A multicentre randomized study of neoadjuvant systemic therapy in oral cavity cancer

ParticipantsPatients will be assessed for the below-mentioned eligibility criteria prior to inclusion in the study. Routine imaging in the form of contrast enhanced, CT or MRI scan for the head and neck region and NCCT thorax for the chest will be performed for staging the patient before enrollment. Alternatively, if the clinical needs additional imaging in the form of PET scan to stage the patient, then will be prescribed. This is a standard of care and will be done prior to enrollment for assessing eligibility. If the imaging has been performed out of the institution, the images will be uploaded on the server as per institutional protocol.

ScreeningEach referred patient will be assessed on the basis of study eligibility criteria for this study. Investigations mentioned under baseline assessment would be performed at the time of screening if necessary for eligibility assessment. Once found eligible, the patient will be enrolled and randomized to either arm. The treatment for either arm, surgery or NACT, will commence with 3-4 weeks of date of randomization. All the study drug administration will be done at the study sites only.

 Safety assessment and other assessments at baselineSubjects will undergo the following assessment at baseline if not done previously:

History and physical examination

Documentation of ECOG PS

Blood investigations (If subject already has blood test within 28 days at baseline assessment and has not received any chemotherapy within last 6 weeks then there is no need for repetition of blood investigations)

Complete blood hemogram (CBC)

Renal function test (RFT)

Liver function test (LFT)

FBS (Fasting Blood Sugar) and PPBS (Post Prandial Blood Sugar)

Serum serology (HIV, HBsAg and HCV). HCV RNA testing will be performed if anti-HCV antibody screening test is positive.

Urine pregnancy test (or any other suitable alternative test like serum beta HCG for women of childbearing potential

Normal urine routine microscopy

Axial imaging of the lesion (If subject already has had imaging at baseline assessment and has not received any chemotherapy within last 6 weeks then there is no need for repeat imaging)

Electrocardiogram (ECG) and 2D-Echo (if age > 45 years or in presence of cardiac comorbidity)

Samples (Tissue and blood) for molecular analysis will be collected if feasible at baseline and at periodic intervals and at progression

Data monitoringA study continuation report and monitoring will be prepared and performed at the Institutional Ethics Committee (IEC) as per the institutions protocol.

Safety reporting****Adverse Event Definitions

Adverse Events (AEs):

Any untoward medical occurrence (including a symptom/disease or an abnormal laboratory finding) during treatment with a pharmaceutical product in a subject or a human volunteer that does not necessarily have a relationship with the treatment being given.

 The following should not be recorded as AEs, if recorded at screening (on Screening Form of CRF).

a. Pre-planned procedure (like surgery, RT or Chemotherapy), unless the condition for which the procedure was planned has worsened since baseline.

b. Pre-existing conditions found as a result of screening procedures or any event due to progression of disease either clinically or radiologically

 Clinical Laboratory Adverse Event:

 A Clinical laboratory AE is any clinical laboratory abnormality that suggests disease and/or organ toxicity and is of severity, which requires active management (i.e. change of dose, discontinuation of the drug, more frequent follow-up or diagnostic investigation).

 Serious Adverse Event (SAE):

 An SAE is any adverse drug experience that at any dose results in any of the following outcomes within 30 days of administration of the experimental arm:

a. Death due to systemic therapy side effect

b. A life-threatening* experience due to systemic therapy-related side effect.

 All serious adverse events must be reported immediately to the IEC and to designated persons. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious drug experience when based upon appropriate medical judgment, they may jeopardize the health of the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

 *The term life-threatening in the definition of the serious adverse event refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death if it was more severe. Death due to progressive disease will not be considered as SAE. Hospitalization post progression wont be considered as SAE. Admissions done for logistic purpose, chemotherapy administration or its supportive medication or for insurance formalities wont be considered as SAE

 Non-Serious Adverse Event:

A non-serious adverse event is any AE, which does not fulfil the definition of an SAE.

 Severity Assessment definitions

Will be done according to common toxicity criteria for adverse events (NCI-CTCAE v5.0).

Relationship to Study Drug Assessment Definitions

 Unrelated:      The AE is clearly NOT related to the intervention. The adverse event is clearly not related to the study drug and is clearly related to an underlying disease, environmental or toxic factors, or other drug/therapy.

 Unlikely:          The AE is doubtfully related to the intervention. The adverse event does not follow a reasonable temporal sequence after study drug administration (e.g., too soon or too long after study drug or study drug was not taken) and is plausibly related to an underlying disease, environmental or toxic factors, or other drug/therapy.

 Possible:         The AE may be related to the intervention. The adverse event occurred in a reasonable time after study drug administration but could be related to an underlying disease, environmental or toxic factors, or other drug/therapy. There is a reasonable possibility of a causal relationship between the study and the adverse event.

 Probable:       The AE is likely related to the intervention. The adverse event occurred in a reasonable time after study drug administration and is unlikely to be related to an underlying disease, environmental or toxic factors, or other drug/therapy. The event may respond to stopping the study drug.

 Definite:         The AE is clearly related to the intervention. The adverse event occurred in a reasonable time after study drug administration but could not be explained by an underlying disease, environmental or toxic factors, or other drug/therapy. The event should respond to stopping the study drug.

 Outcome categories and definitions

 a. Recovered

b. Stabilized: An AE is stabilized when according to the Investigator; the subject is in a clinically stable condition. This term should only be used for chronic conditions and for a given subject only when he/she has completed the protocol

c. Recovered with sequelae: As a result of the SAE, the subject suffered persistent and significant disability/incapacity (e.g. blindness, paralysis, etc.). Any AE recovered with sequelae should be rated as an SAE.

d. Continuing

e. Died

 Collection, Recording and Reporting of Adverse Events

 All events meeting the definition of an adverse event must be collected and reported from the first study-related activity until 30 days after the last administration of study medication. At each visit to the site, the subject must be asked about adverse events. All adverse events, either observed by the Investigator or reported by the subject, will be recorded by the Investigator and evaluated.

 Adverse events will be assessed at each visit. Any worsening of concomitant illness will be recorded as AE. Adverse events will be recorded in both inpatient case notes and CRF. The Investigator should record the diagnosis, if available. If no diagnosis is available, the Investigator should record each sign and symptoms as individual adverse events.

 All adverse events must be recorded by the Investigator on the standard Adverse Event Form. One single Adverse Event Form must be used per adverse event from start to resolution. Laboratory test abnormalities considered by the Investigator to be clinically relevant should be reported on the adverse event page of the CRF.

Adverse events and laboratory test abnormalities fulfilling the definition of "serious" must, in addition, be reported on a special emergency report form. Signs and symptoms of each Adverse Event should be described in detail: start and stop dates, intensity, and relationship to investigational product, action taken and outcome.