Tumor Outcomes of 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 CancerC. M. Anderson1, C. M. Lee2, D. Saunders3, A. E. Curtis4, N. E. Dunlap5,

C. Nangia6, A. Lee7, S. M. Gordon8, P. Kovoor9, V. Bar-Ad10, A. V. Peddada Jr11, K. T. Colvett12, D. M. Blakaj13, M. Bonomi13, F. Worden14,

J. Holmlund15, J. Brill15, M. Downs16, S. T. Sonis17, and J. Buatti11University of Iowa Hospitals & Clinics, Iowa City, IA; 2Cancer Care Northwest, Spokane, WA; 3Northeast Cancer Centre, Health Sciences North, Sudbury, ON,

Canada; 4Gibbs Cancer Center, Spartanburg Medical Center, Spartanburg, SC; 5University of Louisville Hospital/James Graham Brown Cancer Center, Louisville, KY; 6UC/Irvine Medical Center, Orange, CA; 7HOPE Cancer Center of East Texas, Tyler, TX; 8East Carolina University, Greenville, NC; 9Texas Oncology, Plano West, Plano, TX; 10Thomas Jefferson University Hospital, Philadelphia, PA; 11Renown Regional Medical Center, Reno, NV; 12Mountain States Health Alliance, Johnson

City, TN; 13James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, OH; 14University of Michigan, Ann Arbor, MI; 15Galera Therapeutics, Inc., Malvern, PA; 16Statistics Collaborative, Inc., Washington, DC; 17Primary Endpoint Solutions, Watertown, MA

Disclosures• Employed by University of Iowa Hospitals & Clinics• Discussing investigational use of the pharmaceutical GC4419• Uncompensated Research Advisor to Galera Therapeutics, Inc.• Trial funding (NCT02508389) provided by Galera Therapeutics, Inc.

Background

• IMRT + cisplatin is SOC for locally advanced oral cavity/oropharyngeal cancer

• Approx 70% of patients develop severe OM (SOM), defined as WHO Grade 3 or 4

• ~40 Gy median onset• 3-4 weeks median duration• ~20-25% Grade 4

• Superoxide initiates mucosal injury• Phase Ib/2a GC4419

• Anderson, et al. IJROBP 2018 Feb 1;100(2):427-435

GC4419 Mechanistic Rationale

GT-201: Randomized Phase IIb Trial: Efficacy and Safety

Anderson, et al. J Clin Oncol 2019 Dec 1; 37(34):3256-3265

Trial Design

Ran

dom

ize

(1:1:

1)

GC4419 90 mg

GC4419 30 mg

Placebo

Treatment• GC4419 90 mg, 30 mg, or placebo• 60-minute IV infusion, Mon-Fri• Ending <60 mins pre-RT

Population• Subjects with OC, OP• Locally advanced, squamous cell• Eligible for SoC: 7 weeks IMRT + cisplatin

Stratification Factors

• Tumor HPV Status: positive or negative• Cisplatin Schedule: q3wks or weekly

Endpoints

• Primary: Reduction in Duration of Severe Oral Mucositis (SOM) – WHO Grades 3 & 4

• Secondary: Reduction in incidence and severity of SOM at pre-specified timepoints

• Exploratory: Time to SOM onset

• Tumor Outcomes (2-year follow-up)• Locoregional control, distant mets, PFS, OS

POST-RT FOLLOW UP:SAFETY: 30 daysOM: up to 8 weeks OR until WHO=0 or 1JCO 1 Dec 2019

LONG-TERM F/U:2 years for LC, DM, PFS, OSPRESENTED TODAY

Subject Enrollment & Assignment N=223 subjects

(44 US & Canadian sites)

PlaceboN=74

GC4419 30 mgN=73

GC4419 90 mgN=76

Randomized

ITT(efficacy population)

PlaceboN=72

GC4419 30 mgN=73

GC4419 90 mgN=72

PlaceboN=66

GC4419 30 mgN=62

GC4419 90 mgN=62

Treated(safety population)

EvaluablePopulation*

n=2 n=0 n=4RandomizationFailures; Not treated

n=6 n=11 n=10

SOM Efficacy

SOM duration: Days from 1st to last WHO of 3 or 4; 0 days for subjects who never developed SOM**Statistically significant non-parametric test of SOM duration; all subjects 90 mg vs all subjects Placebo—other p values nominal

DURATION (Primary Endpt.)92% Reduction in median days of SOM

90 mg vs. Placebo

0

2

4

6

8

10

12

14

16

18

20

Placebo 30mg 90mg

p=0.024**

INCIDENCE34% Reduction through all RT

90 mg vs. Placebo

0%

10%

20%

30%

40%

50%

60%

70%

Placebo 30mg 90mg

p=0.009

SEVERITY47% Reduction in Grade 4 OM Incidence

90 mg vs. Placebo

0%

5%

10%

15%

20%

25%

30%

Placebo 30mg 90mg

p=0.045

Comparable Safety Across Study ArmsN=217 treated subjects

0102030405060708090

100

Grade 2 or worse Grade 3 or worse Grade 4 or 5 Grade 5 (fatal)

Placebo (n=72) 30 mg GC4419 (n=73) 90 mg GC4419 (n=72)

≥ Maximum Grade AE, all Event Terms/Causalities

GC4419 was well tolerated at both doses

Most Frequent AEs as expected with Standard Cisplatin – RT Regimen

Most Frequent AEs (Any Grade)

Placebo(n=72)

30 mg GC4419(n=73)

90 mg GC4419 (n=72)

Lymphopenia 89% 92% 88%

Nausea 75% 68% 82%

Fatigue 69% 60% 65%

Oropharyngeal pain 64% 63% 61%

Constipation 53% 59% 64%

Radiation skin injury 47% 51% 53%

Vomiting 47% 52% 49%

Dysgeusia (taste) 49% 55% 43%

Dysphagia 43% 42% 47%

Weight decreased 35% 40% 44%

Oral candidiasis 29% 45% 43%

Leukopenia 39% 37% 39%

%

1%

4%

10%

6%

15%

1%

4%

18%

4%

10%

0%

6%

22%

4%

19%

0%

5%

10%

15%

20%

25%

Grade 1-2Syncope

Grade 3Syncope

Grade 1-2Hypotension/Orthostasis

Grade 3Hypotension/Orthostasis

Grade 1(Oral/Facial)Paresthesia

GC4419 “Expected” Events Were Mild and TransientMechanism-related potentiation of nitric oxide

Tumor Control2-year follow-up post IMRT/cisplatin

Tumor Outcomes Maintained – 1 & 2 Years

Final Analysis (Intent-to-Treat Population)OS = Overall Survival, PFS = Progression-Free Survival, LRC = LocoRegional Control, DMF = Free of Distant Metastases

Kaplan-Meier Estimates

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

OS PFS LRC DMF

PBO 30 mg 90 mg

1-Year

2-Year

Placebo (n=74) 30 mg (n=73) 90 mg (n=76)p-value,

Active vs PBO

1-year

OS 93% 91% 88% NS

PFS 82% 86% 80% NS

LRC 95% 95% 91% NS

DMFS 92% 92% 95% NS

2-year

OS 87% 85% 86% NS

PFS 77% 76% 77% NS

LRC 91% 89% 91% NS

DMFS 90% 89% 91% NS

Locoregional Control and Distant Metastasis-Free90 mg vs Placebo

Progression-free Survival and Overall Survival90 mg vs Placebo

Conclusions

• GC4419 (90 mg) provided clinically meaningful reduction in SOM

• Duration (statistically significant)• Incidence• Severity

• Intermediate results for 30 mg• Safety profile comparable to placebo

• 1- and 2-yr Tumor Control similar, 90 mg vs PBO

• c/w drug mechanism and animal models

• FDA Breakthrough Designation & Fast Track Status

• Confirmatory Phase 3 Trial (“ROMAN”) in Progress

• 90 mg vs Placebo• NCT03689712

Acknowledgements – Enrolling SitesPrincipal Investigator Institution Sharon Gordon, DDS, MPH, PhD School of Dental Medicine at East Carolina UniversityPhilip Kovoor, MD/Mark Engleman, MD Texas Oncology, Plano West

Roberto Arevalo-Araujo, MD Pasco Pinellas Cancer Center

Abhinand Peddada, MD Renown Regional Medical Center

James Wheeler, MD Goshen Center for Cancer Care

Voichita Bar Ad, MD Thomas-Jefferson University Hospital

Kyle Colvett, MD Mountain States Health Alliance Research Department

Douglas Miller, MD Meridian Health Research Services

Anshu Jain, MD Ashland-Bellefonte Cancer Center

Madhavi Venigalla, MD Lakeland Regional Cancer Center

Sanjiv Agarwala, MD St. Luke's Hospital Cancer CenterMercedes Porosnicu, MD/Marcelo Bonomi, MD Wake Forest Baptist Health

Madhu Garg, MD Montefiore Medical Center

Francis Worden, MD University of Michigan

Dukagjin Blakaj, MD, PhD Ohio State University

Elizabeth Feldman, MS, DMD UF Health Cancer Center at Orlando Health

Ariel Birnbaum, MD Rhode Island HospitalMichael Trendle, MD/Clint Daniel Kingsley, MD Ellis Fischel Cancer Center - University of Missouri

Ronald Maggiore, MD/Daniel Clayburgh, MD, PhD VA Portland Health Care System

Principal Investigator Institution Kevin Collins, MD, JD Fowler Family Center for Cancer Care

Waqas Rehman, MD Hunterdon Hematology Oncology, LLC

Leander Cannick III, MD Anmed Health Cancer Center

William Wisbeck, MD Providence Regional Medical Center

Steve P. Lee, MD, PhD Long Beach Veteran Affairs Healthcare System

Vernon King, MD St. Mary's Regional Cancer Center

Maria Matsangou, MD Northwestern UniversityGanesh Kudva, MD/Bianca de Souza, MD Henry Ford Allegiance Health

Charles Holladay, MD Charleston Cancer Center

Francois Vincent, MD Centre Intégré Universitaire de Santé et de Services Sociaux de la Mauricie et du Centre du Québec

Joseph Kelley, MD, PhD University of Tennessee Medical Center

Jorge Nieva, MD USC Norris Cancer Center

Rex Mowat, MD Toledo Clinic Cancer Center

Maura Barry, MD The University of Vermont Cancer CenterCeline Ord, MD/Shymal Patel, MD

University of Arizona Cancer Center at Dignity Health St. Joseph's

Patrick Cobb, MD, FACP St. Vincent Frontier Cancer Center

Alan Gowan, DO Scott & White Memorial Hospital and Clinic

Khalil Sultanem, MD Jewish General Hospital

AcknowledgementsThe authors would like to thank:

• Galera Therapeutics, Inc.• Dennis Riley, Ph.D.

• Statistics Collaborative• Janet Wittes, Ph.D.

• Novella Clinical• Mariana Hildesheim

• Participating Patients & their Families

• Alira Health• Chelsea Eckman• Chris Rao• Beth Rayworth• Jen Petrillo

Funding for this study (NCT02508389) was provided by Galera Therapeutics, Inc. (Galera). Graphic services were provided by AOIC, LLC, Exton, PA, USA, and were funded by Galera.

Future Directions – SBRT + GC4419Synergy with high-fxn RT: more H2O2!• Effect replicated in multiple mouse models,

nude and immunocompetent, and multiple histologies, including pancreatic

H2O2 mechanism demonstrated• Engineered to overexpress catalase (disposes

of H2O2) when induced by doxycycline• Overexpressing catalase blocks synergy with

RT by removing GC4419-generated H2O2

Tum

or V

olum

e (m

m3 )

2000

1500

1000

500

RT with Biological Equivalent Doses (H1299 NSCLC Tumors in mice)

Days Post Treatment

RT

RT+GC

vehicle

0

Tum

or V

olum

e (m

m3 )

Days Post Treatment

A

vehicle

GC4419

18 Gy x 1 RT

RT + GC4419

RT + dox

RT + GC4419 + dox

H1299CAT NSCLCin mice

Courtesy of M Story (UTSW)

Questions?

carryn-anderson@uiowa.edu