*DTL REQUIRED- Physicians must sign toxicity grid

Phase II is closed to accrual effective 6/16/17.  

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

-Patients must have histologically or cytologically confirmed ovarian cancer, peritoneal cancer or fallopian tube cancer and must have a histological diagnosis of either serous or endometrioid cancer based on local histopathological findings. Both endometrioid and serous histology should be high-grade for eligibility of non-mutation carriers. Participants with a deleterious germline BRCA-mutation on a commercial CLIA assay with other high-grade histologies, including clear cell, transitional cell, undifferentiated adenoca, mixed epithelial andenoca are also eligible.
-Patients should have recurrent platinum-resistant or- refractory disease - defined as disease that has progressed while receiving platinum or had recurrence within 6 months of the last receipt of platinum-based chemotherapy
-Phase II study: patients must have measurable disease
-Phase III study: patients must have evaluable disease (must NOT have CA-125 disease only)
-Patients must not have had more than 2 prior treatment regimens. Hormonal therapies used as single agents will not count towards this limit.
-Patients must not have had a prior anti-angiogenic agent in the recurrent sitting, but prior use of bevacizumab in the upfront/ upfront maintenance setting is allowed.
-Patients must not have previously received a PART-inhibitor.
-ECOG PS must be 0-2
- Toxicities of prior therapy must have resolved to no more than grade 1
-Patients must not have evidence of brain mets or leptomeningeal disease.

Eligibility Criteria:  

-High grade ovarian cancer, including high grade serous; clear cell; endometrioid, grade 3; and others (adenocarcinoma, NOS; mixed epithelial carcinoma; undifferentiated carcinoma).
-Recurrent, platinum resistant ovarian cancer--defined as progression within < 6 months from completion of platinum based therapy.
-1-2 prior regimens (including primary therapy). Hormonal therapies (e.g., tamoxifen, aromatase inhibitors) will not count toward the prior regimen limit.
-Measurable disease  or evaluable disease
-PS must be 0-2

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

• ANC ≥ 1,500/mcl

• Platelets ≥ 100,000/mcl

• Hgb ≥ 8 g/dl

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

• Creatinine ≤ 1.5 x institutional upper limit of normal (ULN)

• Urine protein creatinine (UPC) ratio must be < 1.0. If UPC ratio > 1, collection of 24- hour urine measurement of urine protein is recommended (24-hour urine protein level must be < 1000 mg for patient enrollment). If UPC ratio cannot be calculated because the urine protein is below the lower limit of detection of the assay this will not exclude the patient.

-UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion – a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm.

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

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

• AST/ALT ≤ 3 x ULN (AST and/or ALT ≤ 5 x ULN for patients with liver involvement)

-INR and aPTT ≤ 1.5 x ULN (or on stable dose of therapeutic anticoagulation, such as lowmolecular-weight heparin, warfarin or rivaroxaban) 

- TSH within normal limits (Euthyroid patients on thyroid replacement therapy allowed provided TSH < ULN.) 

- The patient or 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.
-Patients must not have unresolved adverse events (excluding alopecia)
-Patients must not have prior treatment with anti-PD-1, anti-PD-L1 or anti-CTLA-4 therapeutic antibody or pathway targeting agents.

-Must not have prior treatment with bevacizumab for platinum resistant recurrence
-Must not have prior treatment with PLD or prior RT to the abdomen or pelvis
-Must not be taking bisphosphonate therapy for systemic hypercalcemia within the past 28 days
-Must not have symptomatic CNS disease
-Must not have history or risk of autoimmune disease

**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 noninvasive 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-evaluationher2.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 CNSdirected 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.  

*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 

Eligibility Criteria:

- Histologically confirmed diagnosis of recurrent adult-type granulosa cell tumor.

- Patient must have measurable disease. Measurable disease is defined in the protocol per RECIST 1.1 criteria. 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.

- Patient must have had ≥1 treatment regimen. 

-  Subject must have progressed on an aromatase inhibitor (letrozole, exemestane, anastrozole) in a prior treatment line. 3.2.5 Age ≥ 18 years 

-ECOG Performance Status of ≤ 2 (see Appendix I).

- Not Pregnant and Not Nursing

- Adequate hematologic function defined as follows:

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

• Platelets ≥ 100,000 cells/mm3

 • Hemoglobin ≥ 8 g/dl 

- Adequate hepatic function defined as follows:

• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert’s disease who have bilirubin level ≤ 3 x ULN may be enrolled)

• AST and ALT ≤ 1.5 x institutional ULN

-Adequate cardiac function defined as follows:

• 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. To be eligible for this trial, patients should be class 2B or better (See Appendix II) 

- Comorbid conditions

• No active infection requiring parenteral antibiotics;

• No current evidence of intra-abdominal abscess, abdominal/pelvic fistula (not diverted), gastrointestinal perforation, GI obstruction, and/or need for drainage nasogastric or gastrostomy tube 

- 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 any of the following conditions are NOT eligible for this study.

- Prior treatment with AR inhibitors

- Known hypersensitivity to the study drugs or their ingredients. 

**Please see the current version of protocol for entire eligibility list. ***

 *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

*Credentialing required. **MBS substudy requires additional credentialing.  Please check your site's credentialing status.*
CURRENT SITES CREDENTIALED for main study:
Livonia, SJMH, St. Alphonsus 
Sites credentialed for MBS substudy:
None

Step 1 Eligibility:
-Pathologically proven diagnosis of squamous cell carcinoma (including the histological variants papillary squamous cell carcinoma and basaloid squamous cell carcinoma) of the oropharynx (tonsil, base of tongue, soft palate, or oropharyngeal walls)
-Patients must have clinically or radiographically evident measurable disease at the primary site or at nodal stations.
-Immunohistochemical staining for p16 must be performed on tissue, and this tissue must be submitted for central review.
-Clinical stage T1-T2, N1-N2b or T3, N0-N2b including no distant metastases
-Patients must provide their personal smoking history prior to registration. The lifetime cumulative history cannot exceed 10 pack-years.
-Zubrod Performance Status must be 0-1
-Patients must not have ancers considered to be from an oral cavity site (oral tongue, floor mouth, alveolar ridge, buccal or lip), or the nasopharynx, hypopharynx, or larynx, even if p16 positive;
-Patients must not have carcinoma of the neck of unknown primary site origin (even if p16 positive);
-Patients must not have radiographically matted nodes, defined as 3 abutting nodes with loss of the intervening fat plane;
-Patients must not have supraclavicular nodes, defined as nodes visualized on the same axial imaging slice as the clavicle;
-Patients must not have definitive clinical or radiologic evidence of metastatic disease or adenopathy below the clavicles;
-No prior systemic chemotherapy for the study cancer
-No prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;

Step 2 Eligibility:
-p16 positive by immunohistochemistry (defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells, confirmed by central pathology review;

DTL Required- Physicians must sign the toxicity grids

Current Sites Credentialed: SJMH- (AA, Brighton, Canton, Chelsea), Sparrow, Saginaw

-Patients must have pathologically confirmed, previously untreated, unresected squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or carcinoma of unknown head/neck primary within 60 days prior to Step 1 registration.

-Patients must have stage III-IVB HNSCC (AJCC 7th

edition) based on the following minimum diagnostic workup within 60 days prior to Step 1 registration

-For larynx, hypopharynx, and base of tongue primaries, a laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is required, unless the patient cannot tolerate or refuses -

Age = 70 with moderate to severe comorbidity or vulnerability to cisplatin, defined as having one or more of the following conditions within 30 days prior to Step 1 registration:

--Modified Charlson Comorbidity Index = 1

--ACE-27 Index = 1

--GCE ?PFS score < 0.60

--G-8 score =14

--CARG Toxicity Score =30%

--CIRS-G Score =4
OR

Age < 70 with severe comorbidity or vulnerability to cisplatin, defined as having two or more of the following conditions within 30 days prior to Step 1 registration

--Modified Charlson Comorbidity Index = 1

--ACE-27 Index = 1

--GCE ?PFS-score < 0.60

--G-8 score =14

--CARG Toxicity Score =30%

--CIRS-G Score =4

OR

Age =18 with an absolute or relative contraindication to cisplatin, defined as one or more of the following within 30 days prior to Step 1 registration:

-Creatinine clearance (CC) > 30 and < 60 cc/min

-Zubrod performance status 2 prior to Step 1 registration

-Prior invasive malignancy within the past 3 years

-Zubrod performance status = 3

-Body weight = 30 kg