Duration Of Severe Oral Mucositis Research Articles

RRx-001 potentially reduces financial toxicity for patients and caregivers in head and neck cancer.

31 Background: Of all the toxicities that result from the treatment of head and neck cancer, perhaps the most insidious is financial burden or “out-of-pocket (OOP) expenses” for patients and their caregivers otherwise known as financial toxicity (FT) which is associated with decreased treatment adherence and poor clinical outcomes. A huge unmet need is interventions and strategies to mitigate this problem. Methods: PREVLAR was a Phase 2 study that randomized 53 head and neck cancer patients 1:1 to receive four doses of RRx-001 prior to the start of intensity modulated radiation therapy (IMRT) in 2.0-2.2 Gy fractions/weekday to a cumulative radiation dose of up to 72 Gy plus cisplatin administered either weekly (40 mg/m2) or tri-weekly (100 mg/m2) vs. cisplatin plus IMRT alone (control). The primary outcome was the incidence of severe oral mucositis. Adverse events were evaluated using NCTCAEv5 criteria. Results: The RRx-001 pre-treatment paradigm with four doses (“four before and no more”) dramatically reduced the incidence and duration of severe oral mucositis and associated grade 3-4 adverse events. These anti-toxicity effects translated to a shorter duration of hospitalization, less narcotic use, and less feeding tube placements. Extrapolating from cost estimates in the literature, we project a per patient total cost savings estimate of $12,500 - $22,500 with RRx-001 use based on an average 30% reduction in Grade 3-4 adverse events, a 50% reduction in hospital stay duration, and a 50% reduction in feeding tube placement. Conclusions: The RRx-001 “four before and no more” pre-treatment dosing regimen is not only convenient for patients and their caregivers but also reduces several toxicities including, most likely, financial toxicity. This is likely to bolster its adoption once RRx-001 becomes part of the medical armamentarium for the treatment of SOM. We plan more rigorously to test the effect of RRx-001 on financial toxicity in an upcoming Phase 2b trial in head and neck cancer called KEVLARx, n = 216. Clinical trial information: NCT03515538 .

PREVLAR: Phase 2a Randomized Trial to Assess the Safety and Efficacy of RRx-001 in the Attenuation of Oral Mucositis in Patients Receiving Head and Neck Chemoradiotherapy

No Food and Drug Administration-approved intervention exists for oral mucositis (OM) from chemoradiotherapy (CRT) used to treat head and neck cancers. RRx-001 is a hypoxia-activated, cysteine-directed molecule that affects key pathways involved in OM pathogenesis. This phase 2a, multi-institutional trial was designed to assess the safety and feasibility of 3 schedules of a fixed concentration of RRx-001; a standard-of-care arm was included to identify potential signals of efficacy for further study. This study enrolled patients with oral cavity and oropharynx squamous cell carcinoma receiving definitive or postoperative cisplatin-based CRT. Patients were randomized into 4 cohorts. In arms 1 to 3, RRx-001 was coinfused with patients' blood at differing intervals. Arm 4 was a control cohort of patients treated with CRT alone. Trained evaluators assessed OM using a standardized data collection instrument twice weekly during treatment and then until resolution. OM severity was scored centrally using World Health Organization criteria. Safety outcomes were assessed using National Cancer Institute - Common Terminology Criteriav4 benchmarks. Long-term tumor response was defined by Response evaluation criteria in solid tumors v1.1 criteria. Fifty-three patients were enrolled, with 46 and 45 individuals contributing safety and efficacy data, respectively. There were no severe adverse events attributed to the study drug. Across all 3 active arms, the study drug was infused fully per protocol in 86% of patients. All 3 RRx-001 treatment cohorts appeared to demonstrate a similar or lower OM duration relative to control; arm 1 had the lowest median duration of severe oral mucositis (SOM), 8.5 days versus 24 days in controls among patients who developed at least 1 day of SOM. There were no locoregional failures in any patient. Our results support the safety and feasibility of RRx-001 as an intervention to mitigate SOM. Additional studies are planned to confirm its efficacy.

Phase 2, randomized, double-blind trial of EC-18 versus placebo to mitigate the development and time course of oral mucositis from concomitant chemoradiation for head and neck cancer.

12106 Background: Oral mucositis (OM) is a debilitating side effect of concomitant chemoradiotherapy (CRT) for head and neck cancer (HNC). EC-18 may effectively mitigate OM by minimizing the CRT-induced innate immune response. This Phase II, 2-stage trial evaluated safety, tolerability, and efficacy of EC-18 in reducing the duration, incidence, and trajectory of severe OM (SOM) in HNC patients. Methods: Patients (n = 105) with pathologically confirmed oral cavity, oropharynx, hypopharynx, or nasopharynx squamous cell cancers who received intensity-modulated radiation therapy (IMRT; with ≥ 55 Gy on ≥ 2 oral sites) and weekly or tri-weekly cisplatin were studied. In Stage 1, 24 patients were randomized (n = 6 per arm) to receive 500, 1000, or 2000 mg of EC-18, or placebo. Following independent Data Safety Monitoring Board review, 81 patients in Stage 2 received EC-18 2000 mg (n = 41) or placebo (n = 40) throughout CRT. WHO OM grade was assessed twice weekly during IMRT and then once weekly for up to 6 weeks post-IMRT. The primary efficacy endpoint was duration of SOM during the active and short-term follow-up (STFU) periods in the compliant per-protocol population (PP). Much of Stage 2 was conducted during peak periods of the COVID-19 pandemic which measurably impacted patient compliance relative to test medication dosing and planned radiation. Consequently, to assess efficacy most accurately, the PP population was analyzed (with at least 4 weeks of study drug dosing, minimum cumulative radiation of 55 Gy, 80% study drug compliance in the first 28 days of dosing, and without using not-allowed-therapy). Results: Patient demographics and baseline characteristics were balanced between groups. Adverse events (AEs) were comparable amongst cohorts without drug-related severe AEs. In the PP, the median duration of SOM from baseline through STFU was 0 day in the EC-18 group (n = 22) v 13.5 days in the placebo group (n = 20). SOM incidence through STFU (45.5% v 70%) and opioid use (time to onset: 32.3 v 26.0 days; and duration: 32.8 v 37.5 days) favored EC-18 v placebo. Results of the covariates analyses suggested that EC-18 favorably impacted SOM incidence in patients who experienced SOM treated with weekly low-dose cisplatin (n = 26; 37.5% v placebo 70.0%) and HPV+ tumors (n = 29; 35.3% v placebo 66.7%; Table). One-year long-term follow-up for tumor outcomes is ongoing. Conclusions: EC-18 safely mitigated the development and the time course of SOM in CRT-treated HNC patients. In addition, EC-18 may provide substantial benefits to subpopulations of HPV+ HNC patients treated with low dose cisplatin. Clinical trial information: NCT03200340. [Table: see text]

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.

Pathogenesis and Amelioration of Radiation-Induced Oral Mucositis.

Oral mucositis (OM) causes significant detriment to patient quality of life. Despite advances in RT, chemotherapy, and surgery for HNC which have led to improved local control and survival, management of certain toxicities such as OM have not kept pace. Numerous strategies have emerged with demonstrable benefit in preventing severe OM. However, ones which are not only effective, but practical and affordable to implement are rare. For example, infusion of growth factors or free radical scavengers, and daily treatment of intra-oral sites with lasers are supported by high-quality evidence but have not become widely adopted. It falls to familiarity of the physician with the available preventative measures and ultimately, patient preference in accepting which strategies for OM amelioration are used. In this review, we present a pathophysiological-based review of prevention techniques available for reducing the incidence and duration of severe OM.

A Dose-Escalation Phase Ib International Study to Evaluate the Safety, Pharmacokinetics and Efficacy of ST-617 for the Attenuation of Oral Mucositis in Patients Receiving Chemoradiation for H&N Cancer

Oral Mucositis (OM) is a common, painful, and costly toxicity associated with cytotoxic chemoradiation regimens used to treat H&N cancer, which may interfere with planned treatment and negatively impact tumor control. There are currently no approved interventions to mitigate the incidence, severity or duration of OM. Oxidative stress is a critical event in OM's pathogenesis. Through its effect on Nrf2, ST-617 has marked anti-oxidative activity/properties. Supportive Therapeutics is developing ST-617, a dithioethione, for the attenuation of OM. The objective of this trial was to assess the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of ST-617 in patients at high risk of severe OM (SOM).A dose escalation trial was performed in which ST-617, administered as an oral suspension, 1-2 hours before the administration of daily RT fractions at 9 study sites in South Africa and Australia. Eighteen patients with diagnoses of oral or oropharyngeal CA were enrolled (up to 6 pts/dose). Patients received concomitant cisplatin either weekly or tri-weekly. ST-617 was administered 3 days prior to CRT, and then continuing daily concomitant with BSC (Best Supportive Care) until the end of treatment. Safety outcomes, using CTCAE criteria (v 4.03) were used. Dose escalation occurred in the absence of toxicity. OM occurrence and severity were assessed by trained and validated evaluators using WHO, NCI-CTC and RTOG criteria; scores were centrally assigned. The primary efficacy endpoints included the incidence and duration of SOM (WHO grades 3 or 4) vs historical controls. PD tracking measured total ROS/RNS, GSH/GSSG, regulation in plasma and buccal epithelial cells.17 pts completed the 50, 100 and 150mg/day with no safety issues. No early dose limiting toxicity (DLT) or serious Adverse Event linked to ST-617 were observed. AEs observed were mainly nausea which is usually associated with CRT as expected. As overall SOM incidence (baseline to the last day of radiation) of 50% was less than expected and was related to ST-617 dose: 50 mg/day 83% (n = 6); 100 mg/day 33% (n = 9); 200 mg/day 33% (n = 3). The 100 mg/day dose was well tolerated with no grade 4 OM. No CRT dose interruptions or delays due to OM were noted Total ROS/RNS levels in plasma and buccal samples show significant decrease with increased ST-617 dosing from 50 to 100 mg/day. ST-617 did not alter tumor response at 1 year post-CRT (n = 17).ST-617 administration was safe at all doses tested. The course and severity of patients treated with ST-617 compared favorably with historical controls. A dose-response effect on SOM incidence was noted. Mechanistic correlation between ROS/RNS levels was seen. A randomized, controlled, double blind trial is planned with the recommended dose of 100mg/day.

A Prospective Cohort Study Comparing Long-Term Outcomes with and without Palifermin in Patients Receiving Hematopoietic Cell Transplantation for Hematologic Malignancies

The incidence of debilitating oral mucositis (OM) can be as high as 99% after myeloablative conditioning regimens preparing patients with hematologic malignancies for hematopoietic cell transplantation (HCT). Palifermin (KGF) is a recombinant human keratinocyte growth factor that reduces the incidence and duration of severe OM. The long-term safety of KGF has not been well established, however. In this long-term prospective matched-cohort study, patients who received KGF (cases) and underwent autologous or allogeneic HCT for hematologic malignancies between 2006 and 2013 were matched 1:1 to patients who did not receive KGF (controls). The primary outcome was overall survival (OS). Other outcomes were disease relapse, new malignancies, pancreatitis, renal failure requiring dialysis, pulmonary complications, cataract surgery, and acute and chronic graft-versus-host disease (GVHD). The analysis population comprised 2191 matched pairs with a wide range of diseases and donor types that received diverse conditioning and GVHD preventive regimens, representing contemporary practice patterns. The median duration of follow-up was 8 years (range, 1 to 12.5 years). In multivariate analyses, the probabilities of OS (relative risk [RR], 1.01; 95% confidence interval [CI], 0.91 to 1.12), relapse (RR, 1.06; 95% CI, 0.94 to 1.18), new malignancies (RR, 0.89; 95% CI, 0.67 to 1.18), and cataract surgery (RR, 1.05; 95% CI, 0.74 to 1.50) were not statistically significantly different between cases and controls. In univariate analyses, no increased risks were observed for renal failure requiring dialysis, pancreatitis, acute GVHD, chronic GVHD, interstitial pneumonitis/acute respiratory distress syndrome/idiopathic pneumonia syndrome, or bronchiolitis obliterans/cryptogenic organizing pneumonia/bronchiolitis obliterans organizing pneumonia among cases compared with controls. This long-term prospective safety cohort study demonstrates that the KGF group had no increased risk of overall mortality, relapse, new malignancies, or any other key outcome. The broad inclusion criteria allow the results to be generalized to contemporary practice for patients with a wide range of diseases and receiving a wide range of HCT conditioning regimens and graft sources from diverse donor types.

Phase Ib, international, dose-escalation study to evaluate the safety, pharmacokinetics (PK) and efficacy of ST-617 for the attenuation of oral mucositis (OM) in patients receiving chemoradiation (CRT) for head and neck (H&N) cancer.

6075 Background: OM is a common, painful, and costly toxicity associated with cytotoxic regimens used to treat H&N cancers, which may result in radiotherapy treatment interruptions to negatively impact tumor control. There are currently no approved interventions to successfully prevent or delay OM onset among patients being treated with radiation therapy, with or without concomitant chemotherapy (CRT). Oxidative stress is a critical event in OM’s pathogenesis. Through its effect on Nrf2, ST-617 has marked anti-oxidative activity/properties. Supportive Therapeutics is developing ST-617, a dithioethione, for the attenuation of OM onset, duration and severity. The objective of this trial was to assess the safety, tolerability, PK, PD and efficacy of ST-617 in patients at high risk of severe OM (SOM). Methods: A dose escalation trial in which ST-617 administered as an oral suspension, 1-2 hours before the administration of daily RT fractions was performed at 9 study sites in South Africa and Australia. Eighteen patients with diagnoses of oral or oropharyngeal CA were enrolled (up to 6 pts/dose). Patients received concomitant cisplatin either weekly or tri-weekly. ST-617 was administered 3 days prior to CRT, and then continuing daily until the end of treatment. Safety outcomes, using CTCAE criteria (v 4.03) were used. Dose escalation occurred in the absence of toxicity. OM occurrence and severity were assessed by trained and validated evaluators using WHO, NCI-CTC and RTOG criteria; scores were centrally assigned. The primary efficacy endpoints included the incidence and duration of SOM (WHO grades 3 or 4) vs historical controls. PD tracking measured total ROS/RNS, GSH/GSSG, regulation in plasma and buccal epithelial cells. Results: 17 pts completed the 50, 100 and 150mg/day with no safety issues. No early dose limiting toxicity (DLT) or serious Adverse Event linked to ST-617 were observed. AEs observed were mainly nausea which is usually associated with CRT as expected. The 100 mg/day dose has been well tolerated with no grade 4 OM. No CRT dose interruptions or delays due to OM has been observed. Total ROS/RNS levels in plasma and buccal samples show significant decrease with increased ST-617 dosing from 50 to 100 mg/day. Conclusions: ST-617 administration was safe at all doses tested. The course and severity of patients treated with ST-617 compared favorably with historical controls. Mechanistic correlation between ROS/RNS levels was seen. A randomized, controlled, double blind trial is planned with the recommended dose of 100mg/day. Clinical trial information: 20180138.

Integrated oral care contributes positively to the course of treatment of oncopediatric patients.

The purpose of this study was to implement a model of permanent oral health care for oncopediatric patients and to observe its effects on severe oral mucositis and subsequent treatment interruptions. We performed a quasi-experimental study in the Pediatric Department of Napoleão Laureano Hospital, in the city of João Pessoa, Brazil. A integrated oral care was implemented by a dentistry team for prevention of comorbidities, such as infections, oral pain, oral function maintenance, oral mucositis, and interventions for lesions due to severe oral mucositis. The oral comorbidities were compared before and after the implementation. The duration of severe oral mucositis (SOM) before and after the interventions and the interruptions in treatment due to SOM were the main outcome measures. Permanent oral health care reduced the duration of SOM and reduced pediatric chemotherapy interruptions due to SOM by 81.8%.Conclusion: The permanent oral health care to offer to oncopediatric patients increased surveillance regarding oral comorbidities and reduced chemotherapy interruptions due to severe oral mucositis. This care plan could be adopted anywhere around the world. What is Known: • Several studies on oral care for pediatric oncology patients, especially regarding both prevention of and treatment for oral mucositis during antineoplastic therapy, have been published. What is New: • This study describes the benefits of permanent oral care with daily oral surveillance for pediatric patients, which reduced the duration of severe oral mucositis, increased surveillance and the efficiency in diagnostic for signs of oral mucositis, enabling early intervention, and decreased chemotherapy interruptions, contributing positively to the course of treatment.

Superoxide Dismutase as an Intervention for Radiation Therapy-Associated Toxicities: Review and Profile of Avasopasem Manganese as a Treatment Option for Radiation-Induced Mucositis.

Toxicities associated with radiation therapy are common, symptomatically devastating, and costly. The best chance to effectively mitigate radiation-associated normal tissue side effects are interventions aimed at disrupting the biological cascade, which is the basis for toxicity development, while simultaneously not reducing the beneficial impact of radiation on tumor. Oxidative stress is a key initiator of radiation-associated normal tissue injury as physiologic antioxidant mechanisms are overwhelmed by the accumulation of effects produced by fractionated treatment regimens. And fundamental to this is the generation of superoxide, which is normally removed by superoxide dismutases (SODs). Attempts to supplement the activity of endogenous SOD to prevent radiation-induced normal tissue injury have included the administration of bovine-derived SOD and increasing SOD production using gene transfer, neither of which has resulted in a clinically acceptable therapy. A third approach has been to develop synthetic small molecule dismutase mimetics. This approach has led to the creation and development of avasopasem manganese, a unique and specific dismutase mimetic that, in clinical trials, has shown promising potential to reduce the incidence, severity and duration of severe oral mucositis amongst patients being treated with concomitant chemoradiation for cancers of the head and neck. Further, avasopasem and related analogues have demonstrated mechanism-related antitumor synergy in combination with high dose per fraction radiotherapy, an observation that is also being tested in clinical trials. An ongoing Phase 3 trial seeks to confirm avasopasem manganese as an effective intervention for severe oral mucositis associated with chemoradiation in head and neck cancer patients.

Results of a Randomized, Open Label, Multicenter Trial Assessing the Safety, Dose and Schedule of RRx-001 (R001) in Reducing Severe Oral Mucositis (SOM) in Patients Receiving Chemoradiation (CRT) for Oral Cavity/oropharynx Squamous Cell Carcinoma (OSCC)

Severe oral mucositis (SOM, assessed WHO grade 3 or 4) occurs in up to 70% of patients receiving CRT for OSCC, many of whom require enteral nutrition or experience treatment interruption. Pharmacological targeting of nuclear factor erythroid related factor (Nrf2) represents an opportunity to mitigate radiation-associated toxicities mediated by oxidative species (OS). Preclinical studies demonstrate R001 activates Nrf2, a key regulator of gene expression encoding antioxidant, phase II detoxifying enzymes, and downstream Antioxidant Response Element signaling pathways. Activation of Nrf2 increases the threshold and buffering capacity of OS generated by CRT, and its multi-target activity provides a counterbalance to oxidative stress resulting in focal and systemic radioprotection. This proof of concept Phase 2a randomized clinical trial examined the safety, efficacy and schedule-dependent effects of R001 in reducing the incidence, severity and duration of SOM. Patients with OSCC treated with definitive or postoperative CRT were randomized to one of 4 treatment arms: 2 doses/week for 2 weeks before (pre) CRT (Arm 1); pre-CRT plus 2 doses or pre-CRT plus 6 weekly doses during CRT (Arm 2, 3 respectively); or standard of care (SOC) (Arm 4). The primary endpoint was duration of SOM through resolution < grade 2. Secondary endpoints included safety, time to onset, incidence, and duration of SOM and grade 4 mucositis through 60 and 70 Gy. Between June 2018 and July 2019 across 11 institutions, 53 patients were randomized, with 45 evaluable. Short 15-minute infusions of R001 were well tolerated with no associated serious adverse events (SAE). Side effects were comparable to SOC. Trends in treatment benefits for all endpoints were consistent across the 3 treatment arms, with the greatest effect size in Arm 1. R001 delayed time to onset (38 vs. 26 days) and duration of SOM (22 vs. 40 days), with 83% having resolution vs 60% with SOC, respectively. No patients developed grade 4 mucositis vs 30% SOC arm. A 95% decrease in duration of SOM (1 vs 17 days) through 60 Gy was also observed. Gastrostomy requirement was reduced by 45% (33% vs 60%). In this small open-label trial, R001 demonstrated a favorable benefit-risk profile with a markedly decreased incidence and duration of SOM through 60 Gy, 70 Gy and follow-up post CRT. Treatment effect was greatest in Arm 1 suggesting short periods of Nrf2 activation prior to generation of OS by CRT may be sufficient to increase the threshold and buffering capacity of antioxidants. Larger, blinded trials, confirming the observed dose, schedule and treatment effect are planned.

Results of a randomized, open-label, multicenter trial to assess the safety, dose, and schedule ofRRx-001(001) in reducing incidence, severity and duration of severe oral mucositis (SOM) inpatients receiving concomitant chemoradiation (CRT) for advanced head and neck cancer (HNC).

12081 Background: SOM occurs in 70% of patients receiving CRT for HNC with consequent pain, treatment interruptions and increased costs of care. Supraphysiologic levels of oxidative stress are key SOM initiators. 001 activates nuclear factor erythroid related factor 2 (Nrf2) increasing expression of multiple antioxidant genes including superoxide dismutase glutathione peroxidase and glutathione S-transferase. This trial examined the effect of dose and schedule on safety and efficacy of 001. Primary efficacy endpoint was duration of SOM (WHO criteria assessed); secondary endpoints included time to onset, incidence grade 4 through 60Gy and 70Gy. Methods: Locally advanced HNC treated with definitive or postoperative CRT (cisplatin + RT) received one of 3 001 schedules: (ARM1) 2 doses/wk for 2 weeks (prior to) CRT. ARMS 2, 3: prior to + 2 doses or 6 doses with CRT respectively or standard of care (SOC). Results: 53 patients randomized, 45 evaluable. Benefit trends for endpoints were consistent across all 3 001 arms with greatest effect size in pre-treatment only, ARM1. Compared to SOC, 001 reduced duration of SOM by 45% (40 vs 22 days). Through 60Gy and 70Gy a reduction of 95% and 79% in duration SOM was also observed (17 vs 1 day, and 23 vs 5 days) respectively. No patients in ARM1 developed grade 4, (0% vs SOC 30%). Side effects were comparable to SOC. Conclusions: In this small, open label trial, 001 demonstrated a favorable risk-benefit profile supported by reductions in overall SOM duration including through 60Gy and 70Gy with no grade ARM1 was most effective suggesting short periods of Nrf2 activation before CRT oxidative stress generation may increase the threshold and buffering capacity of upregulated antioxidants. Larger, blinded trials, confirming the observed dose, schedule and treatment effects are warranted. Clinical trial information: NCT03515538 .

Efficacy and safety of Dentoxol\xae in the prevention of radiation-induced oral mucositis in head and neck cancer patients (ESDOM): a randomized, multicenter, double-blind, placebo-controlled, phase II trial

PurposeThe aim of this study was to assess the efficacy and safety of Dentoxol mouthrinse in reducing the severity of oral mucositis (OM) secondary to radiation therapy (RT) for head and neck cancer.MethodsA randomized, double-blind, placebo-controlled, multicenter phase II clinical trial was conducted. Subjects were asked to use Dentoxol (n = 55) or control (n = 53) mouthrinse 5 times/day during RT. Twice a week, OM was assessed clinically using the WHO scale and the Oral Mucositis Daily Questionnaire (OMDQ) was completed.ResultsThe incidence of severe OM was 40.7% in the Dentoxol group and 51% in the control group (p = 0.265). Comparing all recorded clinical assessments, severe OM was seen in 13.3% of all assessments in the Dentoxol group vs. 21.8% in the control group (p = 0.000). There was a statistically significant lower proportion of assessments showing severe OM in the Dentoxol group at weeks 4, 5, and 6 of RT. The mean duration of severe OM was 11.95 days in the Dentoxol group vs. 14.59 days in the control group (p = 0.502). There was no difference between groups in mouth pain and its impact on function. The use of Dentoxol was safe and was not linked to any serious adverse events.ConclusionThe use of Dentoxol 5 times/day is safe and resulted in significantly fewer time-points with severe OM and a delay in the onset of severe OM, compared with a control rinse. A phase III clinical trial is warranted to confirm efficacy and address the limitations of this study.

Factors Contributing to the Duration of Chemotherapy-Induced Severe Oral Mucositis in Oncopediatric Patients.

This study analyzes the factors contributing to the duration of severe oral mucositis in oncopediatric patients. A longitudinal study was conducted in the pediatric department of a cancer referral hospital between 2013 and 2017. Seventy-three patients diagnosed with cancer undergoing chemotherapy protocols were analyzed. Oral evaluations were performed using the Modified Oral Assessment Guide criteria, and the data were collected from the patients’ records. The Kaplan-Meier method was used to estimate survival curves. Most patients were males (52.1%), of mixed race (“pardo”) (49.3%), with a mean age of 7.56 years (±5.34). There was a predominance of patients diagnosed with solid tumors (52.1%), with no metastasis (86.3%), using natural product chemotherapeutics (56.2%), who had not undergone a bone marrow transplant (97.3%); amputation was observed in 35.6% of patients, while death rates were as high as 8.2%. The survival analysis estimated a mean time of 30.6 days until complete remission of severe oral mucositis. The regression analysis showed that patients over 10 years old had a median mucositis duration 1.4 times greater than those at the age of 10 years or younger. Patients without metastasis had a median mucositis duration 1.7 times greater than those with metastasis (p-value ≤ 0.10). Increasing age and the absence of metastasis were conditions that prolonged the duration of severe oral mucositis.

Caphosol for prevention of oral mucositis in pediatric myeloablative haematopoietic cell transplantation

Background:The primary objective was to determine whether topically administered Caphosol, rinsed orally four times daily at the initiation of conditioning, reduces the duration of severe oral mucositis (OM) compared with placebo among children and adolescents undergoing haematopoietic cell transplantation (HCT).Methods:This was a Children’s Oncology Group multicentre randomised double-blinded placebo-controlled clinical trial. Patients between the ages of 4 and 21 years who were scheduled to undergo myeloablative HCT for any indication were randomised to Caphosol or placebo saline rinses four times daily from initiation of conditioning through day +20. Subjects were assessed daily for OM using the World Health Organisation (WHO) Oral Toxicity Scale, Mouth Pain Categorical Scale (0–10) and the Oral Mucositis Daily Questionnaire (OMDQ). The primary end point was duration of severe OM (WHO ⩾3).Results:The study enrolled 220 participants with a median age of 13.7 years (range 4.0–21.9); 163 (74%) received allogeneic HCT. The mean (±s.d.) duration of severe OM was not reduced among Caphosol (4.5±5.0 days) vs placebo (4.5±4.8; P=0.99) recipients. The incidence of severe OM in the Caphosol and placebo arms was 63% (57 out of 91) and 68% (62 out of 91), respectively (P=0.44). There were no significant differences in any of the secondary end points between the groups.Conclusions:Caphosol did not reduce severe OM when compared with placebo among children and adolescents undergoing myeloablative HCT. Studies to identify effective interventions for OM are needed in this population.

A randomised controlled trial of Caphosol mouthwash in management of radiation-induced mucositis in head and neck cancer

PurposeThis phase III, non-blinded, parallel-group, randomised controlled study evaluated the efficacy of Caphosol mouthwash in the management of radiation-induced oral mucositis (OM) in patients with head and neck cancer (HNC) undergoing radical (chemo)radiotherapy. Patients and methodsEligible patients were randomised at 1:1 to Caphosol plus standard oral care (intervention) or standard oral care alone (control), stratified by radiotherapy technique and use of concomitant chemotherapy. Patients in the intervention arm used Caphosol for 7weeks: 6weeks during and 1-week post-radiotherapy. The primary endpoint was the incidence of severe OM (CTCAE ⩾grade 3) during and up to week 8 post-radiotherapy. Secondary endpoints include pharyngeal mucositis, dysphagia, pain and quality of life. ResultsThe intervention (n=108) and control (n=107) arms were well balanced in terms of patient demographics and treatment characteristics. Following exclusion of patients with missing data, 210 patients were available for analysis. The incidence of severe OM did not differ between the intervention and control arms (64.1% versus 65.4%, p=0.839). Similarly, no significant benefit was observed for other secondary endpoints. Overall, compliance with the recommended frequency of Caphosol was low. ConclusionCaphosol did not reduce the incidence or duration of severe OM during and after radiotherapy in HNC.

Safety, Pharmacokinetics, and Efficacy of Palifermin in Children and Adolescents with Acute Leukemias Undergoing Myeloablative Therapy and Allogeneic Hematopoietic Stem Cell Transplantation: A Pediatric Blood and Marrow Transplant Consortium Trial

Currently, effective pharmacologic treatment to reduce severe oral mucositis (OM) resulting from high-dose myeloablative cytotoxic therapy in the pediatric population is not available. Palifermin has been proven to decrease the incidence and duration of severe OM in adults with hematologic malignancies undergoing hematopoietic stem cell transplantation (HSCT). In the pediatric population, however, data on palifermin treatment are limited. A phase I dose-escalation study of palifermin in pediatric patients with acute leukemias undergoing myeloablative HSCT with total body irradiation, etoposide, and cyclophosphamide was performed to determine a safe and tolerable dose and to characterize the pharmacokinetic (PK) profile and efficacy of palifermin. Twenty-seven patients in 3 age groups (1 to 2, 3 to 11, and 12 to 16 years) and 3 dose levels (40, 60, and 80 μg/kg/day) were studied. There were no deaths, dose-limiting toxicities, or treatment-related serious adverse events. Long-term safety outcomes did not differ from what would be expected in this population. PK data showed no differences between the 3 age groups. Exposure did not increase with increase in dose. The maximum severity of OM (WHO grade 4) occurred in 6 patients (22%), none of whom was in the 80-μg/kg/day dosing group. This study showed that all doses were well tolerated and a good safety profile in all 3 pediatric age groups was seen.

Low level laser therapy against radiation induced oral mucositis in elderly head and neck cancer patients-a randomized placebo controlled trial

ObjectivesRadiotherapy (RT) is treatment of choice for Elderly Head and Neck Cancer (HNC) patients. Oral mucositis (OM) during RT affects patient’s routine oral activities and overall health. Low Level Laser Therapy (LLLT) provided some promising results against cancer therapy induced OM in children and adults. No study specifically evaluated effects of LLLT against RT induced OM in elderly HNC patients until date, hence we did this study. Material and methodsThis double blinded study randomized 46 elderly HNC patients scheduled for RT [Dosage=66 Gray (2Gy/fraction), 5 fractions/week, total 33 fractions for 6.5weeks], into laser (22) and placebo (24) groups. Laser group patients received LLLT [Helium–Neon, λ=632.8nm, power density=0.024W/cm2, dosage=3.0J/point at six anatomical sites bilaterally i.e. 12 locations, total dose/session=36J, beam aperture diameter=0.6mm, beam spot size=1cm2, irradiated area diameter=1cm2, irradiation time/point=125s, 5 sessions/week, non-contact method-distance between probe and irradiated tissues <1cm, whereas placebo group did not receive laser. OM grades (RTOG/EORTC Scale), oral pain, weight loss, need for morphine analgesics and tube feeding, and RT break were recorded by a blinded assessor. Descriptive statistics and repeated measures ANOVA were used for analysis keeping p<0.05. ResultsSignificant reduction in the incidence and duration of severe OM (p=0.016) and severe pain (p=0.023) and weight loss (p=0.004) was observed in laser than placebo group. No difference was found for enteral feeding use (p=0.667) between two groups. ConclusionsLLLT decreased the severity of OM and oral pain in elderly HNC patients. Also, lesser weight loss, morphine analgesic use and radiation break happened in laser group.

Cloning and Expression of Human Keratinocyte Growth Factor in Escherichia coli for Recombinant Drug Production

Background: Keratinocyte growth factor (KGF) is a member of fibroblast growth factor (FGF) family which induces proliferation and differentiation in a wide variety of epithelial tissues. KGF plays an important role in protection, repair of various types of epithelial cells, and re-epithelialization of wounds. Therefore, in patients with hematologic malignancies receiving high doses of chemotherapy and radiotherapy, treatment with KGF decreases the incidence and duration of severe oral mucositis. Objectives: The aim of this study was to express the recombinant form of human keratinocyte growth factor in Escherichia coli. Materials and Methods: KGF gene was amplified by PCR and cloned into the expression vector pET28a(+). The recombinant vectors were transformed into E. coli BL21(DE3) as expression host and expression of the desired protein was induced by IPTG. The expression was evaluated at RNA and protein levels by reverse transcriptase PCR (RT-PCR) and SDS-PAGE analyses, respectively and the expressed protein was confirmed through western blotting. Results: Cloning was confirmed by PCR and restriction digestion. RT-PCR and SDS-PAGE represented expression of KGF in E. coli. The optimized expression was achieved 16 hours after induction with 0.3 mM IPTG at 37°C in luria broth (LB) containing kanamycin. The 18 kDa protein was confirmed by western blotting, using anti-His antibodies. Conclusions: The result of the present study indicated that E. coli expression system was suitable for overexpression of recombinant human KGF and the expressed protein can be considered as a homemade product.

Palifermin For Prevention Of Oral Mucositis Has No Negative Effect On Long-Term Outcome In Patients With Hematological Malignancies Undergoing HSCT - Long-Term Follow-Up To 15 Years

Background Palifermin has been shown to reduce the incidence and duration of severe oral mucositis in hematological stem cell transplantation (HSCT) recipients. A follow-up study was performed to rule out a potential long-term safety risk of palifermin use. Objectives to compare long-term disease outcome (overall survival, disease progression and incidence of secondary malignancies) between palifermin and placebo. Methods This is a long-term follow-up study of patients with hematological malignancies undergoing HSCT and treated with palifermin or placebo to prevent oral mucositis. The aim of the study was to detail any potential late complications due to palifermin exposure. Patients were enrolled between 1997-2003 into four randomized, placebo-controlled phase II/III studies conducted at 31 sites in Australia, Europe and the US. The survival outcomes were compared using hazard ratios (HRs) estimated with Cox model including the treatment group, baseline age, disease type (Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, leukemia), ECOG performance status, country and presence of prior radiotherapy as covariates. The incidence of secondary malignancies was compared with chi-squared test. Results A total of 672 patients were randomized to the parent studies (429 palifermin, 243 placebo) and 543 (345, 198) were enrolled to the long-term follow-up. The median follow-up time for subjects alive was 7.9 years (range 0.1-14.9) for palifermin and 8.8 (0.1-14.8) for placebo. No significant differences were seen for either overall survival (HR = 1.01; 95% confidence interval (CI) 0.78-1.31; p=0.921) or progression-free survival (HR=1.04; 95% CI 0.83-1.31; p=0.733). Secondary malignancies were reported by 13% (palifermin) vs. 11% (placebo) of the patients (p=0.477). The most common secondary malignancies were acute myeloid leukemia/myelodysplastic syndrome (5% vs. 5%) and skin cancers (2% vs. 2%). Conclusion The overall survival, progression-free survival, and the incidence of secondary malignancies were comparable between palifermin and placebo in patients undergoing HSCT. After a follow-up of up to 15 years, no negative effect of palifermin on long-term outcomes was observed. Disclosures: No relevant conflicts of interest to declare.