Triple Oral Metronomic Chemotherapy with Paclitaxel and Carboplatin plus Low Dose Nivolumab: First-line Immunotherapy and Repurposed- drug combination — A Phase III Randomized Controlled Trial in Platinum- Sensitive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC), especially oral cancer, is a major health burden in India. Standard chemotherapy regimens like cisplatin + 5FU (EXTREME) or immunotherapy (KEYNOTE-048) have shown modest survival benefits, but are often not affordable for most patients. Less than 3% of eligible patients in India can access immunotherapy due to its high cost.

 To address this challenge, this study evaluates combining weekly paclitaxel + carboplatin with triple oral metronomic chemotherapy (methotrexate, celecoxib, erlotinib) and low-dose nivolumab — known as the PCm-IO regimen. This is a Phase III, multicenter, open-label randomized controlled trial comparing the PCm-IO regimen with standard 3-weekly paclitaxel-carboplatin chemotherapy in the first-line palliative setting for patients with platinum-sensitive advanced or metastatic HNSCC. Around 436 participantswill be enrolled based on defined inclusion and exclusion criteria.

 The study aims to evaluate whether the PCm-IO regimen is non-inferior or superior to standard treatment in terms of overall survival (OS), progression-free survival (PFS), response rate, toxicity, and quality of life**.** The treatment period is approximately 4-6 months, followed by regular follow-ups until disease progression or unacceptable toxicity. The total study duration is expected to be 5 years.