Head and Neck Cancer

SS 31 - H&N 3 - Strategies to Improve Outcomes and Minimize Toxicity in Oropharyngeal Cancer

223 - A?Randomized, Placebo (PBO) Controlled, Double-Blind P2b Trial of GC4419 (Avisopasem Manganese) to Reduce Severe Radiation-Related Oral Mucositis (SOM) in Patients (pts) With Locally Advanced Squamous Cell Cancer of the Oral Cavity (OC) or Oropharynx (OP)

Tuesday, October 23
4:45 PM - 4:55 PM
Location: Room 214 A/B

A Randomized, Placebo (PBO) Controlled, Double-Blind P2b Trial of GC4419 (Avisopasem Manganese) to Reduce Severe Radiation-Related Oral Mucositis (SOM) in Patients (pts) With Locally Advanced Squamous Cell Cancer of the Oral Cavity (OC) or Oropharynx (OP)
C. M. Anderson1, C. Lee2, D. Saunders3, A. Curtis4, N. E. Dunlap5, C. Nangia6, A. Lee7, J. Holmlund8, J. Brill8, S. T. Sonis9, and J. Buatti1; 1Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, IA, 2Cancer Care Northwest, Spokane Valley, WA, 3Northeast Cancer Center/Health Sciences North, Sudbury, ON, Canada, 4Spartanburg Medical Center, Gibbs Cancer Center, Spartanburg, SC, 5University of Louisville Hospital, Department of Radiation Oncology, Louisville, KY, 6UC/Irvine Medical Center, Orange, CA, 7HOPE Cancer Center of East Texas, Tyler, TX, 8Galera Therapeutics, Inc., Malvern, PA, 9BioModels, Boston, MA

Purpose/Objective(s): Intensity-modulated radiation therapy (IMRT) plus cisplatin (CDDP) is established treatment for locally advanced OC/OP cancer, but appx. 70% of patients develop SOM, defined as WHO Grade 3 or 4, which limits patients' ability to eat solids (Gr 3) or liquids (Gr 4, requiring artificial nutrition). An RT-induced burst of superoxide initiates oral mucositis (OM) development. GC4419, a superoxide dismutase mimetic, interrupts this process by potently converting superoxide to H2O2. It showed promising reductions of SOM in a published open-label Phase 1b/2a trial (IJROBP 1 Feb 2018). Hypothesis: GC4419 reduces SOM without increasing toxicity or decreasing tumor control of IMRT/CDDP.

Materials/Methods: 223 pts with OC or OP cancers receiving 70 Gy IMRT (≥50 Gy to > 2 oral sites) plus CDDP (qwk or q3wk), were randomized 1:1:1 to PBO, 30 or 90 mg of GC4419, by 60-minute IV infusion, M-F before each RT fraction. OM by the WHO scale was assessed by trained evaluators during RT & for up to 8 wks post RT. Primary endpoint was duration of SOM. Secondary endpoints included incidence & time to onset of SOM, & safety. Efficacy analyses (each active dose v PBO, ITT) proceeded by a sequential, conditional approach; 2-sided α=0.05.

Results: Baseline patient & tumor characteristics were balanced: 86% M, 77% OP, 77% definitive, 82% IVa, 34% T4, 72% HPV+, 38% q3wk CDDP, number of oral sites receiving ≥ 50 Gy [3-4 sites; 53%; 5+ sites, 38%]); as was treatment delivery (median 70 Gy; 6% had RT breaks ≥ 5 consecutive fractions; 80% received ≥ 200 mg/m2 CDDP; 87% received ≥ 80% of planned GC4419/PBO doses). 90 mg GC4419 reduced SOM across endpoints, including a statistically significant reduction in the primary endpoint of duration (TABLE). Cumulative SOM incidence throughout RT (i.e., through 30, 40, 50 Gy) was also consistently lower with 90 mg GC4419 v PBO. Safety was comparable across arms with no significant GC4419-specific toxicity; chemotherapy toxicity of IMRT/cisplatin did not appear to be increased. 2-year follow up for tumor outcomes is in progress.

Conclusion: GC4419 90 mg produced a clinically meaningful reduction of SOM; the primary analysis (duration) was statistically significant. Efficacy results with 30 mg were intermediate and did not reach significance. The safety profile was comparable to placebo. Interim tumor control data and exploratory correlative analyses will be presented.
PBO 30mg 90mg 90mg vs. PBO
N 74 73 76 Relative δ p=
Duration SOM, median days 19 8 1.5 92% 0.024
Incidence SOM thru 60 Gy 58% 40% 37% 36% 0.010*
Incidence SOM thru last RT 65% 60% 43% 34% 0.009*
Incidence Grade 4 OM 30% 21% 16% 47% 0.045*
Onset SOM, median days 39 47 61 56% 0.080*
*nominal p value, pre-specified secondary endpoint

Author Disclosure: C.M. Anderson: Employee; University of Iowa College of Nursing, University of Iowa Hospitals & Clinics. Officer/Board Member; Iowa Association of Nurse Anesthetists. President; Iowa Society of Therapeutic Radiation Oncology. Uncompensated Research Advisor; Galera Therapeutics,Inc. C. Lee: Partner; Cancer Care Northwest. Research Director; Gamma Knife of Spokane. Speaker's Bureau; Bayor Pharma, Lilly Pharma, Bristol Meyer Squibb Pharma, Merck Pharma. Advisory Board; Elekta. Stock; GK MD. Partnership; Kobold Medical, Gamma Knife of Spokane, Cancer Care Northwest. D. Saunders: None. A. Curtis: Principal Investigator; Southeast Clinical Oncology Research Consortium NCORP. N.E. Dunlap: Honoraria; Osler Institute. C. Nangia: None. A. Lee: None. J. Holmlund: Consultant; Prometheus Labs, OncoNano. Stock Options; Galera Therapeutics. J. Brill: Employee; Incyte Pharmaceuticals. Stock; Incyte Pharmaceuticals. Stock Options; Galera Therapeutics, Inc. S.T. Sonis: Consultant; Clinical Assistance Programs. Stock; Inform Genomics. Partnership; BioInsight Diagnostics. CMO; Primary Endpoint Solutions.

Carryn Anderson, MD

Disclosure:
Employment
University of Iowa College of Nursing: Associate Program Director, Nurse Anesthetist Training Program: Employee; University of Iowa Hospitals & Clinics: Certified Registered Nurse Anesthetist: Employee, Clinical Associate Professor: Employee

Leadership
Galera Therapeutics,Inc: Uncompensated Research Advisor; Iowa Association of Nurse Anesthetists: Officer/Board Member; Iowa Society of Therapeutic Radiation Oncology: President

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223 - A?Randomized, Placebo (PBO) Controlled, Double-Blind P2b Trial of GC4419 (Avisopasem Manganese) to Reduce Severe Radiation-Related Oral Mucositis (SOM) in Patients (pts) With Locally Advanced Squamous Cell Cancer of the Oral Cavity (OC) or Oropharynx (OP)



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