Carryn Anderson, MD

GC4419, A SMALL molecule superoxide dismutase mimetic, reduced the duration, incidence, and severity of chemoradiotherapy-induced mucositis in patients with locally advanced head and neck cancer, with a safety profile comparable to that of placebo. This finding comes from a randomized phase IIb trial, presented by Carryn Anderson, MD, of the University of Iowa Hospitals and Clinics, Iowa City, and colleagues, at the 2018 Multinational Association of Supportive Care in Cancer (MASCC)/ International Society of Oral Oncology (ISOO) Annual Meeting.¹ Based on these results, Breakthrough Therapy designation was granted by the U.S. Food and Drug Administration. GC4419 was previously granted Fast Track designation. 

Intensity-modulated radiation therapy plus cisplatin is the standard of care for patients with locally advanced oral cavity/ oropharyngeal cancer. Approximately 70% of patients develop severe oral mucositis, defined by the World Health Organization (WHO) as grade 3 (mucositis so severe a patient requires a liquid diet) or grade 4 (patient is dependent on a feeding tube). It typically occurs at median onset of approximately 40 Gy of radiation, or approximately 4 weeks into radiation therapy, with a median duration of about 3 to 4 weeks. 

The primary endpoint of this study was to determine whether GC4419 could reduce the duration of severe oral mucositis. Secondary endpoints evaluated the incidence of severe (grade 3 or 4) oral mucositis. 

“GC4419 at a 90-mg dose provides a clinically meaningful reduction in severe oral mucositis duration, incidence, and severity.”

— Carryn Anderson, MD

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Mechanistic Rationale Behind GC4419 

RADIATION INDUCES a large burst of superoxide at a cellular level, and superoxide is a key initiator of radiation-induced mucosal injury. GC4419 acts to rapidly convert superoxide to hydrogen peroxide, thereby blocking the initial step in the development of oral mucositis. 

Secondary enzymes in normal tissues convert the hydrogen peroxide to oxygen and water, thus sparing normal tissues from the toxicity of the superoxide. “These secondary enzymes are often deficient in many cancer cell lines, including head and neck cancers,” Dr. Anderson explained. “This buildup of hydrogen peroxide leads to a cellular environment that is toxic to malignant cells but spares normal cells.” 

Study Design 

DR. ANDERSON and her colleagues recently published phase Ib/ IIa clinical results² and established that GC4419 (at doses of 30 mg and 90 mg) required further study. The data also demonstrated an acceptable safety profile for the drug, with no adverse impact on 1-year tumor outcomes. 

The phase IIb trial included 223 patients at 44 sites in the United States and Canada. Patients had locally advanced oral cavity/ oropharyngeal carcinoma and were receiving definitive or postoperative intensity-modulated radiation therapy with concurrent cisplatin on a weekly or every-3-week schedule. 

“Each patient had to have at least two visible oral sites that received at least 50 Gy or more during their radiation course,” she noted. GC4419 was delivered via 60-minute intravenous infusions prior to every radiation treatment (5×/week), ending less than 60 minutes prior to radiation delivery.

Patients were stratified by tumor human papillomavirus (HPV) status and cisplatin schedule; they were randomized to receive 90 mg of GC4419 (n = 76), 30 mg of GC4419 (n = 73), or placebo (n = 74) over a course of 7 weeks. The majority of patients had HPV-positive oropharyngeal squamous cell carcinoma and were receiving definitive concurrent radiation therapy with weekly cisplatin. 

Between 85% and 95% of the population had 3 or more visible oral sites, and nearly 40% had 5 or more visible sites. “These were heavily treated patients,” she noted. “We were expecting to see [ulcers].” 

Trained evaluators assessed WHO-grade oral mucositis twice weekly during the radiation course and once weekly after completion of radiation therapy, until the ulcers resolved. Radiation treatment breaks exceeding 5 consecutive days were few in all 3 arms, and cisplatin was well tolerated concurrently with GC4419. 

Over 90% Reduction in Duration of Mucositis 

THE DURATION OF severe oral mucositis was reduced in the full study population: patients in the placebo arm had a 19-day median duration of severe oral mucositis, compared with 1.5 days in patients who received GC4419 at the 90-mg dose, a 92% relative reduction (P = .024). (Patients who never developed severe oral mucositis were assigned a duration of 0 days in this analysis.) Patients who received the 90-mg dose had a reduced incidence of both severe (grade 3 or 4) oral mucositis (43% vs 65%; P = .009) and grade 4 mucositis (16% vs 30%; P = .045), compared to placebo. The time to onset of severe oral mucositis was longer (median 61 vs 39 days) at 90 mg vs placebo). Intermediate improvements were seen with the 30-mg dose. 

Safety was comparable across all three arms, and “expected” events with GC4419 (ie, hypotension and oral/facial paresthesia) were mild and transient, usually resolving within 1 hour of infusion discontinuation. 

“GC4419 at a 90-mg dose provides a clinically meaningful reduction in severe oral mucositis duration, incidence, and severity,” Dr. Anderson reported. “Future analyses will include tumor control (through 2 years postradiation) and exploratory cytokine correlates.” 

A phase III randomized trial of the 90-mg dose of GC4419 vs placebo is being planned. 

Exploratory Results 

THE DURATION and incidence of severe oral mucositis were not affected by the cisplatin schedule, tumor HPV status, definitive vs postoperative intensity-modulated radiation therapy, or patient-reported smoking status. 

Grade 2 oral mucositis was comparable across the study arms, and narcotics were used commonly, early and ad lib, often given for multiple reasons including nonoral mucositis–related pain. “But there [was] a trend toward a decreased median total dose of morphine milligram equivalents on the GC4419 arms,” she added. ■

DISCLOSURE: Dr. Anderson received research funding from Galera Therapeutics, Inc. 

REFERENCES 

1. Anderson CM, Lee CM, Saunders D, et al: GC4419, small molecule superoxide dismutase mimetic: Randomized trial to reduce chemoradiotherapy (CRT)-induced mucositis in oral cavity/oropharyngeal carcinoma patients. 2018 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology International Symposium on Supportive Care in Cancer. Abstract PS037. Presented June 29, 2018. 

2. Anderson CM, Sonis ST, Lee CM, et al: Phase 1b/2a trial of the superoxide dismutase mimetic GC4419 to reduce chemoradiotherapy-induced oral mucositis in patients with oral cavity or oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys 100:427-435, 2018.