Part A is a Dose escalation part where the Rolling Six design will be used to estimate the MTDF. With this approach, patients will be continuously enrolled based on available data at the time of enrolment at a particular dose level. Then enrolment will be temporarily halted until at least five out of six patients have undergone evaluation for dose-limiting toxicities (DLT). Dose escalation will be adjusted according to the available data at the time of enrolment. It will be considered if, at the time of enrolment, three out of three, four out of four, five out of five, five out of six, or all six patients at the current dose level are evaluated for DLT and do not exhibit any. Conversely, de-escalation will be considered if, two or more patients have experienced a DLT at the current dose level. This technique offers the advantage of expediting the determination of MTDF. HFRT dose levels 0, +1, and +2 comprise 56 Gy in 25 fractions over 5 weeks, 52 Gy in 20 fractions over 4 weeks, and 46.5 Gy in 15 fractions over 3 weeks, respectively. 

Part B is a dose expansion part where Once MTDF is reached, an additional 24 patients will be enrolled in MTDF level and MTDF-1 level (dose and fractionation level preceding to MTDF) and will be treated as per the dose-expansion protocol to assess additional toxicities that occur during this safety expansion phase and that will provide an opportunity to further refine the estimate of the MTDF. Participants in the dose-expansion cohort (DEC) will be randomized into each of these two groups (either MTDF or MTDF-1) by minimization technique and stratification will be based on age at diagnosis, location of primary tumor in the oral cavity (buccal mucosa complex including buccal mucosa, gingiva-buccal sulcus, retromolar trigone versus oral tongue and floor of mouth) and nodal burden.

Dose-limiting toxicities (DLT) are defined as any one or all of the following: 

1. 1. Occurrence of any Common Terminology Criteria for Adverse Events (CTCAE) version 5.0(53) > grade 3 acute toxicity (Table 4 and appendix) during either the entire course of HFRT or within 12 weeks of conclusion.

2. Persistence of any CTCAE v 5.0 defined  3 acute or consequential toxicity (Table 4 and appendix) at 12 weeks of HFRT.

3. Anytime patient requiring hospitalization or any additional intervention due to any of the HFRT-related > CTCAE v5.0 > grade 3 acute or consequential toxicities either during RT or within 12 weeks of the conclusion of HFRT (Table 4 and appendix).

4. Unplanned and unintentional treatment gap in the management of acute HFRT-related toxicities either during RT for more than 3 working days.