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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Radiation Induced Oral Mucositis

Intervention / Treatment
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* Drug: Low Dose GC4419: 30mg/day
* Drug: High Dose GC4419: 90mg/day
* Drug: Placebo
* Radiation: Intensity-Modulated Radiation Therapy
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. 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. 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. Age 18 years or older Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Adequate hematologic function as indicated by: Absolute neutrophil counts (ANC) ≥ 1,500/mm3 Hemoglobin (Hgb) ≥ 9.0 g/dL Platelet count ≥ 100,000/mm3 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 Human papilloma virus (HPV) status in tumor has been documented using tumor immunohistochemistry for HPV-p16 or other accepted test Serum pregnancy test negative for females of childbearing potential 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 Properly obtained written informed consent Exclusion Criteria: Tumor of the lips, larynx, hypopharynx, nasopharynx, sinuses, or salivary glands Metastatic disease (Stage IV C) 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) Prior induction chemotherapy Receiving any approved or investigational anti-cancer agent other than those provided for in this study Participation in another clinical trial or use of another investigational agent within 30 days of study entry Requirement for significantly modified diet (liquids and/or solids) due to compromised oral/pharyngeal function at baseline Requirement at baseline for parenteral or gastrointestinal tube-delivered nutrition for any reason 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 Active infectious disease excluding oral candidiasis Presence of oral mucositis (World Health Organization Score ≥ Grade 1) at study entry 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) Female patients who are pregnant or breastfeeding Known allergies or intolerance to cisplatin and similar platinum-containing compounds 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Dose GC4419: 30mg/day<br>30 mg GC4419/day prior to IMRT | Drug: Low Dose GC4419: 30mg/day<br>* 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).<br>Radiation: Intensity-Modulated Radiation Therapy<br>* Daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy over approximately 7 weeks<br>Drug: Cisplatin<br>* 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<br>|
| Experimental: High Dose GC4419: 90mg/day<br>90 mg GC4419/day prior to IMRT | Drug: High Dose GC4419: 90mg/day<br>* 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).<br>Radiation: Intensity-Modulated Radiation Therapy<br>* Daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy over approximately 7 weeks<br>Drug: Cisplatin<br>* 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<br>|
| Placebo Comparator: Placebo<br>Placebo daily, prior to IMRT | Drug: Placebo<br>* 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).<br>Radiation: Intensity-Modulated Radiation Therapy<br>* Daily fractions of IMRT (2.0-2.2 Gy) to a total of 60-72 Gy over approximately 7 weeks<br>Drug: Cisplatin<br>* 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<br>|

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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squamous cell carcinoma of the head and neck, oral cavity, oropharynx, intensity-modulated radiation therapy, chemotherapy, oral mucositis, superoxide dismutase, radioprotection