**Effective 03/31/2022, Step 2 (randomization) is closed to patient accrual**

**Effective 11/30/2023, Step 3 is closed to patient accrual**

-Patients must have histologically or cytologically documented adenocarcinoma othe colon or rectum that is metastatic or locally advanced and unresectable.
-All patients must have molecular testing performed in a CLIA certified lab which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation). Patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4[codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible.
-Patients must not have been treated with any of the following prior to Step 1 Initial Registration:
--Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR.

--HER-2 targeting for treatment of colorectal cancer. Patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible.
-Patients must have HER-2 amplification
-Patients must have a Zubrod Performance Status of 0 or 1

-Patients must have measurable disease that is metastatic or locally advanced and unresectable.

-Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease.

Step 1:
-Patients must have a diagnosis of hormone receptor positive (ER+ and/or PR+), HER-2 negative, metastatic (M1) breast cancer and must be receiving or plan to receive first-line systemic treatment for metastatic disease.
-Patients must be registered to step 1 between 14 days prior to and 28 days after start of first-line systemic treatment for metastatic disease
-At least one breast cancer specific STMs after diagnosis of metastatic disease and within 14d of initiation of first-line systemic treatment must have been at least 2 x the ULN
-Patients with known brain mets are not eligible.
-Patients must not have received prior systemic therapy for metastatic breast cancer, except for their current treatment regimen

Step 2:
-At least one of the STMs previously elevated must have decreased from step one by at least 25%
-Patients must not have known progression.
-Must maintain eligibility from step 1. Must be registered to step 2 between 56 d and 112 d after the initiation of first-line systemic therapy for metastatic disease.

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

DTL Required- Physicians must sign toxicity grids

-Patients must have been assigned to S1800A by the SWOG Statistics and Data Management Center (SDMC). Patients who were screened under S1400 (legacy screening/pre-screening study) must have had prior PD-L1 testing by the Dako 22C3 PharmDx IHC assay, and must have results available for stratification purposes.
-Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy.
-Patients must not have an active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
-Patients must not have any history of primary immunodeficiency.
-Patients must not have experienced the following:
--Any Grade 3 or worse immune-related adverse event (irAE). Exception: asymptomatic nonbullous/nonexfoliative rash.

-- Any unresolved Grade 2 irAE.
--Any toxicity that led to permanent discontinuation of prior anti-PD-1/PD-L1 immunotherapy.
-Exception to the above: Toxicities of any grade that requires replacement therapy and has stabilized on therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are allowed.
-Patients must not have any history of organ transplant that requires use of immunosuppressives.
-Patients must not have clinical signs or symptoms of active tuberculosis infection.

- Patients must not have history of (non-infectious) pneumonitis that required steroids or current pneumonitis/interstitial lung disease.
-Patients must not have had a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to sub-study randomization.
-Patients must not have a history of gastrointestinal perforation or fistula within six months prior to sub-study randomization.
-Patients must not have Grade 3-4 gastrointestinal bleeding (defined by NCI CTCAE v5) within three months prior to sub-study randomization.
-Patients must not have any known allergy or reaction to any component of the investigational and standard of care formulations.
-Patients must not have undergone major surgery within 28 days prior to sub-study randomization, or subcutaneous venous access device placement within 7 days prior to randomization. Any patient with postoperative bleeding complications or wound complications from a surgical procedure performed in the last two months should be excluded. The patient must not have elective or planned major surgery to be performed during the course of the clinical trial.
-Patients must not have been diagnosed with venous thrombosis less than 3 months prior to randomization. Patients with venous thrombosis diagnosed more than 3 months prior to randomization must be on stable doses of anticoagulants.

*DTL Required- Physicians must sign toxicity grid

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

Disease Related Criteria

a. Participants must have been assigned to S1800D by the SWOG Statistics and Data Management Center (SDMC). Assignment to S1800D is determined by the LUNGMAP or S1400 protocol.

b. Participants must have measurable or non-measurable disease (see Section 10.1) documented by CT or MRI. Measurable disease must be assessed within 28 days prior to randomization. Non-measurable disease must be assessed within 42 days prior to randomization. The CT from a combined PET/CT may be used only if it is of diagnostic quality as defined in Section 10.1a. All known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1).

c. Participants must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to sub-study randomization.

d. Participants with spinal cord compression or brain metastases must have received local treatment to these metastases and remained clinically controlled and asymptomatic for at least 7 days following stereotactic radiation and/or 14 days following whole brain radiation, and prior to sub-study randomization.

e. Participants with spinal cord compression or brain metastases must not have residual neurological dysfunction, unless no further recovery is expected, and the participant has been stable on weaning doses of corticosteroids (≤ 10 mg daily prednisone or equivalent) prior to sub-study randomization.

f. Participants must not have leptomeningeal disease that requires CNS-specific treatment prior to registration and must not be planning to receive the CNS-specific treatment through the first cycle of the protocol therapy.

g. Participants must not have experienced the following:

• Any Grade 3 or worse immune-related adverse event (irAE). Exception: asymptomatic nonbullous/nonexfoliative rash. • Any unresolved Grade 2 irAE.

• Any toxicity that led to permanent discontinuation of prior anti-PD-1/PD-L1 immunotherapy. Exception to the above: Toxicities of any grade that requires replacement therapy and has stabilized on therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are allowed. h. Participants must not have any history of organ transplant that requires use of immunosuppressives.

i. Participants must not have history of (non-infectious) pneumonitis that required steroids or current pneumonitis/interstitial lung disease.

j. Participants must not have any known allergy or reaction to any component of the investigational formulations. If there is a known allergy or reaction to standard of care formulations, participants must be able to safely receive at least one of the standard of care options.

k. Participants must not have any Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., participants with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, and myocardial infarction within 6 months prior to sub-study randomization, or serious uncontrolled cardiac arrhythmia (see Appendix 18.1).

l. Participants must not have experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to sub-study randomization.

m. Participants must not have an active or uncontrolled infection in the opinion of the treating investigator.

n. Participants must not have a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen.

o. Participants must not have any of following:

• cirrhosis at a level of Child-Pugh B (or worse) (See Appendix 18.4);

• cirrhosis (any degree) and a history of hepatic encephalopathy;

• or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.

p. Participants must not have any family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes or risk factors for Torsade de Pointes including heart failure of hypokalemia.

Prior/Concurrent Therapy Criteria

a. Participants must have progressed (in the opinion of the treating investigator) following the most recent line of therapy for NSCLC.

b. Participants with a known sensitizing mutation for which an FDA-approved targeted therapy for NSCLC exists (e.g. EGFR, ALK gene fusions, ROS1, BRAF, RET, NTRK, and MET sensitizing mutations), must have previously received at least one of the approved therapy(s).

c. Participants must have received exactly one line of anti-PD-1 or anti-PD-L1 therapy for advanced disease (Stage IV or recurrent, or Stage III in certain circumstances outlined below) given alone or in combination with platinum-based chemotherapy. Participants must have experienced disease progression during or after this regimen.

• Continuing the same agent(s) after progression counts as a single line of therapy. However, a change or addition in agent(s) after progression (e.g. the addition of chemotherapy to anti-PD-1 monotherapy after progression) counts as a subsequent line of therapy and would exclude the participant.

• For participants who received consolidation anti-PD-1 or anti-PD-L1 therapy following concurrent chemoradiation for Stage III disease as their only line of anti-PD-1 or anti-PD-L1 therapy:

1. If they experienced disease progression less than () 365 days from the first date of anti-PD-1 or anti-PD-L1 therapy, this counts as the single line of anti-PD-1 or anti-PD-L1 therapy for advanced disease.

2. If they experienced disease progression more than or equal to (≥) 365 days from the first date of anti-PD-1 or anti-PD-L1 therapy, this is not considered a line of anti-PD-1 or anti-PD-L1 therapy for advanced disease.

d. Participants must have recovered (≤ Grade 1) from any side effects of prior therapy, except for alopecia.

e. Participants must not have received anti-CTLA4 therapy (e.g. ipilimumab, tremelimumab), or other immune-modulatory therapy (e.g. anti-TIM-3, anti-LAG-3, anti-GITR, IL-2, IL-15).

f. Participants must not have received any prior systemic therapy (systemic chemotherapy, immunotherapy or investigational drug) within 21 days prior to sub\u0002study randomization.

g. Participants must not have received any radiation therapy within 14 days prior to sub-study randomization. h. Participants must not have received nitrosoureas or mitomycin-c within 42 days prior to sub-study randomization.

i. Participants must not have received systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 7 days prior to sub-study randomization. Inhaled or topical steroids, and adrenal replacement doses ≤ 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.

j. Participants must not have received a live attenuated vaccination within 28 days prior to sub-study randomization (See Appendix 18.6). All COVID-19 vaccines that have received FDA approval or FDA emergency use authorization are acceptable.

k. Participants must not be planning to receive any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment while receiving treatment on this study.

l. Participants must not have had a major surgery within 14 days prior to sub-study randomization. Participant must have fully recovered from the effects of prior surgery in the opinion of the treating investigator.

Clinical/Laboratory Criteria

a. Participants must be able to safely receive at least one of the investigator’s choice of standard of care regimens specified in protocol Section 7.5, per the current FDA\u0002approved package insert.

Note: Pemetrexed is not FDA-approved for squamous cell NSCLC and must not be used to treat participants with squamous cell NSCLC.

b. Participants must have an ANC ≥ 1.5 x 10^3/uL, platelet count ≥ 100 x 10^3/uL, and hemoglobin ≥ 9 g/dL obtained within 28 days prior to sub-study randomization.

c. Participants must have adequate hepatic function as defined by serum bilirubin ≤ Institutional Upper Limit of Normal (IULN) and ALT and AST ≤ 2 x IULN within 28 days prior to sub-study randomization. For participants with liver metastases, bilirubin and ALT and AST must be ≤ 5 x IULN.

d. Participants must have a serum creatinine ≤ the IULN or calculated creatinine clearance ≥ 50 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to sub-study randomization.

e. Participants’ most recent Zubrod performance status must be 0-1 (Section 10.4) and be documented within 28 days prior to sub-study randomization.

f. Participants must have history and physical exam must be obtained within 28 days prior to sub-study randomization.

g. Participants with known human immunodeficiency virus (HIV) infection must be receiving anti-retroviral therapy and have an undetectable viral load at their most recent viral load test within 6 months prior to sub-study randomization.

h. Participants must have an ECG performed, with a QTcF ≤ 470 msec, within 28 days prior to sub-study randomization.

i. Participants must not have an active autoimmune disease that has required systemic treatment within two years prior to sub-study randomization (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.

j. Participants must not have any history of primary immunodeficiency.

k. Participants must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use an effective contraceptive method during the study and 4 months after completion of study treatment. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures during the study and 4 months after study completion.

Specimen Submission Criteria

a. Participants must also be offered participation in banking and in the correlative studies for collection and future use of specimens as described in Section 15.0.

*DTL Required- Physicians must sign toxicity grid

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

CURRENT SITES CREDENTIALED: Trinity Health SJMH IHA (Ann Abror, Brighton, Canton, Chelsea), Livonia, Genesys, Oakland, Sparrow

Eligibility Criteria:

 5.1 Disease Related Criteria

a. Participants must have been assigned to S1800E by the SWOG Statistics and Data Management Center (SDMC). Assignment to S1800E is determined by the LUNGMAP protocol.

b. Participants must have measurable or non-measurable disease (Section 10.1) documented by CT or MRI. The CT from a combined PET/CT may be used to document only non-measurable disease unless it is of diagnostic quality as defined in Section 10.1c. Measurable disease must be assessed within 28 days prior to randomization. Pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease. Non-measurable disease must be assessed within 42 days prior to randomization. All disease must be assessed and documented on the Baseline Tumor Assessment Form. Participants whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to registration.

c. Participants must have a CT or MRI scan of the brain to evaluate for CNS disease within 42 days prior to randomization.

5.2 Prior/Concurrent Therapy Criteria

a. Participants must have received exactly one anti-PD-1 or anti-PD-L1 therapy for advanced disease (Stage IV or recurrent disease, or Stage I-III disease in certain circumstances outlined below). Anti-PD-1 or anti-PD-L1 therapy may have been given alone or in combination with other therapy. For participants who received neoadjuvant, adjuvant, and/or consolidation anti-PD-1 or anti-PD-L1 therapy for Stage I-III disease:

• If they experienced disease progression within (≤) 365 days from initiation (Cycle 1 Day 1) or anti-PD-1 or anti-PD-L1 therapy, this counts as the single allowed anti-PD-1 or anti-PD-L1 therapy for advanced disease.

• If they experienced disease progression more than (>) 365 days from initiation (Cycle 1 Day 1) or anti-PD-1 or anti-PD-L1 therapy, this is not considered anti-PD-1 or anti-PD-L1 therapy for advance disease. These participants must have received anti-PD-1 or anti-PD-L1 therapy for Stage IV or recurrent disease.  

b. Participants must have experienced disease progression (in the opinion of the treating investigator) more than (>) 84 days following initiation (Cycle 1 Day 1) of their most recent anti-PD-1 or anti-PD-L1 therapy.

c. Participants who received anti-PD-1 or anti-PD-L1 therapy for Stage IV or recurrent disease must have had a best response of stable disease, partial response or complete response (in the opinion of the treating investigator) on the anti-PD-1 or anti-PD-L1 therapy for Stage IV or recurrent disease.

d. Participants must have received platinum-based chemotherapy and experienced disease progression (in the opinion of the treating investigator) during or after this regimen.

e. Participants with a known sensitizing molecular alteration for which a FDA-approved targeted therapy for NSCLC exists (e.g., EGFR, ALK, ROS1, BRAF, RET, NTRK, KRAS, HER2, and MET sensitizing mutations), must have previously received at least one of the approved therapy(s). Prior targeted therapy for participants with targetable alterations is allowed if all other eligibility criteria are also met.

f. Participants must have recovered (≤ Grade 1) from any side effects from the most recent anti-cancer treatment prior to randomization.

g. Participants must not have received prior therapy with docetaxel for this disease.

h. Participants must not have received any palliative radiation therapy within 14 days (or palliative bone radiation therapy within 7 days) prior to randomization.

i. Participants must not be planning to receive any concurrent chemotherapy, immunotherapy, or biologic therapy for cancer treatment while receiving treatment on this study.

j. Participants must not have undergone major surgery within 28 days prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization. Participants must not have postoperative bleeding complications or wound complications from a surgical procedure performed within 2 months prior to randomization. The participant must not have elective or planned major surgery to be performed during the course of this study 

5.3 Clinical/Laboratory Criteria

a. Participants must have adequate organ and marrow function as defined below within 28 days prior to randomization:

- absolute neutrophil count ≥1.5 x 10^3/uL

- hemoglobin ≥ 9.0 g/dL - platelets ≥100 x 10^3/uL

- total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless history of Gilbert’s disease. Participants with history of Gilbert’s disease must have total bilirubin ≤ 5 x institutional ULN. 

- AST and ALT ≤ 3 × institutional ULN. Participants with history of liver metastasis must have AST and ALT ≤ 5 x ULN

b. Participants must have a creatinine ≤ the IULN or calculated creatinine clearance ≥ 50 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to randomization 

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

-Patients must have resectable melanoma in order to be eligible for this study. Patients must have clinically detectable Stage III (clinically detectable N1b, N1c, N2b, N2c, N3b and N3c) or Stage IV resectable melanoma. Patients with melanoma of mucosal or acral origin are eligible. Patients with melanoma of uveal origin are not eligible. Patients with a history of brain metastases are not eligible.
-Patients are eligible for this trial either at initial presentation of their melanoma or at the time of the first detected nodal, satellite/in-transit, distant metastases, or recurrent disease in prior lymphadenectomy basin or distant site. Nodal, satellite/in-transit metastasis, distant metastases or disease in a prior complete lymphadenectomy basin must have been confirmed histologically by H & E stained slides.
-Patients with multiple regional nodal basin involvement are eligible. Gross or microscopic extracapsular nodal extension is permitted.
-Patients must not have received previous neoadjuvant treatment for their melanoma. Patients may have received prior non-immunotherapy adjuvant therapy. Patients must not have had prior immunotherapy including, but not limited to ipilimumab, interferon alfa-2b, high dose IL-2, PEG-IFN, anti-PD-1, anti-PD-L1 intra-tumoral, or vaccine therapies. Patients must not be planning to receive any of the prohibited therapies listed in Section 7.2

during treatment phases on the study.
-Patients must not be planning to receive concomitant other biologic therapy, hormonal therapy, other chemotherapy, surgery, while on protocol therapy.
-Patients may have received prior radiation therapy, including after prior surgical resection. All adverse events associated with prior surgery and radiation therapy must have resolved to = Grade 1 prior to randomization.
-All patients must have disease status documented by a complete physical examination and imaging studies within 42 days prior to randomization. Imaging studies must include a total body PET-CT scan that is of diagnostic quality with iodine contrast-enhanced images (with or without brain) or a CT of the chest, abdomen and pelvis with intravenous contrast. For patients with melanoma arising from the head and neck, dedicated neck imaging (CT with intravenous contrast or iodine contrast-enhanced PET-CT through the region) is required. If the patient has unknown primary with disease in the axilla, neck imaging is required to assure region is clear of cancer. CT imaging should be done with intravenous contrast if there are no contraindications for it. Any other clinically-indicated imaging studies if performed (e.g. bone scan) must show no evidence of disease.
-All patients must have a CT or MRI of the brain within 42 days prior to randomization. The brain CT or MRI should be performed with intravenous contrast (unless contraindicated).
-Patients must have Zubrod Performance Status = 2

- Patients must not have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
-Patients must not have active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

 ***CREDENTIALING is required

 Sites Credentialed- SJMH, Saginaw, Sparrow, SJMO, St. Alphonsus, Lehigh Valley (Cedar Crest, Muhlenberg)

-All patients must have a histologically or cytologically proven diagnosis of adenocarcinoma of the prostate. Patients with pure small cell carcinoma* (SCC), sarcomatoid, or squamous cell carcinoma are not eligible. (*morphology must be consistent with SCC; synaptophysin or chromogranin positive by immunohistochemical staining is insufficient to diagnose SCC).
-Patients must have an intact prostate. No prior local therapy for prostate adenocarcinoma is allowed (e.g., brachytherapy, HIFU, cryotherapy, laser ablative therapies). Any prior therapy for benign conditions, such as obstruction, are acceptable (e.g., transurethral resection of the prostate, greenlight laser ablation, microwave ablation).
-Patients must have evidence of metastatic disease on technetium bone scan and CT or MRI within 42 days prior to starting standard systemic therapy. Metastatic disease that is detected by PET scan only (NaF, PSMA, FACBC, C11) but not conventional imaging (Tc99 bone scan, CT or MRI) or solitary metastases by conventional imaging, must be confirmed histologically or cytologically.
-Patients with known brain metastases are not eligible. Brain imaging studies are not required for eligibility if the patient has no neurologic signs or symptoms suggestive of brain metastasis. If brain imaging studies are performed, they must be negative for disease.
-Patients must have received no more than 28 weeks of SST. SST is defined as current NCCN guidelines for metastatic prostate cancer.
-Patients must not have progressed while on SST
-Patients with oligometastatic prostate cancer may receive metastasis directed therapy to up to four sites of disease prior to randomization. Acceptable approaches are included in Section 7.0
-

Patients must have a PSA documented prior to initiation of SST and within 28 days prior to registration. Any additional PSAs measured while receiving SST should be recorded.

-Patients must have a testosterone lab documented within 28 days prior to randomization. Any additional testosterone labs measured while receiving SST should be recorded as well as pretreatment initiation if available.
-No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, adequately treated Stage 0, I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years.

-Patients must have a testosterone < 50 ng/dL within 28 days prior to randomization.

-Patients must have a Zubrod performance status of 0 – 1 within 28 days prior to randomization (see Section 10.5).

**Effective 10/29/21, the TruCulture TM collection has been permanently halted.**

**Effective 03/01/2024 Step 1 Registration is Closed To Accrual**

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

- Patients must have histologically proven, T2-T4a N0M0 urothelial carcinoma of the bladder within 70 days prior to randomization. Patients with mixed urothelial carcinoma will be eligible for the trial, but the presence of small cell carcinoma will make a patient ineligible. Patients with lymph nodes = 1.0 cm in shortest cross-sectional diameter on imaging (CT / MRI) must have a biopsy of the enlarged lymph node showing no tumor involvement within 70 days prior to randomization. These patients may be suitable for neoadjuvant chemotherapy and radical cystectomy and are eligible for this trial if they seek out a bladder sparing treatment strategy, however patients who have received prior systemic chemotherapy for bladder cancer are not eligible for the trial.
-Patients must undergo a TURBT within 70 days prior to randomization. In a situation where a patient is referred from outside to the enrolling institution, patient must have a repeat cystoscopy by the urologist who will be following the patient on the clinical trial to assess the adequacy of the prior TURBT. Patient may then undergo repeat TURBT if deemed necessary as standard of care by the treating urologist. Patients may have either completely or partially resected tumors as long as the treating urologist attempted maximal resection. Patient must not have T4b disease.
-Patients must undergo radiological staging within 70 days prior to randomization. Imaging of chest, abdomen, and pelvis must be performed using CT or MRI. Patients must not have evidence of T4bN1-3 disease. Eligibility is based on the local radiology report.
-Patients with hydronephrosis are eligible if they have unilateral hydronephrosis and kidney function meets criteria specified in Section 5.3e.
-Patients must not have had urothelial carcinoma or histological variant at any site outside of the urinary bladder within the previous 24 months except Ta/T1/Carcinoma in situ (CIS) of the upper urinary tract including renal pelvis and ureter if the patient had undergone complete nephroureterctomy.
-Patients must not have diffuse CIS based on cystoscopy and biopsy.

- Patient must be planning to receive one of the protocol specified chemotherapy regimens.
-All adverse events associated with any prior surgery and intravesical therapy must have resolved to CTCAE Grade = 2 prior to randomization.
-Patient must not have received any systemic chemotherapy for their bladder cancer.
-Patient must not have had prior pelvic radiation.
-Patients must not have received prior treatment for muscle invasive bladder cancer including neoadjuvant chemotherapy for the current tumor.

-Patients must not have received any systemic therapy (including, but not limited to, interferon alfa-2b, high dose IL-2, PEG-IFN, anti-PD-1, anti-PD-L1), for non-muscle invasive bladder cancer. Prior intravesical BCG, interferon, and intravesical chemotherapy are allowed.

- Patients must not have received any of the following prohibited therapies within 28 days prior to randomization or be planning to receive any of the following prohibited therapies during protocol treatment:

• Anti-cancer systemic chemotherapy or biological therapy not specified in the protocol.

• Immunotherapy not specified in this protocol.

• Systemic or intravesical use of any non-study anti-cancer agent (investigational or non-investigational).

• Investigational agents other than atezolizumab.

• Live vaccines: Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed. Prior administration of intravesical BCG is allowed.

• Glucocorticoids for any purpose other than to modulate symptoms from an event of suspected immunologic etiology. The use of physiologic doses of corticosteroids (defined as 10 mg prednisone) are acceptable, however site investigators should consult with the Study Chair for any dose higher than 10 mg prednisone. Dexamethasone 4 mg iv with chemotherapy to prevent nausea is allowed.

•RANKL infusion: Concurrent denusumab (which binds the cytokine RANKL) for any known indication is prohibited due to interaction with study medication.
-Patients must not have a major surgical procedure within 28 days prior to randomization. If patient had any surgical procedure then they should have recovered to full presurgical performance status and surgical adverse events should have resolved to grade < 2. TURBT is not considered a major surgical procedure.
-Patients must not have received treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 14 days prior to randomization. Exceptions:

• Patients may have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea).

• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed. Physiological doses equivalent of 10 mg prednisone daily are allowed. Short term steroids given as antiemetic therapy, e.g. 4 mg dexamethasone or equivalent once a week, is allowed.
-Patients must not have received a live, attenuated vaccine within 4 weeks prior to randomization or anticipate that such a live, attenuated vaccine will be required while on protocol treatment and up to 5 months after the last dose of protocol treatment.

- Inactivated influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine within 4 weeks prior to randomization or while on protocol treatment and up to 5 months after the last dose of protocol treatment.
-Patients must not have undergone prior allogeneic bone marrow transplantation or prior solid organ transplantation.
-Patient may or may not be radical cystectomy candidates.