Effective after 11/15/24- Only participants that consider their primary, or part of their race, to be Black or African American, and/or consider their ethnicity to be Hispanic or Latin American, will be able to screen into the study.

*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, Chealsea, and Livonia, GenHur, Lehigh

Eligibility Criteria:

4.1.1 Participants must have been registered to Master Screening and Re-Assessment Protocol (myeloMATCH MSRP) prior to consenting to this study. Participants must have been assigned to this clinical trial, via MATCHBox Protocol Assignment Team, prior to registration to this study. Participants must have agreed to have specimens submitted for translational medicine (MRD) and must be offered the opportunity to submit biosamples for banking for future research as per the myeloMATCH MSRP. Note: Pre-enrollment/diagnosis labs must have already been performed under the MSRP. See Appendix IX.

4.1.2 Previously untreated, de novo AML defined by >20% myeloblasts in the peripheral blood or bone marrow ( refer to the 2016 updated WHO classification of Myeloid Neoplasms and Acute leukemia) excluding all the following categories of AML (a through g):

a. Favorable cytogenetics: (t(8;21)q22;q22.1); RUNX1-RUNX1T1, inversion 16(p13.1;q22), t(16;16)(p13.1;q22);CBFB-MYH11

b. CEBPA biallelic mutations

c. NPM1 mutation

d. AML with PML-RARa

e. AML with any adverse cytogenetics, TP53 mutation, RUNX1 mutation, ASXL1, 11q23/KMT2 rearrangements

f. AML with FLT3-ITD or FLT3-TKD mutations

g. Therapy related AML, or AML following a diagnosis of myelodysplasia or myeloproliferative neoplasm Participants with CNS disease are eligible for this trial and will be treated according to institutional guidelines with intrathecal chemotherapy for this aspect of their disease.

4.1.3 Age 18-59 years at time of induction therapy 

4.1.4 ECOG performance status ≤ 3.

4.1.5 Patients must have adequate organ function as defined below (must be done within 7 days of enrollment):

a. total bilirubin ≤ 2x institutional upper limit of normal (ULN)

b. AST (SGPT) +/or ALT (SGOT) ≤3 × institutional ULN

c. Cardiac ejection fraction ≥ 50% (echocardiography or MUGA)

d. Calculated Creatinine Clearance ≥30 mL/min/ 1.73m2. Clearance to be calculated using Cockcroft formula.

4.1.6 WBC must be <25x109 /L. Hydroxyurea and leukapheresis are permitted to control the WBC prior to enrollment and initiation of protocol-defined therapy but must be stopped at least 24 hours prior to the initiation of protocol therapy.

4.1.7 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.

4.1.8 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.

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

*Credentials required. Check your site's credentialing status.
CURRENT SITES CREDENTIALED:
SJMH, Sparrow, St. Alphonsus, SJMO, Livonia, St. John,  Macomb, Saginaw, Lehigh

-Diagnosis of rectal adenocarcinoma
-Radiologically measurable or clinically evaluable disease
-ECOG PS must be 0-2
-For this patient, the standard treatment recommendation in the absence of a clinical trial would be combined modality neoadjuvant chemoradiation followed by curative intent surgical resection
-Candidate for sphincter-sparing surgical resection prior to initiation of neoadjuvant therapy according to the primary surgeon
-Clinical stage: T2N1, T3N0, T3N1
-Tumor must not be adherent or invading the mesorectal fascia such that an R0 resection couldn't be performed
-Tumor must not be causing syptomatic bowel obstruction
-Patient must not have received chemotherapy within 5 years
-Patient must not have had prior pelvic RT

5-FU treatment:  5-day continuous infusion = 96 hrs; 7-day continuous infusion = 168 hrs 

Note: The required  biopsy for registration should be done 60 days, a new biopsy will be needed in order to comply with the test schedule requirements. The new biopsy does not need to be done prior to the registration, but it will need to be completed before treatment begins.

*Credentialing Required. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED:
SJMH, St. Marys Saginaw
*Check for eligibility to DCP-001*

-Suspected MDS or MDS/MPN overlap disorders and undergoing diagnostic work-up with planned bone marrow assessments OR
-Diagnosed with de novo or therapy- related MDS within 6 months of enrollment per WHO criteria and undergoing clinical evaluation and planned bone marrow assessments to confirm MDS or evaluate disease status
-Bone marrow aspirate expected to be performed within 1 week of reg and no later than 4 weeks post enrollment
-No prior treatment for MDS at entry and through the time of the entry bone marrow aspirate
-No treatment with hematopoietic growth factors in prior 6 months
-No treatment with RT in past 2 years
-No non-hormonal treatment for malignancy in the past 2 years

For new registrations: Look for NHLBI-MDS BL study Aid under the IRB library and patient documents tabs - questionnaire will be needed for baseline data entry. 

**Effective 12/20/16, the photon cohort of this study is closed to accrual. SJMH can no longer participate.
*Credentialing required. Please check your site's credentialing status.*
CURRENT SITES CREDENTIALED:
St. Alphonsus, SJMH
Please note: MCRC is not participating in the Advanced Imaging Substudy.

Step 1
-A diagnostic contrast-enhanced MRI (no other scan type allowed) of the brain must be performed postoperatively within 72 hours of resection. The enhancing tumor must have a maximal diameter of 5 cm. For cases where residual disease or postoperative surgical cavity is NOT identifiable, the patient will be excluded from the trial. 
-The GBM tumor must be located in the supratentorial compartment only (any component involving the brain stem or cerebellum is not allowed). 

Step 2:
-Patients must have histologically proven diagnosis of glioblastoma (WHO grade IV) confirmed by central review.
-Diagnosis must be made by surgical excision, either partial or complete. Stereotactic biopsy or CUSA technique are not allowed. 
-Karnofsky performance status must be greater than or equal to 70
-Patients must not have recurrent or multifocal malignant gliomas.
-Patients must not have any site of distant disease
-Patients must not have had prior chemotherapy or radiosensitizers for cancers of the head and neck region
-Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted. 
-Patients must not have had prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields     

**DTL is required for this study- Physicians must sign the toxicity grids

Current sites credentialed: SJMH (Ann Arbor, Brighton, Canton, Chelsea), St. Mary's Livonia, Saginaw, Genesys, St. John Hospital, Macomb, LVHN

Eligibility Criteria:

Prior to Step 1 Registration:

3.1.1 No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered).

3.1.2 Availability of FFPE tumor tissue block and H&E stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status (See Sections 3.1.1, 3.1.2, and 10). Note that tissue for central pathology review and central MGMT assessment must be received by the NRG Oncology Biospecimen Bank on or before postoperative calendar day 23. If tissue cannot be received by postoperative calendar day 23, then patients may NOT enroll on this trial as central pathology review and stratification will not be complete in time for the patient to start treatment no later than 6 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be conveyed to NRG Oncology within 10 business days of receipt of tissue.

3.1.3 Contrast-enhanced brain MRI within 72 hours after surgery.

• MRI with Axial T2 weighted FLAIR{preferred} or T2 TSE/FSE and 3D contrast-enhanced T1 sequences are required.

• 3D pre contrast-enhanced T1 sequences are strongly suggested.

3.1.4 Women of childbearing potential (WOCBP) and men who are sexually active with WOCBP must be willing to use an adequate method of contraception hormonal or barrier method of birth control; or abstinence during and after treatment (see Section 9.0).

3.1.5 The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

Prior to Step 2 Registration:

3.1.6 Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype of glioblastoma) confirmed by central pathology review (See Section 10 for details);

3.1.7 MGMT promoter without methylation confirmed by central pathology review (See Section 10 for details). Note: Patients with tissue that is insufficient or inadequate for analysis, fails MGMT testing, or has indeterminate or methylated MGMT promoter are excluded.

3.1.8 IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e IDH wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at Step 2.)

3.1.9 History/physical examination within 28 days prior to Step 2 registration;

3.1.10 Karnofsky Performance Status (KPS) = 70 within 28 days prior to Step 2 registration;

3.1.11 Neurologic Function assessment within 28 days prior to Step 2 registration;

3.1.12 Age = 18 years;

3.1.13 Adequate hematologic, renal, and hepatic function within 7 days prior to Step 2 registration defined as follows:

- hemoglobin =10 g/dl (Note: the use of transfusion or other intervention to achieve Hgb =10.0 g/dl is acceptable)

- leukocytes =2,000/mm3

- absolute neutrophil count =1,500/mm3

- platelets =100,000/mm3

- total bilirubin =1.5× institutional/lab upper limit of normal (ULN)

-AST(SGOT) =.5 × ULN

-ALT(SGPT) =.5 × ULN

-serum creatinine =.5× ULN

OR

-creatinine clearance (CrCl) =0 mL/min (if using the Cockcroft-Gault formula

3.1.14 For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable 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.

3.1.15 For women of childbearing potential (WOCBP), negative serum or urine pregnancy test within 7 days prior to Step 2 registration. Note that it may need to be repeated if not also within 72 hours prior to treatment start (see section 4)

• Women of childbearing potential (WOCBP) is defined as any female 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.

Ineligibility Criteria

3.2.1 Prior therapy for tumor except for biopsy or resection. For example, prior chemotherapy, immunotherapy, or targeted therapy for GBM or lower grade glioma is disallowed (including but not limited to temozolomide, lomustine, bevacizumab, any viral therapy, ipilimumab or other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, PDL-1 or 2 antibody, vaccine therapy, polio or similar viral injection as treatment for the tumor, and/or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) as is prior Laser interstitial thermal therapy (LITT), Gliadel wafer, radiotherapy, radiosurgery, gamma knife, cyber knife, vaccine or other immunotherapy, brachytherapy, or convection enhanced delivery;

• Note that 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent

3.2.2 Current or planned treatment with any other investigational agents for the study cancer

3.2.3 Definitive clinical or radiologic evidence of metastatic disease outside the brain

3.2.4 Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer in situ and melanoma in situ) unless disease free for a minimum of 2 years

3.2.5 Prior radiotherapy to the head or neck that would result in overlap of radiation therapy fields

3.2.6 Pregnancy and nursing females due to the potential teratogenic effects and potential risk for adverse events in nursing infants.

3.2.7 History of severe hypersensitivity reaction to any monoclonal antibody.

3.2.8 History of allergic reactions attributed to compounds of similar chemical or biologic composition to ipilimumab, nivolumab, or temozolomide

3.2.9 On any dose of any systemically administered (oral, rectal, intravenous) corticosteroid within 3 days prior to Step 2 registration (see also section 4). Inhaled, topical, and ocular corticosteroids are allowed without limitation but must be recorded. Note that treatment with systemically administered corticosteroid after initiating study treatment is allowed as needed.

3.2.10 Patients with known immune impairment who may be unable to respond to anti-CTLA 4 antibody.

3.2.11 History of interstitial lung disease including but not limited to sarcoidosis or pneumonitis.

3.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, defined as 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), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

3.2.13 Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).

3.2.14 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, are excluded. These include but are not limited to: patients with a history of immune-related neurologic disease, CNS or motor neuropathy, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as autoimmune vasculitis [e.g., Wegener’s Granulomatosis]), systemic lupus erythematosus (SLE), connective tissue diseases (e.g., systemic progressive sclerosis), scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome, Hashimoto’s thyroiditis, autoimmune hepatitis are excluded because of the risk of recurrence or exacerbation of disease.

• Exceptions: patients with a history of the following conditions are not excluded: o vitiligo

• endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids

• rheumatoid arthritis and other arthropathies

• Sjögren’s syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA) ? anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.

3.2.15 Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess, GI obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation are also excluded

3.2.16 Current or planned therapy with warfarin

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

CURRENT SITES CREDENTIALED:  SJMH (AA, Brighton, Canton, Chelsea), Livonia, LVHN, Sparrow, Saginaw, Oakland

Eligibility Criteria: 

A patient cannot be considered eligible for this study unless ALL of the following conditions are met. Prior to Step 1 Registration  

-No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered).

- Availability of FFPE tumor tissue block and H&E stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status (See Sections 3.1.1 and 10).

Note that tissue for central pathology review and central MGMT assessment must be received by the NYU Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 23. If tissue cannot be received by postoperative calendar day 23, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 6 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be conveyed to NRG Oncology within 10 business days of receipt of tissue. Note: In the event of an additional tumor resection(s), tissue must be received within 23 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection. Surgical resection is required; stereotactic biopsy alone is not allowed because it will not provide sufficient tissue for MGMT analysis.

- Contrast-enhanced brain MRI within 4 days after surgery.

• MRI with Axial T2 weighted FLAIR{preferred} or T2 TSE/FSE and 3D contrastenhanced T1 sequences are required.

• 3D pre contrast-enhanced T1 sequences are strongly suggested.

- Willing to use highly effective method of contraception for participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) during therapy and for 6 months after completing treatment; 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.

Prior to Step 2 Registration

- Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype of glioblastoma) confirmed by central pathology review (See Section 10 for details);

- MGMT promoter with methylation confirmed by central pathology review (See Section 10 for details). Note: Patients with tissue that is insufficient or inadequate for analysis, fails MGMT testing, or has indeterminate or unmethylated MGMT promoter are excluded. Patients with unmethylated MGMT may be considered for enrollment on NRGBN007. Please see Section 10 for additional information.

- IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e IDH wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at Step 2.)

- History/physical examination within 28 days prior to Step 2 registration;

- Karnofsky Performance Status (KPS) ≥ 70 within 28 days prior to Step 2 registration;

- Neurologic Function assessment within 28 days prior to Step 2 registration;

- Age 18-70 years; 

Adequate hematologic, renal, and hepatic function within 7 days prior to Step 2 registration defined as follows:

- hemoglobin ≥10 g/dl (Note: the use of transfusion or other intervention to achieve Hgb ≥10.0 g/dl is acceptable)

- leukocytes ≥2,000/mm3

- absolute neutrophil count ≥1,500/mm3

- platelets ≥100,000/mm3

- total bilirubin ≤1.5× institutional/lab upper limit of normal (ULN)

- AST(SGOT) ≤2.5 × ULN

- ALT(SGPT) ≤2.5 × ULN

- serum creatinine ≤1.5× ULN OR

- creatinine clearance (CrCl) ≥50 mL/min 

-For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B).

- For 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. Note: Known positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy.

- Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to step 2 registration are eligible for this trial. Testing is not required for entry into protocol.

- Negative serum or urine pregnancy test (in persons of childbearing potential) within 7 days prior to Step 2 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.

Prior to Step 2 Registration

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

Prior therapy for tumor except for resection. For example, prior chemotherapy, immunotherapy, or targeted therapy for GBM or lower grade glioma is disallowed (including but not limited to temozolomide, lomustine, bevacizumab, any viral therapy, ipilimumab or other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, PDL-1 or 2 antibody, vaccine therapy, polio or similar viral injection as treatment for the tumor, and/or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) as is prior Laser interstitial thermal therapy (LITT), Gliadel wafer, radiotherapy, radiosurgery, vaccine or other immunotherapy, brachytherapy, or convection enhanced delivery;

• Note: 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent

- Current or planned treatment with any other investigational agents for the study cancer

- Definitive clinical or radiologic evidence of metastatic disease outside the brain

- Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer in situ and melanoma in situ) unless disease free for a minimum of 2 years

- Prior radiotherapy to the head or neck that would result in overlap of radiation therapy fields

- Pregnancy and individuals unwilling to discontinue nursing due to the potential teratogenic effects and potential risk for adverse events in nursing infants.

- History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or lomustine.

- History of pulmonary fibrosis.

-Uncontrolled intercurrent illness including, but not limited to:

• Ongoing or active infection requiring IV antibiotics, IV antiviral, or IV antifungal treatment,

• Symptomatic congestive heart failure, defined as 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),

• Unstable angina pectoris within 6 months prior to Step 2 registration,

• Uncontrolled cardiac arrhythmia,

• Psychiatric illness/social situations that would limit compliance with study requirements.

NIH Participant Population Inclusion Policy

NIH policy requires that participants regardless of gender identity 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. Participants of childbearing potential should not be routinely excluded from participation in clinical research. Please see http://grants.nih.gov/grants/funding/phs398/phs398.pdf

SRS Head Phantom is credentialed to be done MI013 only

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: Trinity Health Ann Arbor 

Eligibility Criteria:

3.2 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 Pathologically

(histologically or cytologically) proven diagnosis of one of the following solid tumor malignancies within 5 years prior to registration:

• non-small cell lung cancer

• melanoma

• breast cancer

• renal cell carcinoma

• gastrointestinal cancer

If the original histologic proof of malignancy is greater than 5 years, then more recent pathologic confirmation (e.g., from a systemic site or brain metastasis) or unequivocal imaging confirmation of extracranial metastatic disease (e.g. CT of the chest/abdomen/pelvis, PET/CT, etc.) is required.

3.2.2 Definition of Disease

• Patients must have at least 1 and up to 8 total intact brain metastases detected on a contrast-enhanced MRI (see Appendix I for imaging guidelines) performed ≤ 21 days prior to registration.

• At least 1 of the up to 8 lesions must be a study eligible lesion, defined as lesion with a maximum diameter as measured on any orthogonal plane (axial, sagittal, coronal) of ≥ 1.0 cm and ≤ 3.0 cm.

• All brain metastases must be located outside of the brainstem and ≥5 mm from the optic nerves or optic chiasm and ≤ 3.0 cm in maximum dimension.

Note: brainstem metastases per the MRI within 21 days of registration are an exclusion criterion; however, if the MRI used for treatment planning performed within 7 days of SRS/FSRS reveals a brainstem metastasis, the patient remains eligible if the patient is considered an appropriate radiosurgery candidate per the local investigator.

• Patients must have a diagnosis-specific graded prognostic assessment ≥1.5 (see Appendix II).

• No more than 2 lesions planned for resection if clinically indicated 

• No known leptomeningeal disease (LMD) 

Note: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive CSF cytology and/or unequivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator’s discretion based on level of clinical suspicion.

3.2.3 Age ≥ 18 years

3.2.4 Karnofsky performance status (KPS) ≥ 60

3.2.5 Not Pregnant and Not Nursing 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

3.2.6 Prior Treatment No prior radiotherapy to the brain (partial or whole brain irradiation, SRS, FSRS, or prophylactic cranial irradiation [PCI]) 

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

-ECOG PS must be 0-1
-The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
-The following staging criteria must be met:
--by pathologic evaluation, primary tumor must be pT1-3
--by pathologic evaluation, ipsilateral nodes must be pN0, pN1, pN2a, pN2b, pN3a, or pN3b
---if pN0, tumor must be greater than 3cm 
-The tumor must be HER2-negative 
-The tumor must have been determined to be ER/PR-negative
-The patient must have undergone either a mastectomy or lumpectomy. Margins must be negative.
-Patients must have completed one of the following procedures for evaluation of nodal status:
--sentinel lymphadenectomy alone-- if pN0 or pN1b; or, if pN1mi or pN1a and the patient has undergone breast conserving surgery and the primary tumor is T1-2 and nodal involvement is limited to 1-2 postitive nodes
--sentinel lymphadenectomy followed by removal of additional non-sentinel nodes if SN is positive
--axillary lymphadenectomy with or without SN isolation
-Interval between the last surgery for breast cancer and randomizatio must be no more than 60d.
-Patients must not have definitive clinical or radiologic evidence of metastatic disease.
-Patients must not have synchronous or previous contralateral or ipsilateral breast cancer (including ipsilateral DCIS).
-Patients must not have had previous therapy with anthracyclines or taxanes for any malignancy. 
-Patients must not have had any previous chemotherapy for the currently diagnosed breast cancer.