Two-Year Tumor Outcomes of a Phase 2B, Randomized, Double-Blind Trial of Avasopasem Manganese (GC4419) Versus Placebo to Reduce Severe Oral Mucositis Owing to Concurrent Radiation Therapy and Cisplatin for Head and Neck Cancer.

PURPOSE: Avasopasem manganese (GC4419), an investigational selective dismutase mimetic radioprotector, reduced duration, incidence, and severity of severe oral mucositis (World Health Organization grade 3-4) in a phase 2b, randomized, double-blind trial of patients receiving concurrent cisplatin (cis) and radiation therapy (RT) for head and neck cancer. We report the secondary endpoints of final 1- and 2-year tumor outcomes and exploratory data on trismus and xerostomia. METHODS AND MATERIALS: Patients with locally advanced oral cavity or oropharynx cancer to be treated with definitive or postop cis and RT were randomized to 1 of 3 arms: 30 mg avasopasem, 90 mg avasopasem, or placebo. Pairwise comparisons of Kaplan-Meier estimates (each active arm separately vs placebo) were made for overall survival, progression-free survival, locoregional control, and distant metastasis-free survival. Xerostomia and trismus data were collected at each follow-up visit and analyzed for trends by post-RT timepoint and treatment group. RESULTS: At a median follow-up for the entire cohort of 25.5 months (25th-75th percentile, 24.6-26.2 months; range, 0.2-31.9 months), Kaplan-Meier estimates of 1- and 2-year overall survival, progression-free survival, locoregional control, and distant metastasis-free survival were not statistically different. No trends were apparent in xerostomia or trismus data. CONCLUSIONS: Avasopasem does not lead to statistically different tumor control outcomes when used concurrently with cis and RT for head and neck cancer. There was no detectable effect on trismus or xerostomia.

Is levoleucovorin an alternative to racemic leucovorin? A literature review.

PURPOSE: Our purpose is to perform a comprehensive literature review of the use of levoleucovorin in gastrointestinal malignancies and to assess whether levoleucovorin is a reasonable alternative to racemic leucovorin. DESIGN: This is an extensive literature review of levoleucovorin use in patients with gastrointestinal tract malignancies. Our review revealed 125 citations with abstracts in the English language, including 16 randomized, controlled trials; 40 case studies; and 69 nonrandomized, controlled trials that included 6 pharmacokinetic (PK)/pharmacodynamic studies with 1 population PK study. RESULTS: Upon our review, there were 2 randomized controlled trials that directly compared racemic leucovorin with levoleucovorin. Goldberg et al noted that there was no statistically significant difference between time to progression (P = .78) and time to death (P = .57). Furthermore, Scheithauer et al again noted no significant difference in terms of response rates (25% vs. 32%; P = .25), median survival time (15 months vs. 14.5 months; P = .28), overall survival at 1 year (58.3% vs. 60.6%; P = .72), and probability of survival at 2 years (15.3% vs. 23%; P = .16). In addition, multiple other studies, including randomized, controlled; nonrandomized, controlled; and case studies, demonstrate similar efficacy and tolerability between the use of racemic leucovorin or levoleucovorin as a modulator of 5-FU. CONCLUSION: In many studies of patients with gastrointestinal malignancies, levoleucovorin has been used interchangeably and solely for racemic leucovorin for 5-FU modulation. Our literature review demonstrates that levoleucovorin has similar efficacy and tolerability when compared with racemic leucovorin, whether used in combination with other chemotherapeutic agents or alone.

Phase IIb, Randomized, Double-Blind Trial of GC4419 Versus Placebo to Reduce Severe Oral Mucositis Due to Concurrent Radiotherapy and Cisplatin For Head and Neck Cancer.

PURPOSE: Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM). PATIENTS AND METHODS: A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading. RESULTS: Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced (P = .024; median, 1.5 v 19 days). SOM incidence (43% v 65%; P = .009) and severity (grade 4 incidence, 16% v 30%; P = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing. CONCLUSION: GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety. A phase III trial (ROMAN; ClinicalTrials.gov identifier: NCT03689712) has begun.

Treatment of resectable gastric cancer: current standards of care.

Gastric cancer is the second leading cause of cancer death worldwide. The local surgical treatment of gastric cancer varies geographically. However, there has been a confluence of opinion regarding the optimal therapy of gastric cancer toward multimodality therapy. In the East, many clinicians pursue adjuvant chemotherapy after a D2 resection. However, in the West, clinicians use either perioperative chemotherapy or postoperative chemoradiation. It remains unclear at this time whether either perioperative approach is the optimal approach.