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.

Abstract

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.

• Authors: Carryn M Anderson, Christopher M Lee, Deborah P Saunders, Amarinthia Curtis, Neal Dunlap, Chaitali Nangia, Arielle S Lee, Sharon M Gordon, Philip Kovoor, Roberto Arevalo-Araujo, Voichita Bar-Ad, Abhinand Peddada, Kyle Colvett, Douglas Miller, Anshu K Jain, James Wheeler, Dukagjin Blakaj, Marcelo Bonomi, Sanjiv S Agarwala, Madhur Garg, Francis Worden, Jon Holmlund, Jeffrey M Brill, Matt Downs, Stephen T Sonis, Sanford Katz, John M Buatti
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 37 Issue 34 Pg. 3256-3265 (12 01 2019) ISSN: 1527-7755 [Electronic] United States
• PMID: 31618127 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Organometallic Compounds
• Radiation-Protective Agents
• avasopasem manganese
• Cisplatin

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects)
• Chemoradiotherapy (adverse effects)
• Chemoradiotherapy, Adjuvant (adverse effects)
• Cisplatin (administration & dosage, adverse effects)
• Double-Blind Method
• Female
• Humans
• Incidence
• Male
• Middle Aged
• Mouth Neoplasms (drug therapy, epidemiology, pathology)
• Ontario
• Organometallic Compounds (therapeutic use)
• Oropharyngeal Neoplasms (drug therapy, epidemiology, pathology)
• Radiation Injuries (diagnosis, epidemiology, prevention & control)
• Radiation-Protective Agents (adverse effects, therapeutic use)
• Radiotherapy, Intensity-Modulated (adverse effects)
• Risk Factors
• Severity of Illness Index
• Stomatitis (diagnosis, epidemiology, prevention & control)
• Time Factors
• Treatment Outcome
• United States