A Phase II Study for p16+ Oropharyngeal Cancer PerSonalized De-escalation Treatment at University of MIchigan (CuSToMIze)

Inclusion Criteria:

• Patients must have FDG-avid (maximum SUV ≥ 4.0) (from PET scan of any date, anyscanner) and histologically or cytologically proven squamous cell carcinoma of theoropharynx (tonsil, base of tongue, oropharyngeal wall, soft palate) or unknownprimary that is p16 positive by immunohistochemistry or HPV positive by in situhybridization

• Clinical stage: Stage I-II AJCC 8th edition staging

• Appropriate stage for protocol entry, including no distant metastases, based uponthe following minimum diagnostic workup:

• History/physical examination, including documentation of weight within 4 weeksprior to registration;

• For Cohort B, FDG-PET/CT scan for staging within 6 weeks prior to registration.For Cohort A, acceptable imaging for staging can include diagnostic CTneck/chest or PET-CT within 6 weeks prior to registration

• Zubrod Performance Status 0-1 within 4 weeks prior to registration;

• Age ≥ 18;

• Able to tolerate PET/CT imaging required to be performed

• For Cohort A, tumors must be potentially surgically resectable via a transoralapproach, at the discretion of the treating surgeon. Additionally, they must have 0-2 clinically positive LNs on diagnostic CT or PET-CT according clinical consensusof the treatment team

• For both cohorts, CBC required within 4 weeks prior to registration. For Cohort B,CBC/differential obtained within 4 weeks prior to registration on study, withadequate bone marrow function defined as follows:

• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3;

• Platelets ≥ 100,000 cells/mm3;

• Hemoglobin ≥ 8.0 g/dL

• Serum creatinine within normal institutional limits or a creatinine clearance ≥ 45ml/min within 4 weeks prior to registration.

• Women of childbearing potential and male participants must agree to use a medicallyeffective means of birth control throughout their participation in the treatmentphase of the study.

• The patient must provide study-specific informed consent prior to study entry.

Exclusion Criteria:

• cT4, cN3, or cM1 disease (also explained as AJCC 8th edition clinical staging,)

• Patients with radiographic ECE or matted lymph nodes, defined as three nodesabutting one another with loss of intervening fat plane that is a replaced withradiologic evidence of extracapsular spread.

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease freefor a minimum of 3 years (For example, carcinoma in situ of the breast, oral cavity,or cervix are all permissible);

• Any prior therapy for the study cancer; note that prior chemotherapy for a differentcancer is allowable if >3 years prior to study;

• Prior radiotherapy to the region of the study cancer that would result in overlap ofradiation therapy fields;

• Prior allergic reaction or hypersensitivity reactions to paclitaxel, carboplatin orother platinum containing products. This also includes patients with a history ofsevere hypersensitivity reaction to products containing Cremophor EL.

• Severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within thelast 6 months;

• Transmural myocardial infarction within the last 3 months;

• Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of registration;

• Chronic Obstructive Pulmonary Disease (COPD) exacerbation or other respiratoryillness requiring hospitalization or precluding study therapy at the time ofregistration;

• Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition.Note, however, that HIV testing is not required for entry into this protocol.The need to exclude patients with AIDS from this protocol is necessary becausethe treatments involved in this protocol may be significantlyimmunosuppressive.

• Hepatic insufficiency resulting in clinical jaundice and/or coagulationdefects; note, however, that laboratory tests for liver function andcoagulation parameters are not required for entry into this protocol.

• Severe bone marrow depression or significant bleeding

• Pregnancy or women of childbearing potential and men who are sexually active and notwilling/able to use medically acceptable forms of contraception; this exclusion isnecessary because the treatment involved in this study may be significantlyteratogenic.

• For Cohort B, poorly controlled diabetes (defined as fasting glucose level > 200mg/dL) despite 2 attempts to improve glucose control by fasting duration andadjustment of medications. Patients with diabetes will preferably be scheduled inthe morning and instructions for fasting and use of medications will be provided inconsultation with the patients' primary physicians.

• Active enrollment on another clinical trial involving active treatment for the studycancer.