CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: Trinity Health (AA, Canton, Chelsea, Brighton, Livonia), Genesys, Hurley, Saginaw, Sparrow

Eligibility Criteria:

3.2.1 Documentation of Disease Pathologically (histologically or cytologically) proven diagnosis of adenocarcinoma of prostate cancer.

3.2.2 Definition of Disease 1. High-risk disease defined as having at least one or more of the following: o cT3a-T3b by digital exam or imaging (AJCC 8th Ed.) Note: cT4 by imaging or on digital rectal exam is not allowed.

o The patient’s PSA value >20 ng/mL prior to starting ADT Note: Patients taking a 5-alpha reductase inhibitor (ex finasteride or dutasteride) are eligible The baseline PSA value should be doubled for PSAs taken while on 5-alpha reductase inhibitors.

o Gleason Score of 8-10 o Pelvic node positive by conventional imaging with a short axis of at least 1.0 cm 2. Prostate gland volume less than 100 cc prior to initiation of ADT as reported at time of biopsy or by separate measure with ultrasound or other imaging modalities including MRI or CT scan. 3. No definitive clinical or radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e. bone scan, CT scan, MRI); Negative PSMA PET is an acceptable substitute.

3.2.3 Age ≥ 18

3.2.4 ECOG Performance Status of 0-2

3.2.5 Prior Treatment

• No prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;

• No prior radical prostatectomy;

• Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both LHRH agonist and oral anti-androgen) is ≤ 185 days prior to registration; Please note: PSA prior to the start of any ADT will be used to define disease in 3.2.2.

3.2.6 Co-Enrollment with NRG-GU009 (ONLY Applies to Patients enrolled in NRGGU009) Patients enrolled in NRG-GU009 must be enrolled in NRG-GU013 prior to radiation therapy treatment planning and start of radiation therapy. For details, see Section 5.4.  

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

No new sites are allowed to participate in this study per the sponsor effective 5/22/17.
CURRENT SITES CREDENTIALED: Lehigh    

-Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer with documented disease progression (disease not amendable to curative therapy). NOTE: Patients with mucinous histology are NOT eligible.

-All patients must have measurable disease
-Patients are allowed to have received up to three prior cytotoxic regimens for treatment of their disease. They must have had one prior platinum-based chemotherapeutic regimen.
-Patients are allowed to have received, but are not required to have received, one or two cytotoxic regimens for management of recurrent or persistent disease. If two cytotoxic regimens had been received for management of recurrent or persistent disease, one of these regimens would have had to contain either a platinum or a taxane agent. (For the purposes of this study PARP inhibitors given for recurrent or progressive disease will be considered cytotoxic.) 
-ECOG PS must be 0-2
-Patients must have progressed < 12 months after completion of their last platinum-based chemotherapy
-Patients must not have had prior therapy with nivolumab or with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune check point pathways
-Patients must not have CNS disease
-Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded.
-Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration

*Credentialing required. Please check your site's credentialing status.*
**Documentation of GCP training for treating investigator, and research associates (CRAs/ RNs), Conflict of interest form must be completed by the treating investigator, and Documentation of Protocol training for treating investigator, and research associates (CRAs/ RNs)**

CURRENT SITES CREDENTIALED:
Sparrow, SJMH, St. Alphonsus, Oakland, Genesys Hurley, Hurley

-Patients must have platinum-sensitive recurrent high-grade serous or high-grade endometrioid ovarian, primary peritoneal, or fallopian tube cancers. Patients with known deleterious germline BRCA1 or BRCA2 mutation on a clinical assay with an ovarian, primary peritoneal, or fallopian tube cancer of the following other Mullerian histologies are also eligible: clear cell, mixed epithelial, undifferentiated carcinoma, or transitional cell carcinoma.
-Platinum-sensitive disease defined as no disease recurrence for greater than 6 months after last receipt of platinum-based therapy.
-Patients must have had a complete response to their prior line of platinum therapy and cannot have had progression through prior platinum-based therapy. Patients who have no measurable disease following their initial cytoreductive surgery and have no evidence of disease progression for at least 6 months following their last receipt of platinum-based therapy or their date of surgery (whichever is later) will also be considered eligible.
-Patients must have measurable or evaluable disease
-Prior chemotherapy must have included a first-line platinum-based regimen with or without intravenous consolidation chemotherapy.
-Patients may have received an unlimited number of platinum-based therapies in the recurrent setting.
-Patients may have received up to 1 non-platinum-based line of therapy in the recurrent setting. Prior hormonal therapy will not be considered to count as this non-platinum-based line.
-Patients may not have had a prior anti-angiogenic agent in the recurrent setting. Prior use of bevacizumab in the upfront or upfront maintenance setting is allowed.
-Patients may not have previously received a PARP-inhibitor.
-Prior hormonal-based therapy for ovarian, primary peritoneal, or fallopian tube cancer is acceptable.
-ECOG PS must be 0-2
-Toxicities of prior therapy (excepting alopecia) should be resolved to less than or equal to Grade 1
-Patients must not have known brain mets, spinal cord compression or leptomeningeal disease

*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. ***