A Clinical Study to Compare BupiZenge With Lidocaine for Pain Due to Oral Mucositis in Patients With Head and Neck Cancer.

A Randomized, Open-label, Phase III Trial to Assess the Efficacy and Safety of BupiZenge Compared to Lidocaine for Pain Associated With Oral Mucositis in Head and Neck Cancer

Most patients who receive radiation therapy for head and neck cancer develop painful sores in the mouth called oral mucositis. For many of them, these sores are severe and result in debilitating pain. The sores usually start in the third week of radiation and last aboutfive weeks, often continuing for two weeks after treatment ends. Current pain treatments, for instance lidocaine solution, only give short-lasting pain relief.

BupiZenge is a lozenge that dissolves slowly in the mouth and contains bupivacaine. Bupivacaine is a long-acting pain-relieving medicine and has been safely used for many years for both children and adults, and its safety profile is well understood. The BupiZenge lozenge is designed to give longer and more reliable pain relief for patients with mucositis in their mouth.

This study will check if BupiZenge works better to reduce pain than lidocaine, and if better pain control improves quality of life and reduces the need for strong pain medicines like opioids.

The main goal is to see how much mouth pain decreases after taking BupiZenge compared to lidocaine. This is measured by asking the patients to rate their pain score on a scale from 0 (no pain) to 10 (worst possible pain). This is done at different time-points, from before the dose until three hours after dose on the last day of radiotherapy.

The study will include 150 adults, both women and men, aged 18 to 80 years, who have head and neck cancer and are scheduled to receive radiotherapy, with or without chemotherapy. These patients will be randomly assigned to one of the treatment groups. The first is BupiZenge, which is a lozenge containing bupivacaine, which dissolves slowly in the mouth. The second is lidocaine, which is a liquid solution for use in the mouth that you gurgle or swish around in the mouth.

The study begins with a combined screening and run-in period that can last up to five weeks. During radiotherapy, patients record their mouth pain each day using a number scale from 0 (no pain) to 10 (worst possible pain). If the pain score is at least 4 (moderate pain) and they have developed mucositis in the mouth within 5 weeks, patients are randomly assigned to receive either BupiZenge or Lidocaine.

Treatment continues at least until radiotherapy is completed. If the patient has pain and mouth sores, and the treatment is working well, it may continue after radiotherapy ends, but only until the sores heal or for a maximum of six weeks in total, whichever occurs first. After treatment ends, there is a 30-day follow-up period.

Pharmacokinetic (PK) parameters of bupivacaine in plasma will be evaluated in a sub-trial including participants randomized to the BupiZenge treatment arm.

Approximately 15 participants (no more than 25), across all designated PK sites, will participate in a PK sub-trial. Blood samples will be collected before the dose and at scheduled time points up to three hours after the dose for PK evaluation. Samples will be analyzed by a central laboratory, and results will be reported to the Sponsor or Sponsor's designee during the course of the trial. Overall, the PK sub-group represents a targeted, ethical, and efficient approach to verify systemic safety parameters for BupiZenge in the intended patient population.

Inclusion Criteria:

• Participant must provide signed written informed consent prior to trial participation and must be willing and able to comply with all requirements and restrictions of the trial.
• Male or female aged ≥ 18 on the day of consent and ≤ 80 on the first day of dosing.
• Pathologically confirmed diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or nasopharynx.
• About to start IMRT with curative intent with daily fractions of 2.0 Gy to 2.2 Gy to a cumulative intended dose of at least 60 Gy and a maximum of 72 Gy. Proton therapy given at equivalent biological doses is allowed.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.
• Female participants of childbearing potential (WOCBP) must agree to use a highly effective contraceptive measure or practice total sexual abstinence from the time of giving informed consent until at least 24 hours after last dose of IMP.

Exclusion Criteria:

• Participation in another investigational interventional clinical trial within 3 months prior to first dosing, or for a longer period if required by local regulations, or within 5 half-lives of the investigational agent taken (whichever is longer). An exception is studies where patients are randomized to different radiotherapy settings, e.g. participation in DAHANCA 35 is allowed.

• Previous radiation therapy to the head and/or neck area.

• Pre-existing OM, active herpes simplex virus (HSV) infection, or untreated or uncontrolled oral candidiasis.

• Receiving high-dose (> 15 mg per day prednisolone), corticosteroids (for any indication).

• Known allergy or intolerance to bupivacaine, lidocaine, or any of the excipients in the products.

• Significant cardiac disease such as AV block II-III or requiring treatment with antiarrhythmic drugs in class III (e.g., amiodarone).

• Inability to eat or drink, or dependence on an enteral feeding tube (percutaneous endoscopic gastrostomy [PEG] or nasogastric tube) for any reason.

• Moderate/severe liver or kidney disease defined as:

  1. AST/ALT > 3 × upper limit of normal (ULN) or bilirubin > 1.5 × ULN (unless related to Gilbert's syndrome)
  2. glomerular filtration rate (GFR) < 30 mL/min/1.73 m2

• Known diagnosis of epilepsy.

• Known phenylketonuria (PKU).

• Pregnancy or breastfeeding.

• Any condition or circumstance-based on the investigator's assessment-that could increase risk to the participant, confound trial results, or interfere with compliance / participation (including inability or unwillingness to follow trial procedures, or any clinically significant physical or psychiatric condition).