Background: Around 85% of head and neck cancer patients in India are seen in locally advanced stage which either relapse or fail after the first line treatment. The options of systemic therapy treatment in second line (after first line palliative chemotherapy or failure within 6 months of chemotherapy as part of multimodality treatment) are limited. The median progression free survival (PFS) of 1-3 months and median overall survival (OS) of 4-6 months are reported across various studies. There is need for having effective medical treatment option. Rationale- Triple metronomic is oral, cheap and requires minimum resources. We will be comparing physician choice of standard systemic therapies with ASCO recommended triple metronomic therapy. Methods: Design- Open label randomized, superiority. Study Period- 4 years. Inclusion- Head and Neck cancer patients (Age > 18 years) either platinum refractory or planned for second line (ECOG PS ≤2 and adequate organ function). Exclusion- Uncontrolled comorbidities, Pregnancy & lactating women. Baseline - blood parameters, EORTC QOL & HN module and baseline axial imaging. Central stratified randomization (Computer generated randomization sheet) will be done- ; the stratification will be for site of tumor (oral cavity versus others) and ECOG PS (0-1/2). Arm A: Triple metronomic (Per Oral )- Erlotinib 150 mg once daily, Celecoxib 200 mg twice daily & Weekly Methotrexate 9 mg/m². Arm B: Physician choice therapy- Docetaxel, Paclitaxel, Cetuximab, Nivolumab, Afatinib, Pembrolizumab, 5-Flurouracil, Capecitabine Therapy will be continued till progression or intolerable side effects. Adverse events monitoring as per the NCI CTCAE 5 criteria. The response will be monitored in accordance with institutional standards. Quality of life (EORTC) would be collected at baseline, at 2 months and at 6 months. The 6 month OS assumed on the basis of previous data of docetaxel was 55, we assume that it would increase with a target hazard ratio 0.561 with type 1 error of 5%, type 2 error of 20% and 10% lost to follow up rate. The sample size is 114. Events required for analysis-93. Outcome measures & Statistical analysis:OS- from date of randomization to date of death. Patients alive at their last follow ups would be censored. PFS from date of randomization to date of progression or death whichever is earlier. Patients who have not progressed at their last follow ups would be censored. OS and PFS will be estimated by Kaplan meier analysis and would be compared between the arms by the log rank test. Cox proportional hazard model would be constructed for calculation of hazard ratio. The model would also be used to see the impact of chemotherapy regimen on overall survival in accordance with known prognostic factors. Age (below or above 60 years), gender, site, hemoglobin level (equal to or below 12 g/dl or above it) and PS (0-1 versus 2). To compare the QOL scores between the 2 arms. Clinical trial information: CTRI/2021/08/036002.