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.

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.

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