Eligibility Criteria:

3.1.1Patients must have recurrent or persistent endometrial carcinoma, which is refractory to curative therapy or established treatments. Histologic confirmation of the original primary tumor is required. Patients with the following histologic epithelial cell types are eligible: Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified (N.O.S.). NOTE: Clear cell and carcinosarcoma histology is excluded.

3.1.2 Patients must have measurable disease as defined by RECIST 1.1 or non-measurable (detectable) disease.

3.1.2.1 Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be >10 mm when measured by CT, MRI or caliper measurement by clinical exam; or > 20 mm when measured by chest x-ray. Lymph nodes must be > 15 mm in short axis when measured by CT or MRI (See section 14). Patients with measurable disease must have at least one “target lesion” to be used to assess response on this protocol as defined by RECIST version 1.1 (Section 14). Tumors within a previously irradiated field will be designated as “non-target” lesions unless progression is documented, or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy.

3.1.2.2 Non-measurable (detectable) disease in a patient is defined in this protocol as one who does not have measurable disease but has at least one of the following conditions:

• Ascites and/or pleural effusion attributed to tumor.

• Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 (see Section 14) definitions for target lesions.

3.1.3 Patients must have signed an approved informed consent and authorization permitting release of personal health information. 

3.1.4 Prior Therapy:

3.1.4.1 Patients must have had one prior chemotherapeutic regimen for management of endometrial carcinoma. Initial treatment may include chemotherapy, chemotherapy and radiation therapy, and/or consolidation/maintenance therapy. Chemotherapy administered in conjunction with primary radiation as a radio-sensitizer WILL be counted as a systemic chemotherapy regimen.

3.1.4.2 Patients are allowed to receive, but are not required to receive, one additional cytotoxic regimen for management of recurrent or persistent disease according to the following definition: Cytotoxic regimens include any agent that targets the genetic and/or mitotic apparatus of dividing cells, resulting in dose-limiting toxicity to the bone marrow and/or gastrointestinal mucosa. Note: Patients on this non-cytotoxic study are allowed to receive one additional cytotoxic chemotherapy regimen for management of recurrent or persistent disease, as defined above. However, due to the novel nature of biologic compounds, patients are encouraged to enroll on second-line non-cytotoxic studies prior to receiving additional cytotoxic therapy.  

**PLEASE SEE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST**

**Effective 06/15/22, Step 1 is Closed to Accrual**  

** Closed to enrollment for endometrial patients as of 7/26/19 **

**Effective 02/08/2022: REOPENED TO ACCRUAL for patients with Ovarian Clear Cell Carcinoma with ARID1A mutation only** 

--Pathologically (histologically or cytologically) proven diagnosis of recurrent or persistent ovarian endometrioid or clear cell carcinoma, OR recurrent or persistent endometrioid endometrial adenocarcinoma. Patients with recurrent endometrial cancer must have MMR immunohistochemistry completed. If they are found to be mismatch repair deficient, they should be offered treatment with immune checkpoint inhibition before consideration for treatment on trial.
-Primary ovarian tumors must be at least 50% endometrioid or clear cell morphology, or have histologically documented recurrence with at least 50% endometrioid or clear cell morphology. Institutional pathology reports must be provided indicating at least 50% endometrioid or clear cell morphology for ovarian tumors (primary or recurrent lesions).
-All patients must have measurable disease as defined by RECIST v 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be = 10 mm when measured by CT, MRI or caliper measurement by clinical exam; or = 20 mm when measured by chest x-ray. Lymph nodes must be =15 mm in short axis when measured by CT or MRI. Refer to Section 13.1.2

for details if in site of previous radiation.
-Patients must have had at least one, but no more than 3, prior cytotoxic regimens for management of primary disease. Unlimited prior hormonal therapy, targeted therapy (including immunotherapy) or antiangiogenic therapy will be permitted.
-Appropriate stage for study entry based on the following diagnostic workup:

• History/physical examination within 14 days prior to registration;

• Imaging of the chest, abdomen and pelvis within 28 days prior to registration
-ECOG Performance Status of 0, 1 or 2 within 14 days prior to registration
-Adequate hematologic function within 14 days prior to registration defined as follows:

• Platelets = 100,000/mcl

• ANC = 1,500/mcl

• Manual differential with no significant morphologic abnormalities on complete blood count (CBC) testing.

-Adequate renal function within 14 days prior to registration defined as follows:

• GFR =50 mL/min/1.73m2

• GFR (estimated creatinine clearance or CLcr) will be estimated using the Cockcroft and Gault equation for females: CLcr (mL/min) = 0.85 x (140-age [years]) x weight (kg) / (creatinine [mg/dL] x 72).

Followed by conversion to a value normalized to 1.73m2 with the patient’s BSA.
-Adequate hepatic function within 14 days prior to registration defined as follows:

• AST and ALT = 3 x ULN

• Total serum bilirubin level = 1.5 x ULN; Direct bilirubin = ULN for subjects with total bilirubin > 1.5 x ULN (patients with isolated indirect bilirubin elevations and a history of Gilbert’s Syndrome are eligible)
-

Prior Therapy	Time from Last Prior Therapy Regimen
Chemotherapy: cytotoxic	At least 28 days since last dose of chemotherapy prior to registration.
Chemotherapy: nitrosoureas	At least 6 weeks since last dose of chemotherapy prior to registration.
Chemotherapy: non- cytotoxic (e.g. small molecule inhibitor)	At least 28 days since last dose of chemotherapy prior to registration.
Monoclonal antibody(ies)	At least 28 days since last dose of monoclonal antibody prior to registration.
Immunotherapy	At least 28 days since last dose of immunotherapy prior to registration.
Radiotherapy (RT)	At least 14 days from last local site RT prior to registration. At least 21 days from stereotactic radiosurgery prior to registration. At least 12 weeks from craniospinal, =50% radiation of pelvis or total body irradiation prior to registration. Patients with CNS disease should demonstrate evidence of stabilization after the 28-day time point after definitive treatment. Full recovery of radiation related side effects prior to registration. All subjects must have evidence of measurable disease  outside of the radiation field at the time of registration.

***Effective 08/17/22, Enrollment of dMMR patients is Closed to Accrual***

Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

***DTL Required- Physicians must sign toxicity grid***

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH, Sparrow, LVHN, Geneseys

***(Please note that these site statuses have reverted back to "Pending" until the Specific Protocol Training for Amendment #5 has been completed/submitted)

Eligibility Criteria:

Patients must have newly diagnosed, Stage II-IV low-grade serous ovarian cancer (submission of pathology report(s) required). Ovarian cancer = ovarian, fallopian tube and primary peritoneal cancers. p53 immunohistochemistry (IHC) is required and must show nonaberrant pattern (nonaberrant p53 expression is consistent with normal/wildtype TP53). If aberrant p53 expression is found on p53 IHC, the patient is NOT eligible (aberrant p53 expression is consistent with mutant TP53 and supports diagnosis of high grade serous ovarian cancer).

A copy of the pathology report that includes the diagnosis of low grade serous ovarian cancer and nonaberrant p53 IHC result must be submitted in RAVE.

- Appropriate stage for study entry based on the following diagnostic workup:

• History/physical examination within 14 days prior to registration;

• Contrast-enhanced Imaging of the chest, abdomen and pelvis within 28 days prior to registration; 

- Age = 18

- Patients must have undergone an attempt at maximal upfront cytoreductive surgery, with either optimal (<=1cm diameter residual disease/nodule) or suboptimal residual disease (>1 cm diameter residual disease/nodule) status allowed.

Patients must have undergone a bilateral salpingo-oophorectomy

- Patients must have an ECOG Performance Status of 0, 1 or 2 within 14 days prior to registration (Appendix I).

- Patients must be within =8 weeks of primary cytoreductive surgery at time of randomization.

- Patients must be able to take per oral (P.O.) medications.

- Patients must have adequate organ and marrow function as defined below:

NOTE: Institutional/laboratory upper limit of normal = ULN

- Bone marrow function within 14 days prior to registration defined as follows:

• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl

• Platelets greater than or equal to 100,000 cells/mcl 3.2.9.2 Adequate renal function within 14 days prior to registration defined as follows:

• Creatinine less than or equal to 1.5 x ULN

Adequate hepatic function within 14 days prior to registration defined as follows:

• Bilirubin less than or equal to 1.5 x ULN

• ALT and AST less than or equal to 3 x ULN 3.2.10 The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.

Ineligibility Criteria:

Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

- Patients may not have received neoadjuvant chemotherapy or radiotherapy for the treatment of this disease.

- Patients may not have received previous hormonal therapy for the treatment of this disease.

- Patients with known hypersensitivity to letrozole or hypersensitivity/intolerance to carboplatin/paclitaxel therapy.

- Patients with severe cardiac disease:

• Myocardial infarction or unstable angina within 6 months prior to registration.

• New York Heart Association (NYHA) Class II or greater congestive heart failure (Appendix II). 3.3.6 Patients with known central nervous system metastases

- Patients with active (except for uncomplicated urinary tract infection) or uncontrolled systemic infection.

- Patients with =grade 2 baseline neuropathy

Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

**ePRO training required prior to first patient enrollment.** 

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: Trinity Health IHA (Ann Arbor, Brighton, Canton, Chelsea), Livonia, Genesys, Hurley, Oakland, Lehigh

Eligibility Criteria:

FIGO 2009 Stage IA-IVB, non-recurrent, chemo-naïve, HER2-positive endometrial serous carcinoma or endometrial carcinosarcoma. See Appendix I. Histologic confirmation of the original primary tumor is required. Submission of surgical pathology report (or endometrial biopsy pathology report in patients who never undergo hysterectomy) is required. Patients must be within 8 weeks of primary surgery (or endometrial biopsy in patients who never undergo hysterectomy) at the time of study registration.

3.1.2 Patients may have measurable disease, non-measurable disease, or no measurable disease. In patients with measurable disease, lesions will be defined and monitored by RECIST v 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be ≥ 10 mm when measured by CT or MRI. Lymph nodes must be ≥ 15 mm in short axis when measured by CT or MRI. For patients with uterine-confined (stage I) disease, the tumor must be invasive into the myometrium. Any amount of myoinvasion is acceptable for eligibility. Patients with non\u0002invasive disease, endometrial intraepithelial carcinoma alone, or disease confined to a polyp will be excluded.

3.1.3 Additionally, patients must have the following histologic types to be eligible:

• Serous adenocarcinoma (may include ≤10% non-serous histology) 

• Carcinosarcoma with serous epithelial component (only the serous component needs to be HER2 positive as defined in Section 3.1.4; may include ≤10% non-serous histology)

• In cases where determination of serous is equivocal or challenging, aberrant p53 immunohistochemistry (IHC) (defined as overexpression of p53 compared to internal controls) will be sufficient for inclusion.

3.1.4 All patients must have tumors that are HER2 positive as defined by ASCO/CAP 2018 Breast Cancer guidelines (https://documents.cap.org/documents/algorithim-evaluation\u0002her2.pdf. In general HER2 positivity is defined as any of the following: ? 3+ immunohistochemistry (IHC), ? 2+ IHC with positive in situ hybridization (ISH) ? Average HER2 copy number ≥ 6.0 signals/cell ? Average HER2 copy number ≥ 4.0 and < 6.0 signals/cell, with concurrent IHC 3+ ? HER2/CEP17 ratio ≥ 4.0 signals/cell ? HER2/CEP 17 ratio ≥ 2.0 and < 4.0, with concurrent IHC 3+ IHC and ISH testing will be done locally, at each participating institution and interpreted by local pathologists. Alternatively, patients could be eligible if next generation sequencing (NGS) demonstrates HER2 (ERBB2) amplification. NGS testing can be performed through any designated labs as per the NCI MATCH/NCI Combo-MATCH trial (https://ecog-acrin.org/nci-match-eay131-designated-labs). Pathology report showing results of institutional HER2 testing (or NGS testing results) must be submitted. Sites must submit all results available (IHC, ISH, and NGS).

3.1.5 ECOG Performance Status of 0, 1 or 2. See Appendix III. 3.1.6 Age ≥ 18.

3.1.7 Adequate hematologic function within 14 days prior to registration defined as follows:

• Platelets ≥ 100,000/mcl

• Absolute neutrophil count (ANC) ≥ 1,500/mcl.

3.1.8 Adequate renal function within 14 days prior to registration defined as follows: Creatinine ≤ 1.5 x institutional/laboratory upper limit of normal (ULN) or estimated Glomerular filtration rate (eGFR) ≥ 50 mL/min using either the Cockcroft-Gault equation, the Modification of Diet in Renal Disease Study, or as reported in the comprehensive metabolic panel/basic metabolic panel (eGFR).

3.1.9 Adequate hepatic function within 14 days prior to registration defined as follows:

• Total serum bilirubin level ≤ 1.5 x ULN (patients with known Gilbert’s disease who have bilirubin level ≤ 3 x ULN may be enrolled)  

AST and ALT ≤ 3 x ULN.

3.1.10 HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.

3.1.11 Although the uterus will have been removed in the vast majority of patients, for patients of child-bearing potential: negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. Patients will be considered of non-reproductive potential if they are either:

• Postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women <45 years of age, a high follicle stimulating hormone [FSH] level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient); OR

• Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion at least 6 weeks prior to registration.

• Have a congenital or acquired condition that prevents childbearing.

3.1.12 Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. NOTE: Patients with prior anthracycline exposure are NOT eligible.

3.1.13 Patients with evidence of chronic hepatitis B virus (HBV) infection must have an undetectable HBV viral load on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

3.1.14 Patients with treated brain metastases are eligible if follow-up brain imaging after CNS\u0002directed therapy shows no evidence of progression.

3.1.15 The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.

Ineligibility Criteria 

3.2.1 Prior Therapy:

• Patients must NOT have received prior chemotherapy, biologic therapy, or targeted therapy for treatment of endometrial carcinoma.

• Patients must NOT have received prior radiation therapy for treatment of endometrial carcinoma. Prior radiation includes external beam pelvic radiation therapy, external beam extended field pelvic/para-aortic radiation therapy, and/or intravaginal brachytherapy. NOTE: Vaginal brachytherapy for treatment of endometrial cancer is permitted during study treatment (See Section 5.2). Planned use of vaginal brachytherapy must be declared at time of registration.

• Patients may have received prior hormonal therapy for treatment of endometrial carcinoma. All hormonal therapy must be discontinued at least one week prior to registration.

3.2.2 Patients may not have a planned interval cytoreduction or hysterectomy, prior to documentation of progression, after study registration.

3.2.3 Patients may not have planned external beam radiotherapy, prior to documentation of progression, after study registration.

3.2.4 Significant cardiovascular disease including:

• Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm Hg despite antihypertensive medications.

• Myocardial infarction or unstable angina within 6 months prior to registration.

• New York Heart Association functional classification II, III or IV (See Appendix IV).

• Serious cardiac arrhythmia requiring medication. This does not include asymptomatic, atrial fibrillation with controlled ventricular rate.

3.2.5 Significant lung disease: dyspnea at rest grade 2 or greater (resulting from extensive tumor involvement or other causes), pneumonitis grade 2 or greater, interstitial lung disease grade 2 or greater, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia).

3.2.6 Patients with uncontrolled intercurrent illness including, but not limited to: ongoing or active infection (except for uncomplicated urinary tract infection), uncontrolled interstitial lung disease, symptomatic congestive heart failure, or psychiatric illness/social situations that would limit compliance with study requirements.

3.2.7 Treatment with strong CYP2C8 or CYP3A4 inhibitors or inducers within 14 days or 5 drug-elimination half-lives, whichever is longer, prior to registration.

3.2.8 Women who are unwilling to discontinue nursing.  

Eligibility Criteria:

A patient cannot be considered eligible for this study unless ALL of the following conditions are met. 3.2.1 Documentation of Disease

Patients with newly diagnosed, pathologically confirmed, FIGO Stage III or IV ovarian cancer of the following types:

• high grade serous,

• high grade endometrioid, and/or

• other epithelial ovarian cancer with BRCA1/2 deleterious alteration (germline or somatic). Submission of pathology report is required Ovarian cancer = ovarian, fallopian, or primary peritoneal cancer.

Patients must have:

1) Documented variant (tumor or germline) in BRCA1 or BRCA2 that is predicted to be pathogenic or suspected pathogenic (deleterious alteration).

• Submission of testing report is required. OR

2) BRCA 1/2 wildtype AND known HRD deficient tumor determined by any commercial or academic, CLIA-certified laboratory (e.g., Myriad MyChoice©)

• Submission of testing report is required.

3.2.2 Prior Treatment

Patient must have undergone cytoreductive surgery (primary or interval).

Patients must have completed first line platinum-based therapy prior to registration:

• Platinum based chemotherapy course must have consisted of a minimum of 4 treatment cycles and a maximum of 9, although it is strongly recommended that patients receive at least 6 cycles unless medically contraindicated.

o For those receiving less than 6 cycles of platinum-based therapy, the reason for this must be documented and could include hematologic toxicity or non\u0002hematologic toxicities directly related to therapy.

• Intravenous, intraperitoneal, or neoadjuvant platinum-based chemotherapy is allowed; for weekly therapy, three weeks are considered one cycle.

• Patients must not have received an investigational agent during their first line course of chemotherapy. Patients must have, in the opinion of the investigator, no clinical evidence of disease progression following completion of this chemotherapy course (partial or complete response to platinum-based chemotherapy).

Patients with treated brain metastases are eligible if follow up brain imaging after CNS directed therapy shows no evidence of progression and patients are neurologically stable off steroid therapy. Patients must be randomized at least 3 weeks and no more than 12 weeks after their last dose of chemotherapy (last dose is the day of the last infusion of platinum agent).

No previous treatment with a PARP inhibitor, including olaparib, niraparib, and rucaparib

3.2.3 Age ≥ 18

3.2.4 ECOG Performance Status of ≤ 2 See Appendix I for performance criteria.

3.2.5 Not Pregnant and Not Nursing 3.2.6 Required Organ Function Adequate hematologic function defined as follows:

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

• Platelets ≥ 100,000 cells/mm3

• Hemoglobin ≥ 9 g/dl

** PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY LIST**

DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.

CURRENT SITES CREDENTIALED:

Eligibility Criteria:

3.2.1 Documentation of Disease

Patients must have pathologically confirmed newly diagnosed cervical cancer. Eligible pathologic types: squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma

3.2.2 Definition of Disease

Patients must have locally advanced cervical cancer (LACC) with T3 or T4 disease with or without lymph node involvement (see Appendix 1 for FIGO and TMN staging):

• IIIA (T3aN0M0)

• IIIB (T3bN0M0)

• IIIC1(T3aN1M0, T3bN1M0)

• IIIC2 (T3aN2M0, T3bN2M0)

• IVA (T4aN0M0, T4aN1M0, T4aN2M0)

No prior hysterectomy defined as removal of the entire uterus. NOTE: prior partial/subtotal hysterectomy for reasons other than cervical cancer are eligible to participate in the study. No plan to perform a hysterectomy as part of initial cervical cancer therapy.

No paraaortic lymph node (PALN) metastases above the T12/L1 interspace. 

Note: Nodal status can be confirmed by imaging (CT, MRI, or PET/CT), fine needle aspirate/core biopsy, extra peritoneal biopsy, laparoscopic biopsy, or lymphadenectomy.

Radiologic Definition of Lymph node staging:

N1:

• One or more pelvic lymph nodes with short axis diameter of ≥ 15 mm (axial plane) by CT or MRI, and/or

• One or more pelvic lymph nodes with short axis diameter of ≥ 10 mm and SUVmax ≥ 2.5 by FDG-PET N2:

• One or more para-aortic lymph node with short axis diameter of ≥ 15 mm (axial plane) by CT or MRI, and/or

• One or more para-aortic lymph node with short axis diameter of ≥ 10 mm and SUVmax ≥ 2.5 by FDG-PET.  

3.2.3 Prior Treatment

• No prior definitive surgical, radiation, or systemic therapy for cervical cancer.

• No prior immunotherapy.

• No prior pelvic radiation therapy for any disease.

3.2.4 Age ≥ 18

3.2.5 ECOG Performance Status of ≤ 2  

 **PLEASE SEE THE CURRENT VERSION OF PROTOCOL FOR FULL ELIGIBILITY **

 *Credentialing required. Please check your site's credentialing status.*
CURRENT SITES CREDENTIALED:
Livonia, SJMH, SJMO, Sparrow, Saginaw

-Biopsy proven (from primary lesion and/or lymph nodes) diagnosis of cancer of the nasopharynx;
-Patients must have detectable pretreatment plasma EBV DNA, determined by the central lab
-Stage II-IVB disease with no evidence of distant metastasis
-Zubrod Performance Status must be 0-1
-Patients must not have prior systemic chemotherapy for the study cancer
-Patients must not have prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields

** Temporarily Closed p16-positive OPC/CUP Cohort Effective 10/07/2024**

**Temporarily Closed: Non-OPC/p16-negative OPC Cohort (Effective 09/19/2025) **

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Chelsea, Canton), St. Mary's Livonia, Genesys, St Joseph Mercy Oakland

Eligibility Criteria:

-A patient cannot be considered eligible for this study unless ALL of the following conditions are met.

-Pathologically (histologically or cytologically) proven diagnosis of SCCHN of the oropharynx, larynx, hypopharynx, or p16-positive unknown primary prior to registration; specimen from cervical lymph nodes with a well-defined primary site documented clinically or radiologically is acceptable; in patients with carcinoma of unknown primary this will be sufficient for pathologic confirmation without a clinically or radiographically defined primary site. For patients with oropharyngeal cancer (OPC)/cancer of unknown primary (CUP): P16 status based on local site immunohistochemical tissue staining is required. A cell block obtained from a fine needle aspiration (FNA) biopsy specimen may be used as the sole diagnostic tissue. Centers are encouraged to contact the pathology chair for clarification. Note: Institutions must screen patients for p16 status by immunohistochemistry (IHC) in order to be eligible for the trial using a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. A rigorous laboratory accreditation process similar to the U.S. CLIA certification, such as the provincial accreditation status offered by the Ontario Laboratory Accreditation (OLA) Program in Canada, the College of American Pathologists (CAP), or an equivalent accreditation in other countries, is acceptable. The p16 results must be reported on the pathology report being submitted. The p16 positivity is defined as > 70% of tumor cells showing strong nuclear and/or cytoplasmic immunostaining with p16 antibody. For patients with laryngeal and hypopharyngeal primaries: Analysis of p16 status is NOT required;

- Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations. Simple tonsillectomy or local excision of the primary without removal of nodal disease is permitted, as is excision removing gross nodal disease but with intact primary site. Limited neck dissections retrieving ≤ 4 nodes are permitted and considered as non-therapeutic nodal excisions.  

-Clinical stage (AJCC, 8th ed.) as indicated in the tables below, including no distant metastases based on the following diagnostic workup:  

• History/physical examination within 60 days prior to registration;

• One of the following imaging studies is required within 60 days prior to registration:

1. CT scan of neck (diagnostic quality with contrast, unless contraindicated) OR

2. MRI of the neck (diagnostic quality with contrast, unless contraindicated) OR

3. FDG-PET/CT of the neck; the CT component should be of diagnostic quality with contrast, unless contraindicated. Note: A diagnostic quality CT or MRI with contrast or FDG-PET/CT scan of neck performed for the purposes of radiation planning may serve as both staging and planning tools.

• One of the following imaging studies is required within 60 days prior to registration:

1. FDG-PET/CT of the chest; FDG-PET/CT scan is strongly preferred and highly recommended to be used for eligibility. OR 2. Chest CT

• Exam with laryngopharyngoscopy (mirror or in office direct procedure acceptable) within 70 days prior to registration;

 The following formula is used to calculate the pack-years during the periods of smoking in the patient’s life; the cumulative total of the number of pack-years during each period of active smoking is the lifetime cumulative history. Number of pack-years = [Frequency of smoking (number of cigarettes per day) × duration of cigarette smoking (years)] / 20

- Age ≥ 18;

- Zubrod (ECOG) performance status of 0-1 within 14 days prior to registration;

- Adequate hematologic function within 30 days prior to registration defined as follows:

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

• Platelets ≥ 75,000 cells/mm3

• Hemoglobin ≥ 8.0 g/dL

(Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dL is acceptable).

- Adequate renal function within 30 days prior to registration defined as calculated creatinine clearance (CrCl) ≥ 50 mL/min by the Cockcroft-Gault formula: CrCl (mL/min) = [140 – age (years)] x weight (kg) {x 0.85 for female patients} 72 x serum creatinine (mg / dL) 3.1.8 Adequate hepatic function within 30 days prior to registration defined as follows:

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (not applicable to patients with known Gilbert’s syndrome);

• AST and ALT ≤ 1.5 x institutional ULN.

- Known human immunodeficiency virus (HIV) infected patients on effective anti\u0002retroviral therapy with undetectable viral load within 6 months and CD4 T Cell count > 200 cells/mm3 are eligible for this trial. Testing is not required for entry into protocol.

- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. 

- Negative urine or serum pregnancy test (in persons of childbearing potential) within 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes.

- Willing to use highly effective contraceptives for participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) during therapy and for 14 months (females); for 11 months (males) following last dose of cisplatin; this inclusion is necessary because the treatment in this study may be significantly teratogenic (See Section 9 for definition of highly effective contraception).

- The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the U.S., authorization permitting release of personal health information.

2 Ineligibility Criteria Patients with any of the following conditions are NOT eligible for this study.

- Patients with oral cavity cancer, nasopharynx cancer, or p16-negative cancer of unknown primary (CUP);

- Recurrence of the study cancer;

- Definitive clinical or radiologic evidence of distant metastatic disease; 3.2.4 Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable, however, any prior exposure to cisplatin is excluded;

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

- Severe, active co-morbidity defined as follows:

• Unstable angina requiring hospitalization in the last 6 months;

• Myocardial infarction within the last 6 months;

• New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.);

• Persistent Grade 3-4 (CTCAE version 5.0) electrolyte abnormalities that cannot be reversed despite replacement as indicated by repeat testing;

• Patient must not have an active infection requiring IV antibiotics prior to registration;

• Other chronic renal disease like nephrotic syndrome, that could be worsened by cisplatin therapy;

• History of allogenic organ transplantation;

• Any symptomatic peripheral sensory neuropathy Grade ≥ 2 (CTCAE version 5.0);

- Pregnancy and individuals unwilling to discontinue nursing. 

-Inclusion of Women and Minorities NIH policy requires that women and members of minority groups and their subpopulations be included in all NIH-supported biomedical and behavioral research projects involving NIH-defined clinical research unless a clear and compelling rationale and justification establishes to the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. Exclusion under other circumstances must be designated by the Director, NIH, upon the recommendation of an IC Director based on a compelling rationale and justification. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources. Women of childbearing potential should not be routinely excluded from participation in clinical research. Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf