Phase 2-3 trial evaluating the Integration of metronomic methotrexate, celecoxib,erlotinib with maximum tolerable dose chemotherapy in advanced Head and Neck Cancer

Background& Rationale:Both metronomic chemotherapy (MCT) and maximum tolerable dose chemotherapy(MTD)  provide modest survivalimprovement in palliative setting in head and neck cancers.. The mechanism ofaction of MTD chemotherapy and metronomic chemotherapy differ. They inhibitdifferent aspects of cancer environment. The resistance mechanism of MTD isovercome by metronomic chemotherapy. The toxicity of metronomic chemotherapyalone is minimal. Hence it can be assumed that the combination of MTDchemotherapy and metronomic might lead to an improvement in outcomes with minimalincrease in toxicity. To test this rationale the study is planned.

Aim: To study whether administration ofmetronomic chemotherapy with MTD chemotherapy would lead to an improvement outcome in palliative setting in head and neck cancer.

Objective:

Phase  2 : To determine whether the combination ofmetronomic methotrexate (9 mg/m2) with fixed dose of celecoxib (200 mg PO BD),erlotinb (150 mg PO OD) with MTD combination of Paclitaxel (175 mg/m2) and Carboplatin ( AUC-5) leads to an improvement in 6 month progressionfree survival over the MTD combination of Paclitaxel (175 mg/m2)  and Carboplatin (AUC-5)

Phase 3 : Tocompare the OS between the  arms.

Trialdesign: Multi-stage, parallel design, open label, explanatory, superioritydesign,  randomized controlled study.

Studysetting: The studywould be conducted over the next 5 years in Head and Neck Medical oncologyunit  in Tata Memorial Centre. Patientssent for the study would be consented and post consenting would be screened forthis study.

Interventions: Arms of the study

Arm A –Paclitaxel plus Carboplatin

Arm B  - Paclitaxel plus Carboplatin with  Celecoxib 200 mg PO twice daily plus TabMethotrexate 9 mg/m2  weekly ( D1,D8,D15)plus erlotinib ( 150 mg OD) { Concurrent administration}

Arm C-  Paclitaxel plus Carboplatin followed by  Celecoxib 200 mg PO twice daily plus TabMethotrexate 9 mg/m2  weekly ( D1,D8,D15)plus erlotinib ( 150 mg OD) {Maintenance administration}

Allocation: The patients will be randomlyallocated to each arm by minimization. The allocation would be stratifiedaccording to the site (oral versus non oral) and previous treatment (previouschemotherapy versus none) and presence or absence of metastatic disease.

Method : In stage  II & III : Patients would be administeredthe interventions and would be followed by till death. The adverse events(CTCAE version 5), response (RECIST criteria version 1.1), quality of life(FACIT) , date of progression and date of death would be noted .

 Significance: Head and neck cancers are one of thecommonest cancers in the country. Approximately 85% are seen in locallyadvanced stage and nearly 70-80% of these require palliative chemotherapy. Thecurrent survival with palliative chemotherapy is modest. The proposal  aims to improve this survival by adding arelatively non toxic and affordable therapy. This intervention has thepotential to impact nearly 1,08,537 patients in India itself who succumb tothis malignancy