositis grade 2-4 and the duration of oral mucositis grade 3-4 or 2-4, or in the kinetics of mucositis over time. In univariate and multivariate analysis, severe oral mucositis correlated with TBI in the conditioning regimen and lack of folinic acid rescue following MTX administration. Thus, cryotherapy during MTX administration does not reduce severe oral mucositis in patients undergoing myeloablative allogeneic HSCT. Future studies will assess cryotherapy before allogeneic HSCT.

Final analysis of the phase II, randomized, double-blind, placebo-controlled trial of single dose velafermin (CG53135–05) for the prevention of oral mucositis

6537 Background: Oral mucositis (OM) is a commonly occurring side effect of high-dose chemotherapy (HDCT) in patients (pts) undergoing autologous hematopoietic stem cell transplant (AHSCT). Velafermin, recombinant human fibroblast growth factor 20, is being investigated for prevention of OM. Velafermin promotes epithelial and mesenchymal cell proliferation in vitro and in vivo. Methods: A phase II trial was conducted to evaluate safety, efficacy, and pharmacokinetics (PK) of velafermin. Inclusion criteria: pts undergoing HDCT and AHSCT with or without total body irradiation (TBI) were enrolled. Velafermin at 0.03, 0.1, or 0.2 mg/kg or placebo was administered as single dose IV at 24h after stem cell infusion. Safety and PK were assessed. Pts were scored daily for presence of OM using the WHO grading scale. The primary endpoint was the incidence of Grade 3/4 OM. Results: A total of 212 pts were randomized to either placebo (n=51) or velafermin at 0.03 (n=50), 0.1 (n=56), or 0.2 (n=55) mg/kg (intent-to-treat or ITT sample). 206 pts (97%) received study drug or placebo. Pt diagnoses included multiple myeloma (57%), non-Hodgkin’s (25%), or Hodgkin’s (11%) lymphoma and 13 pts (6%) received TBI as part of the conditioning regimen. The Grade 3/4 OM incidence rates (%) in the placebo or velafermin arms (0.03, 0.1, and 0.2 mg/kg) were 37, 18, 38, and 36, respectively. The primary analysis of dose dependent reduction of severe OM was not statistically significant (p = 0.549). However, velafermin at 0.03 mg/kg did reduce the incidence of Grade 3/4 OM when compared to placebo alone (p = 0.031). Duration of Grade 3/4 OM was reduced significantly in the 0.03 mg/kg when every pt was evaluated or in the 0.1 mg/kg dose when only pts with Grade 3/4 OM were included in the analysis (p = 0.037 and 0.014, respectively). A total of 5 related SAEs (3 in 0.1 mg/kg, 1 in 0.03 mg/kg, and 1 in placebo cohort) occurred within 4hr of study drug infusion. All symptoms were transient. Conclusion: Single dose velafermin at 0.03mg/kg is may be active in reducing CT induced severe OM in AHSCT pts. Safety profile supports continuing study to define the optimal dose for prevention of severe OM. A new Phase II study will be conducted to confirm velafermin activity at 0.03mg/kg dose. [Table: see text]