**Effective 04/24/23, HRQOL sub study is closed to accrual**

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

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Canton, Chelsea), Livonia, Saginaw St. Mary's, and SJMO; St. John, Macomb, Genesys, 

Eligibility Criteria:

Patient Pre-Entry and Randomization

For the NRG-BR007 study, patients with a T1a tumor (≤0.5 cm in size) who do not have an Oncotype DX Recurrence Score must have a tissue sample sent to Genomic Health for a Recurrence Score to determine eligibility. For these patients, Genomic Health will cover the cost of the test.

 Pre-Entry (ALL patients)

• Step 1: All patients will have to be registered in NRG-BR007 before being randomized.

• The authorized site staff must obtain a signed consent form from the potential patients before any study specific procedures are performed.

• The authorized site staff must determine patient eligibility. See Sections 3.2 and 3.3.

• During Pre-Entry in OPEN, patients will be assigned a unique patient identifier which will be used to identify the sample to be sent for central Oncotype DX Recurrence Score testing (for patients with a T1a tumor (≤0.5 cm in size) who have not had a Recurrence Score), the eCRFs in Medidata RAVE, and any other trial-related communications. See Section 10.0 and the NRG-BR007 Pathology and Correlative Science Instructions for ordering the Oncotype DX Recurrence Score test.

• Patients who already have a Recurrence Score result of ≤ 18, will be registered in Step 1 and go straight to randomization in Step 2.

• When a Recurrence Score result of ≤ 18 is received on central testing for patients with a T1a tumor (≤ 0.5 cm in size), the patient should be randomized. Patients who do not have a Recurrence Score result of ≤ 18 by central testing will not be randomized, will be treated per investigator discretion, and will not be followed on BR007. 

Randomization (ALL patients)

• Step 2: If a patient meets all eligibility requirements, the authorized site staff will randomize the patient using OPEN.

• OPEN will randomly assign treatment (breast radiation therapy + endocrine therapy or no breast radiation + endocrine therapy) 

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

- The patient must be ≥ 50 years and < 70 years of age.

- The trial is open to female and male patients.

- The patient must have an ECOG performance status of 0 or 1.

- The patient must have undergone a lumpectomy and the margins of the resected specimen or reexcision must be histologically free of invasive tumor and DCIS with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. (Patients with margins positive for LCIS are eligible without additional resection.)

- The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.

- Patient must have undergone axillary staging (sentinel node biopsy and/or axillary node dissection).

- The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:

• By pathologic evaluation, primary tumor must be pT1 ( ≤ 2 cm).

• By pathologic evaluation, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0(i+) or pN0(mol+) are NOT eligible.)

- Oncotype DX Recurrence Score of ≤ 18 on diagnostic core biopsy or resected specimen.**

** For patients with a T1a tumor (≤ 0.5 cm in size) who do not already have an Oncotype DX Recurrence Score at study entry, a specimen (unstained blocks or slides) must be sent to the Genomic Health centralized laboratory.

- The tumor must have been determined to be ER and/or PgR positive assessed by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Patients with ≥ 1% ER or PgR staining by IHC are considered positive.

- The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines.

- Patients may be premenopausal or postmenopausal at the time of study entry. For study purposes, postmenopausal is defined as:

• Age 56 or older with no spontaneous menses for at least 12 months prior to study entry; or a documented hysterectomy; or

• Age 55 or younger with no spontaneous menses for at least 12 months prior to study entry (e.g., spontaneous or secondary to hysterectomy) and with a documented estradiol level in the postmenopausal range according to local institutional/laboratory standard; or

• Documented bilateral oophorectomy.

- The interval between the last surgery for breast cancer (including re-excision of margins) and study entry must be no more than 70 days. 

-The patient must have recovered from surgery with the incision completely healed and no signs of infection.

- Bilateral mammogram or MRI within 6 months prior to study entry.

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

- Patients must be intending to take endocrine therapy for a minimum 5 years duration (tamoxifen or aromatase inhibitor). The specific regimen of endocrine therapy is at the treating physician’s discretion.  Ineligibility Criteria Patients with any of the following conditions are NOT eligible for this study.

- Definitive clinical or radiologic evidence of metastatic disease.

- pT2 - pT4 tumors including inflammatory breast cancer.

- Pathologic staging of pN0(i+) or pN0(mol+), pN1, pN2, or pN3 disease.

- Patient had a mastectomy.

- Palpable or radiographically suspicious ipsilateral or contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.

- Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign.

- Non-epithelial breast malignancies such as sarcoma or lymphoma.

- Proven multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant or separated by 4 or more centimeters. (Patients with multifocal carcinoma are eligible.) .

- Paget's disease of the nipple.

- Any history, not including the index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated or not treated. (Patients with synchronous or previous ipsilateral LCIS are eligible.)

- Synchronous or previous contralateral invasive breast cancer or DCIS. (Patients with synchronous and/or previous contralateral LCIS are eligible.)

- Surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re-excision, the patient is eligible.)

- Treatment plan that includes regional nodal irradiation.

- Any treatment with radiation therapy, chemotherapy, biotherapy, and/or endocrine therapy administered for the currently diagnosed breast cancer prior to study entry. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is < 18.)

- History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to study entry.

Current therapy with any endocrine therapy such as raloxifene (Evista®), tamoxifen, or other selective estrogen receptor modulators (SERMs), either for osteoporosis or breast cancer prevention. (Short course endocrine therapy of < 6 weeks duration is acceptable post core biopsy pre surgery if the Oncotype DX Recurrence Score is assessed on the biopsy core and is < 18.)

- Patients intending to continue on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible. Patients that discontinue oral, transdermal, or subdermal estrogen replacement prior to registration are eligible.

- Prior breast or thoracic RT for any condition.

- Active collagen vascular disease, specifically dermatomyositis with a CPK level above normal or with an active skin rash, systemic lupus erythematosis, or scleroderma 

-Pregnancy or lactation at the time of study entry or intention to become pregnant during treatment. (Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to study entry.)

- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of study therapy or that may affect the interpretation of the results or render the patient at high risk from treatment complications.

- Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.

- Use of any investigational product within 30 days prior to study entry.  

*SJMH TH Locations will not be participating*

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

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: Oakland, Genesys, Hurley, Sparrow

Eligibility Criteria:

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

3.1.1 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.

3.1.2 The trial is open to female and male patients who have undergone breast conserving surgery and completed a minimum of 4 cycles (12 weeks) of neoadjuvant or adjuvant chemotherapy in combination with HER2-targeted therapy.

3.1.3 The patient must be ≥ 40 years of age.

3.1.4 The patient must have an ECOG performance status of 0 ,1, or 2/Karnofsky performance status above 60. (See Appendix A).

3.1.5 Histologically or cytologically confirmed invasive breast carcinoma.

3.1.6 The tumor must have been determined to be HER2-positive by current ASCO/CAP guidelines based on local testing results.

3.1.7 The tumor must have ER and PgR status assessed locally using current ASCO/CAP Guidelines. 3.1.8 Patient must have undergone axillary staging, either sentinel node biopsy (SNB) or axillary lymph nodal dissection (ALND). In neoadjuvant patients, SNB following neoadjuvant therapy is strongly recommended. SNB prior to neoadjuvant therapy is discouraged, but patients are permitted if node negative (pN0).

3.1.9 The following staging criteria must be met according to AJCC 8th edition criteria:

Adjuvant cohort 

• By pathologic evaluation, the patient’s primary tumor must be < 2 cm and ipsilateral nodes must be pN0. Surgical lumpectomy margins must be negative for invasive cancer and ductal carcinoma in situ (no ink on tumor).

Neoadjuvant cohort

• Prior to neoadjuvant therapy, the patient’s primary tumor must be < 3 cm by imaging studies, with negative axillary nodes (cN0) based on axillary U/S, CT, PET or MRI. Physical examination is not sufficient documentation of cN0 status.

• Must be ypT0N0 at surgery (lumpectomy); patients with residual non-invasive disease (DCIS) in the surgical specimen (ypTis), are NOT eligible. 

3.1.10 For the Adjuvant cohort, adjuvant therapy must have consisted of a minimum of 4 cycles (12 weeks) of chemotherapy in combination with HER2-targeted therapy.

3.1.11 For the Neoadjuvant cohort, neoadjuvant therapy must have consisted of a minimum of 4 cycles (12 weeks) of chemotherapy in combination with HER2-targeted therapy.

• Patients who did not receive chemotherapy in the neoadjuvant setting are not eligible, even if they achieved pCR with their preoperative treatment; nor would these patients become eligible by receiving chemotherapy after surgery.

3.1.12 In patients assigned to radiation therapy, treatment should start ≤ 12 weeks from surgery on the Neoadjuvant cohort and ≤ 8 weeks from the completion of chemotherapy on the Adjuvant cohort. Patients should continue HER2-targeted therapy during assigned study treatment (radiation or observation).

3.1.13 Bilateral mammogram or MRI within 52 weeks prior to randomization.

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

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

Eligibility Criteria:

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

3.2.2 Female patients must be ≥ 18 years of age.

3.2.3 Patients must be premenopausal (evidence of functioning ovaries) at the time of pre-entry. For study purposes, premenopausal is defined as:

• Age 50 years or under with spontaneous menses within 12 months; or

• Age > 50-60 years with spontaneous menses within 12 months plus follicle-stimulating hormone (FSH) and estradiol levels in the premenopausal range; or

• Patients with amenorrhea due to IUD or prior uterine ablation must have FSH and estradiol levels in the premenopausal range; or

• Patients with prior hysterectomy must have FSH and estradiol levels in the premenopausal range. 3.2.4 The patient must have an ECOG performance status of ≤ 2 (or Karnofsky ≥ 60%).

3.2.5 Patients may have ipsilateral or contralateral synchronous breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy.

3.2.6 Patients may have multicentric or multifocal breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy.

3.2.7 Patient may have undergone a total mastectomy, skin-sparing mastectomy, nipple-sparing mastectomy, or a lumpectomy.

3.2.8 For patients who undergo a lumpectomy, the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. Positive posterior margin is allowed if surgeon deems no further resection possible. (Patients with margins positive for LCIS are eligible without additional resection.)

3.2.9 For patients who undergo mastectomy, the margins must be free of residual gross tumor. (Patients with microscopic positive margins are eligible if post-mastectomy RT of the chest wall will be administered.)

3.2.10 Patient must have undergone axillary staging with sentinel node biopsy (SNB), targeted axillary dissection (TAD), or axillary lymph node dissection (ALND).

3.2.11 The following staging criteria must be met postoperatively according to AJCC 8 th edition criteria:

• By pathologic evaluation, primary tumor must be pT1-3. (If N0, must be T1c or higher.)

• By pathologic evaluation, ipsilateral nodes must be pN0 or pN1 (pN1mi, pN1a, pN1b, pN1c).

• Patients with positive isolated tumor cells (ITCs) in axillary nodes will be considered N0 for eligibility purposes. 

• Patients with micrometastatic nodal involvement (0.2-2 mm) will be considered N1

. 3.2.12 Oncotype DX RS requirements*:

• If node-negative:

- Oncotype DX RS must be RS 21-25, or

- Oncotype DX RS must be 16-20 and disease must be high clinical risk, defined as: low histologic grade with primary tumor size > 3 cm, intermediate histologic grade with primary tumor size > 2 cm, or high histologic grade with primary tumor size > 1 cm.

• If 1-3 nodes involved:

- Oncotype DX RS must be < 26.

* Patients with a “Low Risk” or “MP1” MammaPrint result must have eligibility assessed with an Oncotype DX RS at pre-entry (see Section 3.1). Blocks or unstained slides must be sent to the Genomic Health centralized laboratory for testing at no cost to these patients. If MammaPrint High Risk or MP2, these patients are not eligible.

3.2.13 The tumor must be ER and/or PgR-positive by current ASCO/CAP guidelines based on local testing results. Patients with ≥ 1% ER and/or PgR staining by IHC will be classified as positive. 

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

*Credentials required. Please check your site's credentialing status.*
CURRENT SITES CREDENTIALED: (Please note first patient randomized to Arm 2 requires pre-tx review which may take 5 business days.)
SJMH, St. Alphonsus, SJMO, Livonia, Genesys Hurley
*Check for eligibility to DCP-001*
Step 1 Eligiblity:
-Histologic proof or unequivocal cytologic proof of SCLC within 250 days prior to Step 1 registration
-Patients must be registered on study no earlier than 7 days and no later than 56 days prior to Step 1 registration after completing chemotherapy (+/- thoracic radiotherapy)
-Patients must have a SPGR, MP-RAGE, or turbo field echo (TFE) MRI scan
-Prior to chemotherapy +/- thoracic radiotherapy, patients must be defined as limited-stage or extensive-stage SCLC after clinical staging evaluation
-After chemotherapy, patients must be restaged within 56 days prior to Step 1 registration using the same diagnostic work-up as required pre-chemotherapy
-Patients must not have CNS metastases nor progression in any site
-Patients must have radiographic partial or complete response to chemotherapy in at least one disease site.
-Zubrod PS must be 0-2

Step 2 Eligibility:
-Patients must complete neurocognitive assessments and have a baseline raw score greater than 2 on the HVLT-R Delayed Recall assessment as determined by the neurocognitive co-chair

Ineligibility:
-Patients must not have had prior RT to the head or neck, resulting in overlap of RT fields
-Patients must not have planned concurrent chemotherapy or anti-tumor agent during PCI
-Patients must not have evidence of hydrocephalus

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

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton), Saginaw

***SJMH: Patients randomized to the SRS arm can ONLY be treated in Ann Arbor.*** 

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 small cell lung cancer within 5 years of registration. If the original histologic proof of malignancy is greater than 5 years, then pathological (i.e., more recent) confirmation is required (e.g., from a systemic or brain metastasis);

o Patients with de novo or recurrent small cell lung cancer are permitted. 

Ten or fewer brain metastases ≤3cm in largest diameter and outside a 5-mm margin around either hippocampus must be visible on contrast-enhanced MRI performed ≤21 days prior to study entry.

o Brain metastases can be diagnosed synchronous to the initial diagnosis of small cell lung cancer or metachronous to the initial diagnosis and management of small cell lung cancer.

o The total tumor volume must be 30 cm3 or less. Lesion volume will be approximated by measuring the lesion’s three perpendicular diameters on contrastenhanced, T1-weighted MRI and the product of those diameters will be divided by 2 to estimate the lesion volume (e.g. xyz/2). Alternatively, direct volumetric measurements via slice by slice contouring on a treatment planning software package can be used to calculate the total tumor volume.

o Brain metastases must be diagnosed on MRI, which will include the following elements:

REQUIRED MRI ELEMENTS

• Post gadolinium contrast-enhanced T1-weighted three-dimensional (3D) spoiled gradient (SPGR). Acceptable 3D SPGR sequences include magnetizationprepared 3D gradient recalled echo (GRE) rapid gradient echo (MP-RAGE), turbo field echo (TFE) MRI, BRAVO (Brain Volume Imaging) or 3D Fast FE (field echo). The T1-weighted 3D scan should use the smallest possible axial slice thickness, not to exceed 1.5 mm.

• Pre-contrast T1 weighted imaging (3D imaging sequence strongly encouraged).

• A minimum of one axial T2 FLAIR (preferred) or T2 sequence is required. This can be acquired as a 2D or 3D image. If 2D, the images should be obtained in the axial plane. 

ADDITIONAL RECOMMENDATIONS

• Recommendation is that an axial T2 FLAIR (preferred) sequence be performed instead of a T2 sequence.

• Recommendation is that that pre-contrast 3D T1 be performed with the same parameters as the post-contrast 3D T1.

• Recommendation is that imaging be performed on a 3 Tesla (3T) MRI.

• Recommendation is that the study participants be scanned on the same MRI instrument at each time point.

• Recommendation is that if additional sequences are obtained, these should meet the criteria outlined in Kaufmann et al., 2020.

• If additional sequences are obtained, total imaging time should not exceed 60 minutes. See Appendix IV for a summary of key imaging requirements, and contact the Principal Investigators and Imaging Co-Chairs for further information or assistance if needed.

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

- Age ≥ 18;  

Karnofsky Performance Status of ≥70 within 28 days prior to registration;

-Adequate renal function within 28 days prior to registration defined as follows:

• Creatinine clearance ≥30 ml/min

- Following the diagnosis of brain metastases, patients can initiate and treat with systemic (chemotherapy and/or immunotherapy) before enrollment only if their brain metastases are asymptomatic and not located in eloquent locations (e.g., brainstem, pre-/post-central gyrus, visual cortex). However, within 21 days prior to enrollment, brain MRI must be repeated to confirm eligibility.

o Patients with symptomatic brain metastases and/or brain metastases in eloquent locations (e.g., brainstem, pre-/post-central gyrus, visual cortex) are eligible for enrollment on the trial; however, the specific treatment approach of starting with systemic therapy alone and delaying brain radiation is not recommended for these patients.

- Concurrent immunotherapy with brain radiation (SRS or HA-WBRT) is permitted.

- Negative urine or serum pregnancy test (in women of childbearing potential) within 14 days prior to registration. Women of childbearing potential and men who are sexually active must use contraception while on study.

- Patients may have had prior intracranial surgical resection. Patients must have completed prior intracranial surgical resection at least 14 days prior to registration.

- Because neurocognitive testing is the primary goal of this study, patients must be proficient in English or French Canadian.

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

• Patients with impaired decision-making capacity are not permitted on study.  

Eligibility Criteria Prior to Step 2 Registration

- The following baseline neurocognitive tests must be completed within 21 days prior to Step 2 registration: HVLT-R, TMT, and COWA. The neurocognitive tests will be uploaded into RAVE for evaluation by Dr. Wefel. Once the upload is complete, within 1 business day a notification will be sent via email to the RA to proceed to Step 2. NOTE: Completed baseline neurocognitive tests can be uploaded at the time of Step 1 registration.

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

- Planned infusion of cytotoxic chemotherapy on the same day as SRS or HA-WBRT treatment. Patients may have had prior chemotherapy. As noted in 3.1.8, concurrent immunotherapy is permitted.

- Prior allergic reaction to memantine.

- Intractable seizures while on adequate anticonvulsant therapy; more than 1 seizure per month for the past 2 months.

- Patients with definitive leptomeningeal metastases.

- Known history of demyelinating disease such as multiple sclerosis

- Contraindication to MR imaging such as implanted metal devices that are MRIincompatible, allergy to MRI contrast that cannot be adequately addressed with pre- contrast medications, or foreign bodies that preclude MRI imaging. (Questions regarding MRI compatibility of implanted objects should be reviewed with the Radiology Department performing the MRI).

- Current use of (other NMDA antagonists) amantadine, ketamine, or dextromethorphan

- Radiographic evidence of hydrocephalus or other architectural change of the ventricular system resulting in significant anatomic distortion of the hippocampus, including placement of external ventricular drain or ventriculoperitoneal shunt.

• Mild cases of hydrocephalus not resulting in significant anatomic distortion of the hippocampus are permitted

- Prior radiotherapy to the brain, including SRS, WBRT, or PCI 3.3.10 Severe, active co-morbidity defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months

• Transmural myocardial infarction within the last 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration

• Chronic obstructive pulmonary disease exacerbation or other acute respiratory illness precluding study therapy at the time of registration

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

Eligibility Criteria:

3.2.1 The participant must provide study-specific informed consent prior to any study specific procedures and authorization permitting release of personal health information.

3.2.2 The participant must be ≥ 18 years of age.

3.2.3 The participant must have a first time diagnosis of non-metastatic breast cancer which is Stage I-III. 3.2.4 The participant must have a score of < 12 on the PROMIS Adult v2.0 - Cognitive Function 4a.

3.2.5 Participants with ≥ 6 months to 5 years post-treatment (completion of initial surgery +/- adjuvant chemotherapy/radiation therapy) except may still be taking endocrine therapy or HER2-directed adjuvant therapy.

3.2.6 The participant must be able to understand, speak, read, and write in English or Spanish. 

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

*DTL Required- Physicians must sign toxicity grid
Current sites credentialed: SJMH, Sparrow, Livonia, Lehigh, Saginaw, Oakland

-ECOG Performance Status of 0, 1 or 2
-Diagnosis of metastatic adenocarcinoma of colon or rectum without previous chemotherapy or any other systemic therapy for metastatic colorectal cancer.
-Tumor determined to be mismatch-repair deficient (dMMR) by CLIA-certified immunohistochemical (IHC) assay with a panel of all four IHC markers, including MLH1, MSH2, PMS2, and MSH6.
-An adequate amount of archived tumor tissue, either from primary colorectal cancer site or metastatic lesions, for central confirmation of dMMR status:

  -Either whole or part of the FFPE block containing tumor tissue; or

  -At least 8 unstained slides containing tumor sections

Eligibility Criteria:

- The patient must have signed and dated an IRB-approved consent form that conforms to federal and institutional guidelines.

- Age = 18 years at diagnosis.

- ECOG Performance Status of 0 or 1 (see Appendix A).

- Histologically/pathologically confirmed stage IIA adenocarcinoma of the colon (T3, N0, M0) with at least 12 lymph nodes examined at the time of surgical resection.

- Appropriate for active surveillance (i.e., no adjuvant chemotherapy) at the discretion of and as documented by the evaluating oncologist based on current practice patterns.

- The distal extent of the tumor must be =12 cm from the anal verge on pre-surgical endoscopy (i.e., excluding rectal adenocarcinomas warranting treatment with chemoradiation). If the patient did not undergo a pre-surgical endoscopy, then the distal extent of the tumor must be =12 cm from the anal verge as determined by surgical examination or pre-operative imaging.

- The patient must have had an en bloc complete gross resection of tumor (curative resection) as definitive surgical cancer treatment within 14 to 60 days of study randomization. Patients who have had a two-stage surgical procedure to first provide a decompressive colostomy and then, in a later procedure, to have the definitive surgical resection, are eligible.

- Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling.

-Adequate hematologic function within 28 days before randomization defined as follows:

• Absolute neutrophil count (ANC) must be = 1200/mm3;

• Platelet count must be = 100,000/mm3; and

• Hemoglobin must be = 9 g/dL.

- Adequate hepatic function within 28 days before randomization defined as follows:

• total bilirubin must be = ULN (upper limit of normal) for the lab unless the patient has a chronic grade 1 bilirubin elevation due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin; and

• alkaline phosphatase must be < 2.5 x ULN for the lab; and

• AST and ALT must be < 1.5 x ULN for the lab.

- Adequate renal function within 28 days before randomization defined as serum creatinine = 1.5 x ULN for the lab or measured or calculated creatinine clearance = 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x ULN for the lab.

- Pregnancy test (urine or serum according to institutional standard) done within 14 days before randomization must be negative (for women of childbearing potential only).

- Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring of INR if they are randomized to Arm 2 and receive capecitabine.

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

CURRENT SITES CREDENTIALED:  SJMH (AA, Brighton, Canton, Chelsea), Livonia, Genesys, St. John, Macomb, Saginaw, LVHN, Sparrow, SJMO, Holy Cross

Eligibility Criteria: 

Patient Entry and Randomization

The following sections outline procedures for Study Entry and Randomization.

Step 1: Study Entry and ctDNA assay testing.

• The authorized site staff must obtain signed informed consent from the potential patient before any study specific procedures are performed.

• The authorized site staff must determine patient eligibility by completing the assessments on Table 1 that are required prior to study entry. See Sections 3.2 and 3.3.

• Step 1 Entry in OPEN: Patients will be assigned a unique patient identifier which will be used to identify the blood and tumor samples to be sent for central Signatera? ctDNA testing for patients who have not had ctDNA testing performed using the Signatera? assay as routine care outside the study and for those patients who already have had a ctDNA status performed using the Signatera? assay as routine care outside of the study, the eCRFs in Medidata RAVE, and any other trial-related communications.

Step 2: Randomization

• Following ctDNA assay testing, the authorized site staff will randomize the patient using OPEN. For the patients who had their ctDNA status checked with the Signatera? assay as routine care outside of the study, the ctDNA test result from the central testing will be the result used to place the patients in Cohort A or Cohort B. When the result of the central ctDNA testing is not the same as the result of the Signatera? assay done as routine care outside of the study, the patient/physician may choose not to proceed with participation in the study.

• OPEN will randomly assign treatment by cohort (ctDNA-ve or ctDNA+ve).

Second Randomization (Cohort A-Arm 2 patients who convert to ctDNA +ve)

• Cohort A-Arm 2 patients who develop a positive ctDNA assay during serial monitoring will transition to the ctDNA+ ve cohort (Cohort B) and undergo a second randomization to Arm 3 or Arm 4 treatment.

• The authorized site staff must determine patient eligibility (see Section 3.4).

• Patients must reaffirm their willingness to be enrolled in Cohort B and randomized to Arm 3 or 4 after review of the current consent form and signing a reaffirmation form.

• OPEN will randomly assign patient to Arm 3 or Arm 4.

 Eligibility Criteria

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

- The patient must have signed and dated an IRB-approved consent form that conforms to federal and institutional guidelines.

- The patient must be ≥ 18 years old.

- The patient must have an ECOG performance status of 0 or 1 (see Appendix A).

- Patients must have histologically/pathologically confirmed Stage IIIA or Stage IIIB colon adenocarcinoma (T1-3, N1/N1c) with R0 resection accordingly to AJCC 8th edition criteria. NOTE: Patients with pathologic stages II or IIIC colon adenocarcinoma with R0 resection who have a commercially obtained Signatera? ctDNA+ve assay result post-operatively meeting all timelines and eligibility requirements otherwise, are eligible for enrollment and inclusion in Cohort B.

- No radiographic evidence of overt metastatic disease within 28 days prior to study entry (CT with IV contrast or MRI imaging is acceptable and must include chest, abdomen, and pelvis).

- The distal extent of the tumor must be ≥ 12 cm from the anal verge on colonoscopy or above the peritoneal reflection as documented during surgery or on pathology specimen (i.e., excluding rectal adenocarcinomas warranting treatment with chemoradiation).

- The patient must have had an en bloc complete gross resection of tumor (curative resection). Patients who have had a two-stage surgical procedure, to first provide a decompressive colostomy and then in a later procedure to have the definitive surgical resection, are eligible.

-The resected tumor specimen and a blood specimen from patients with Stage IIIA or Stage IIIB colon cancer must have central testing for ctDNA using the Signatera assay by Natera. NOTE: Patients with stage IIIA or IIIB colon cancer who otherwise meet eligibility criteria and have had ctDNA status checked with the Signatera? assay as routine care outside of the study, are allowed to be enrolled, and will be retested and placed in either Cohort A or Cohort B depending on the central ctDNA testing result. NOTE: Patients with stage II or IIIC colon cancer who otherwise meet eligibility criteria and have had ctDNA status checked with the Signatera? assay as routine care outside of the study AND have a ctDNA+ve result, are allowed to be enrolled. Patients will have central ctDNA testing, confirmed to be ctDNA+ve, and placed in Cohort B.

-Tumor must be documented as microsatellite stable or have intact mismatch repair proteins through CLIA-approved laboratory testing. Patients whose tumors are MSI-H or dMMR are excluded.

- The treating investigator must deem the patient a candidate for all potential agents used in this trial (5FU, LV, oxaliplatin and irinotecan).

- The interval between surgery (post-operative Day 7) and study entry must be no more than 60 days.

- Availability and provision of adequate surgical tumor tissue for molecular diagnostics and confirmatory profiling.

Adequate hematologic function within 28 days before study entry defined as follows:

• Absolute neutrophil count (ANC) must be ≥ 1500/mm3;

• Platelet count must be ≥ 100,000/mm3; and  

• Hemoglobin must be ≥ 9 g/dL. 3.2.14 Adequate hepatic function within 28 days before study entry defined as follows:

• total bilirubin must be ≤ ULN (upper limit of normal) for the lab and

• alkaline phosphatase must be < 2.5 x ULN for the lab; and

• AST and ALT must be < 2.5 x ULN for the lab. 3.2.15 Adequate renal function within 28 days before study entry defined as serum creatinine ≤ 1.5 x ULN for the lab or measured or calculated creatinine clearance ≥ 50 mL/min using the CockroftGault formula for patients with creatinine levels > 1.5 x ULN for the lab. For Women Creatinine Clearance (mL/min) = (140 – age) x weight (kg) x 0.85 72 x serum creatinine (mg/dL) For Men Creatinine Clearance (mL/min) = (140 – age) x weight (kg) 72 x serum creatinine (mg/dL)

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

- Pregnancy test (urine or serum according to institutional standard) done within 14 days before study entry must be negative (for women of childbearing potential only).

- Patients receiving a coumarin-derivative anticoagulant must agree to weekly monitoring of INR if they are randomized to Arm 1 or Arm 3 and receive capecitabine.

Ineligibility Criteria

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

- Colon cancer histology other than adenocarcinoma (i.e., neuroendocrine carcinoma, sarcoma, lymphoma, squamous cell carcinoma, etc.).

- Pathologic, clinical, or radiologic overt evidence of metastatic disease. This includes isolated, distant, or non-contiguous intra-abdominal metastases, even if resected.

- Tumor-related bowel perforation.

- History of prior invasive colon malignancy, regardless of disease-free interval.

- History of bone marrow or solid organ transplantation (regardless of current immunosuppressive therapy needs). Bone grafts, skin grafts, corneal transplants and organ/tissue donation are not exclusionary.

- Any prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy administered as treatment for colorectal cancer (e.g., primary colon adenocarcinomas for which treatment with neoadjuvant chemotherapy and/or radiation is warranted are not permitted).

- Other invasive malignancy within 5 years before study entry. Exceptions are colonic polyps, non-melanoma skin cancer or any carcinoma-in-situ.

- Synchronous primary rectal and/ or colon cancers.

- 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. 

-Sensory or motor neuropathy ≥ grade 2, according to CTCAE v5.0.

- Blood transfusion within two weeks before collection of blood for central ctDNA testing.

- Active seizure disorder uncontrolled by medication.

- Active or chronic infection requiring systemic therapy.

- Known homozygous DPD (dihydropyrimidine dehydrogenase) deficiency.

- Patients known to have Gilbert's Syndrome or homozygosity for UGT1A1*28 polymorphism.

- Pregnancy or lactation at the time of study entry.

- Co-morbid illnesses or other concurrent disease that would make the patient inappropriate for entry into this study (i.e., unable to tolerate 6 months of combination chemotherapy or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or prevent required follow-up).

- Eligibility Criteria for Cohort A Arm-2 patients on Second Randomization

- Patient must have developed a ctDNA +ve assay during serial monitoring.

- Patient's willingness to be re-randomized affirmed.

- The patient must continue to have an ECOG performance status of 0 or 1 (see Appendix A).

- No radiographic evidence of overt metastatic disease.

- Pregnancy test (urine or serum according to institutional standard) done within 14 days before second randomization must be negative (for women of childbearing potential only).

- Adequate hematologic function within 28 days before second randomization defined as follows:

• Absolute neutrophil count (ANC) must be ≥ 1500/mm3;

• Platelet count must be ≥ 100,000/mm3; and

• Hemoglobin must be ≥ 9 g/dL.

- Adequate hepatic function within 28 days before second randomization defined as follows:

• total bilirubin must be ≤ ULN (upper limit of normal) for the lab and

• alkaline phosphatase must be < 2.5 x ULN for the lab; and

• AST and ALT must be < 2.5 x ULN for the lab.

- Adequate renal function within 28 days before second randomization defined as serum creatinine ≤ 1.5 x ULN for the lab or measured or calculated creatinine clearance ≥ 50 mL/min using the Cockroft-Gault formula for patients with creatinine levels > 1.5 x ULN for the lab. 

-Ineligibility Criteria for Cohort A Arm-2 patients on Second Randomization

- Pregnancy or lactation at the time of second randomization.

- No longer a candidate for systemic chemotherapy (FOLFOX, CAPOX, and mFOLFIRINOX) in the opinion of the treating investigator.  

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

-Patients post-prostatectomy with baseline Gleason ? 7 (per prostatectomy pathology)
-Baseline PSA nadir ? 0.2 ng/ml
-Pathologically proven diagnosis of adenocarcinoma of the prostate. Prostatectomy must have been performed within 365 days (1 year) prior to Step 1
-Prior androgen deprivation therapy (LHRH agonist and/or non-steroidal anti-androgen) is allowed if discontinued at least 90 days prior to study enrollment and given for ? 90 days duration.
-Pathologically lymph node negative by pelvic lymphadenectomy (pN0) or lymph node status pathologically unknown
-Any pT-stage is eligible.
-ECOG PS must be 0-1
-Must NOT have clinical or radiologic evidence of metatstatic disease
-Must not have prior RT that would result in overlap of fields
-Must not have prior systemic chemotherapy for this cancer
-Prior whole gland ablative therapy is not allowed