A Study of the Effects of GC4419 on Radiation Induced Oral Mucositis in Patients With Head/Neck Cancer

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Trial of the Effects of GC4419 on Severe Oral Mucositis in Patients Receiving Cisplatin + Intensity-modulated Radiation Therapy (IMRT) for Locally Advanced Non-Metastatic Squamous Cell Carcinoma (SCC) of the Oral Cavity/Oropharynx

The purpose of the phase 2, GT-201 clinical study is to determine if GC4419 administered prior to intensity-modulated radiation therapy (IMRT) reduces the incidence, duration, and severity of radiation induced oral mucositis in patients who have been diagnosed with locally advanced, non-metastatic squamous cell carcinoma of the head and neck.

Study Overview

• Status: Completed
• Conditions: Radiation Induced Oral Mucositis
• Intervention / Treatment: Drug: Low Dose GC4419: 30mg/day; Radiation: Intensity-Modulated Radiation Therapy; Drug: Cisplatin; Drug: High Dose GC4419: 90mg/day; Drug: Placebo

Detailed Description

GT-201 is a randomized, double-blind, placebo-controlled, multi-center study conducted in the U.S. to evaluate GC4419 administered via an intravenous line (IV) for the reduction of incidence, duration, and severity of radiation induced oral mucositis in patients receiving cisplatin plus intensity-modulated radiation therapy for post-operative, or definitive treatment of locally advanced, non-metastatic squamous cell carcinoma of the head and neck, limited to the oral cavity or oropharynx. Patients will be randomized equally to 1 of 3 treatment arms:

Arm A: 30 mg GC4419 per day (60 min IV infusion to complete within 60 minutes prior to IMRT), concurrent with daily fractions of IMRT (2.0 - 2.2 Gy) to a total of 60 - 72 Gy over approximately 7 weeks, plus cisplatin administered 80 - 100 mg/m2 once every three weeks for 3 doses or 30 - 40 mg/m2 once weekly for 6-7 doses (investigator's choice).

Arm B: 90 mg GC4419 per day (60 min IV infusion to complete within 60 minutes prior to IMRT), concurrent with daily fractions of IMRT (2.0 - 2.2 Gy) to a total of 60 - 72 Gy over approximately 7 weeks, plus cisplatin administered 80 - 100 mg/m2 once every three weeks for 3 doses or 30 - 40 mg/m2 once weekly for 6-7 doses (investigator's choice).

Arm C: Placebo daily (60 min IV infusion to complete within 60 minutes prior to IMRT), concurrent with daily fractions of IMRT (2.0 - 2.2 Gy) to a total of 60 - 72 Gy over approximately 7 weeks, plus cisplatin administered 80 - 100 mg/m2 once every three weeks for 3 doses or 30 - 40 mg/m2 once weekly for 6-7 doses (investigator's choice).

Planned radiation fields in all 3 arms must include at least two oral sites (buccal mucosa, floor of mouth, tongue, soft palate) with each site receiving a dose of at least 50 Gy.

All patients will be assessed twice weekly for oral mucositis per WHO grading criteria until the completion of IMRT, and once weekly thereafter (if necessary) for 8 weeks, or until oral mucositis resolves to ≤ Grade 1.

Approximately 200 total to ensure that roughly 60 patients per arm receive study drug and complete requirements for primary endpoint analysis, which is defined as patients receiving a minimum cumulative dose of 60 Gy.

• Study Type: Interventional
• Enrollment (Actual): 223
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Sudbury, Ontario, Canada, P3E 5J1
      • Northeast Cancer Centre, Health Sciences North
  • Quebec
    • Montreal, Quebec, Canada
      • Jewish General Hospital
    • Trois-Rivières, Quebec, Canada, G8Z 3R9
      • Centre integre universitaire de sante et de services sociaux de la Mauricie-et-du-centre-du-quebec
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • Fundación de Investigación
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • University of Arizona Cancer Center at Dignity Health St. Joseph's
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • Arkansas
    • Jonesboro, Arkansas, United States, 72401
      • Fowler Family Center for Cancer Care
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences- Winthrop P. Rockefeller Cancer Institute
  • California
    • Long Beach, California, United States, 90822
      • VA Long Beach Healthcare System
    • Los Angeles, California, United States, 90033
      • USC Norris Comprehensive Cancer Center
    • Montebello, California, United States, 90604
      • Clinical Trials and Research Associates, Inc.
    • Orange, California, United States, 92868
      • UC Irvine Chao Family Comprehensive Cancer Center
    • Stanford, California, United States, 94305
      • Stanford Cancer Institute
  • Colorado
    • Grand Junction, Colorado, United States, 81501
      • St. Mary's Regional Cancer Center
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • UConn Health School of Dental Medicine
  • Florida
    • Holiday, Florida, United States, 34691
      • Pasco Pinellas Cancer Center
    • Lakeland, Florida, United States, 32504
      • Lakeland Regional Health Cancer Center
    • Orlando, Florida, United States, 32806
      • UF Health Cancer Center at Orlando Health
    • Pensacola, Florida, United States, 32504
      • Sacred Heart Medical Oncology Group
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Indiana
    • Goshen, Indiana, United States, 46526
      • University of Indianan, Goshen Center for Cancer Care
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Department of Radiation Oncology University of Iowa Hospitals & Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Ashland, Kentucky, United States, 41101
      • Ashland-Bellefonte Cancer Center
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky, Albert B. Chandler Medical Center
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Hospital, James Graham Brown Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Cancer Center
    • Shreveport, Louisiana, United States, 71101
      • Christus Schumpert Cancer Treatment Center
  • Massachusetts
    • Springfield, Massachusetts, United States, 01199
      • Baystate Regional Cancer Program
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Jackson, Michigan, United States, 49201
      • Henry Ford Allegiance Health
    • Port Huron, Michigan, United States, 48060
      • Lake Huron Medical Center
  • Missouri
    • Columbia, Missouri, United States, 65212
      • Ellis Fichel Cancer Center, University of Missouri
  • Montana
    • Billings, Montana, United States, 59102
      • St. Vincent Frontier Cancer Center
    • Billings, Montana, United States, 59101
      • Billings Clinic
  • Nevada
    • Reno, Nevada, United States, 89502
      • Renown Cancer Institute
  • New Jersey
    • Flemington, New Jersey, United States, 08822
      • Hunterdon Hematology Oncology, LLC Hunterdon Regional Cancer Center
    • Neptune, New Jersey, United States, 07753
      • Jersey Shore University Medical Center- Hackensack Meridian Health
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • East Carolina University, Leo W. Jenkins Cancer Center
    • Washington, North Carolina, United States, 27889
      • Marion L. Shepard Cancer Center
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Health
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University, James Cancer Center
    • Toledo, Ohio, United States, 43623
      • Toledo Clinic Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
    • Portland, Oregon, United States, 97239
      • VA Portland Health Care System
  • Pennsylvania
    • Easton, Pennsylvania, United States, 18045
      • St. Luke's University Health Network
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas-Jefferson University Hospital-Bodine Center for Cancer Treatment
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital, Allegheny Cancer Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • AnMed Health Cancer Center
    • Charleston, South Carolina, United States, 29406
      • Charleston Cancer Center
    • Spartanburg, South Carolina, United States, 29303
      • Spartanburg Medical Center
  • South Dakota
    • Watertown, South Dakota, United States, 57201
      • Prairie Lakes Health Care System
  • Tennessee
    • Johnson City, Tennessee, United States, 36704
      • Mountain States Health Alliance
    • Knoxville, Tennessee, United States, 37920
      • University of Tennessee Medical Center
  • Texas
    • Plano, Texas, United States, 75093
      • Texas Oncology
    • Temple, Texas, United States, 76508
      • Scott and White Memorial Hospital and Clinic
    • Tyler, Texas, United States, 75701
      • Hope Cancer Center
  • Vermont
    • Burlington, Vermont, United States, 05401
      • The University of Vermont Medical Center
  • Washington
    • Everett, Washington, United States, 98201
      • Providence Regional Medical Center
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System
    • Spokane, Washington, United States, 99216
      • Cancer Care Northwest
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Pathologically-confirmed diagnosis of squamous cell carcinoma of the head and neck, defined as SCC of the oral cavity or oropharynx that will be treated with cisplatin plus concurrent IMRT Note: Patients with unknown primary tumors whose treatment plan matches the requirements specified in Inclusion Criteria #2 and #3 below are eligible for the trial.
2. Treatment plan to receive a continuous course of IMRT delivered as single daily fractions of 2.0 to 2.2 Gy with a cumulative radiation dose between 60 Gy and 72 Gy. Planned radiation treatment fields must include at least two oral sites (buccal mucosa, floor of mouth, tongue, soft palate) that are each planned to receive a total of > 50 Gy. Patients who have had prior surgery are eligible, provided they have fully recovered from surgery, and patients who may have surgery in the future are eligible.
3. Treatment plan to receive standard cisplatin monotherapy administered either every three weeks (80-100 mg/m2 for 3 doses) or weekly (30-40 mg/m2 for 6-7 doses). The decision on which chemotherapy regimen to use in combination with IMRT and GC4419 will be at the discretion of the investigator.
4. Age 18 years or older
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

6. Adequate hematologic function as indicated by:

   • Absolute neutrophil counts (ANC) ≥ 1,500/mm3
   • Hemoglobin (Hgb) ≥ 9.0 g/dL
   • Platelet count ≥ 100,000/mm3

7. Adequate renal and liver function as indicated by:

   • Serum creatinine acceptable for treatment with cisplatin per institutional guidelines
   • Total bilirubin ≤ 1.5 x upper-normal limit (ULN)
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
   • Alkaline phosphatase ≤ 2.5 x ULN
8. Human papilloma virus (HPV) status in tumor has been documented using tumor immunohistochemistry for HPV-p16 or other accepted test
9. Serum pregnancy test negative for females of childbearing potential
10. Males and females must agree to use effective contraception starting prior to the first day of treatment and continuing for 30 days after the last dose of GC4419
11. Properly obtained written informed consent

Exclusion Criteria:

1. Tumor of the lips, larynx, hypopharynx, nasopharynx, sinuses, or salivary glands
2. Metastatic disease (Stage IV C)
3. Prior radiotherapy to the region of the study cancer or adjacent anatomical sites or more than 25% of total body marrow-bearing area (potentially interfering with chemotolerance)
4. Prior induction chemotherapy
5. Receiving any approved or investigational anti-cancer agent other than those provided for in this study
6. Participation in another clinical trial or use of another investigational agent within 30 days of study entry
7. Requirement for significantly modified diet (liquids and/or solids) due to compromised oral/pharyngeal function at baseline
8. Requirement at baseline for parenteral or gastrointestinal tube-delivered nutrition for any reason
9. Malignant tumors other than head and neck cancer (HNC) within the last 5 years, unless treated definitively and with low risk of recurrence in the judgment of the treating investigator
10. Active infectious disease excluding oral candidiasis
11. Presence of oral mucositis (World Health Organization Score ≥ Grade 1) at study entry
12. Known history of HIV or active hepatitis B/C (patients who have been vaccinated for hepatitis B and do not have a history of infection are eligible)
13. Female patients who are pregnant or breastfeeding
14. Known allergies or intolerance to cisplatin and similar platinum-containing compounds
15. Requirement for concurrent treatment with nitrates or other drugs that may, in the judgment of the treating investigator, create a risk for a precipitous decrease in blood pressure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Dose GC4419: 30mg/day; 30 mg GC4419/day prior to IMRT	Drug: Low Dose GC4419: 30mg/day; Low Dose GC4419 will be administered by 60 minute IV infusion, within 1 hour prior to daily IMRT fractions, until IMRT is complete (generally M-F for approximately 7 weeks).; Radiation: Intensity-Modulated Radiation Therapy; Daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy over approximately 7 weeks; Drug: Cisplatin; Administered 80-100 mg/m2 once every three weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 doses. Substitution of other systemic agents due to related toxicities (i.e., carboplatin) would be evaluated to determine eligibility by the Medical Monitor
Experimental: High Dose GC4419: 90mg/day; 90 mg GC4419/day prior to IMRT	Radiation: Intensity-Modulated Radiation Therapy; Daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy over approximately 7 weeks; Drug: Cisplatin; Administered 80-100 mg/m2 once every three weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 doses. Substitution of other systemic agents due to related toxicities (i.e., carboplatin) would be evaluated to determine eligibility by the Medical Monitor; Drug: High Dose GC4419: 90mg/day; High Dose GC4419 will be administered by 60 minute IV infusion, within 1 hour prior to daily IMRT fractions, until IMRT is complete (generally M-F for approximately 7 weeks).
Placebo Comparator: Placebo; Placebo daily, prior to IMRT	Radiation: Intensity-Modulated Radiation Therapy; Daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy over approximately 7 weeks; Drug: Cisplatin; Administered 80-100 mg/m2 once every three weeks for 3 doses or 30-40 mg/m2 once weekly for 6-7 doses. Substitution of other systemic agents due to related toxicities (i.e., carboplatin) would be evaluated to determine eligibility by the Medical Monitor; Drug: Placebo; Placebo will be administered by 60 minute IV infusion, within 1 hour prior to daily IMRT fractions, until IMRT is complete (generally M-F for approximately 7 weeks).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration (in Days) of Radiation Induced Severe Oral Mucositis (OM) Per World Health Organization (WHO) Criteria	Assessed from the first determination of ≥Grade 3 OM to the first instance of non-severe OM (≤Grade 2), without a subsequent instance of ≥Grade 3	From start of Intensity-modulated radiation therapy (IMRT) through 8 weeks follow-up, an average of 15 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events	Number of participants with treatment emergent adverse events (TEAE) per arm	First dose of IMRT through the completion of IMRT, estimated to be up to 7 weeks.
Number of Participants Who Experience Severe OM	Number of participants who experience severe OM from the first IMRT fraction through the last IMRT fraction	Minimum of 60 Gy administered to tumor, approximately 30 IMRT fractions, which is estimated to be 6-7 weeks.
Number of Participants Who Experienced Grade 4 OM From the First IMRT Fraction Through the Last IMRT Fraction	Number of Participants who experienced Grade 4 OM	First dose of IMRT through the completion of IMRT, estimated to be up to 6-7 weeks.
Number of IMRT Fractions Delivered at Onset of Severe OM	Onset of severe OM: number of IMRT fractions delivered at onset of severe OM	Onset of Severe OM, estimated to be between first dose of IMRT and 7 weeks.
Number of Participants Who Experienced Grade 4 Oral Mucocitis (OM) From the First IMRT Fraction Through the Last IMRT Fraction	Number of Participants who experienced Grade 4 OM	Onset of Grade 4 OM, estimated to be between first dose of IMRT and 7 weeks.
Number of Participants With Tumor Outcomes Defined as Locoregional Failure, Distant Metastases, Disease Progression and Deaths	Effect of treatment assignment on tumor outcomes (locoregional failure, distant metastases, progression-free survival, overall survival) Only 73 subjects in Placebo Arm were analyzed for locoregional failure, distant disease and progression-free survival because 1 subject was determined after enrollment to have a non-head and neck cancer and was therefore excluded from these analyses	Up to 1 year following completion of chemoradiation.

Collaborators and Investigators

• Sponsor: Galera Therapeutics, Inc.

Publications and helpful links

General Publications

• Anderson CM, Lee CM, Saunders D, Curtis AE, Dunlap NE, Nangia C, Lee AS, Kovoor P, Bar-Ad V, Pedadda AV Jr, Holmlund J, Downs M, Sonis ST. 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. Int J Radiat Oncol Biol Phys. 2022 Nov 1;114(3):416-421. doi: 10.1016/j.ijrobp.2022.06.063. Epub 2022 Jun 17.

Study record dates

Study Major Dates

• Study Start: October 12, 2015
• Primary Completion (Actual): September 18, 2017
• Study Completion (Actual): August 29, 2019

Study Registration Dates

• First Submitted: July 16, 2015
• First Submitted That Met QC Criteria: July 23, 2015
• First Posted (Estimate): July 24, 2015

Study Record Updates

• Last Update Posted (Actual): September 20, 2021
• Last Update Submitted That Met QC Criteria: August 23, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: chemotherapy; oropharynx; squamous cell carcinoma of the head and neck; intensity-modulated radiation therapy; oral mucositis; oral cavity; superoxide dismutase; radioprotection
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Stomatognathic Diseases; Mouth Diseases; Mucositis; Stomatitis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Protective Agents; Antioxidants; Cisplatin; Avasopasem manganese
• Other Study ID Numbers: GT-201