-Patients must have histologically or cytologically proven pancreatic adenocarcinoma. Histologies other than adenocarcinoma, or any mixed histologies, will NOT be eligible.
-Patients must have measurable disease in the pancreas
-Patients must have resectable primary tumor based on contrast-enhanced CT or MRI.
-Patients must not have received prior surgery, radiation therapy, chemotherapy, targeted therapy, or any investigational therapy for pancreatic cancer.
-Patients must have a Zubrod Performance Status of 0-1
-Patients must be greater than or equal to 18 and less than or equal to 75 years old.

***Credentialing required- Check Your Sites Status***

Current sites credentialed: SJMH, Sparrow

-Patients must have histologically proven Ta, carcinoma in situ (CIS) or T1 stage urothelial cell carcinoma of the bladder within 90 days prior to registration
-Patients must have had all grossly visible papillary tumors removed within 30 days prior to registration or cystoscopy confirming no grossly visible papillary tumors within 30 days prior to registration
-Patients with T1 disease must have re-resection confirming ? T1 disease within 90 days prior to registration.
-Patients must have high-grade bladder cancer
-Patients must not have pure squamous cell carcinoma or adenocarcinoma.
-Patients’ disease must not have micropapillary components.
-Patients must have no evidence of upper tract (renal pelvis or ureters) cancer
-Patients must not have nodal involvement or metastatic disease.
-ECOG PS must be 0-2
-Patients must not have received prior intravesical BCG.

Effective 01/15/2023, Arm 1 - TGR-1202 plus Obinutuzumab is Closed to Accrual. 

*Credentialing required. Please check your site's credentialing status.*
CURRENT sites credentialed:
SJMH, St. Mary's Saginaw, Livonia, Oakland, LVHN, St. John, Sparrow

-Patients must have follicular lymphoma (Grade I, II or IIIa) confirmed at initial

diagnosis and at relapse with identifiable FDG avid disease on PET/CT.

-Patients must not have clinical evidence of central nervous system involvement by lymphoma,

-Patients must have either failed to achieve a complete remission, or must have relapsed within 2 years after completing first line bendamustine containing chemoimmunotherapy (including an anti-CD20 monoclonal antibody), as measured from the last dose of bendamustine. Relapsed patients must not have received any intervening chemotherapy

-Patients must have received at least 3 cycles of bendamustine as first line therapy

-Patients must not have any prior treatment with any PI3K inhibitor, or lenalidomide

-Zubrod PS must be 0-2

**Effective 03/15/23, all cohorts are closed to patient accrual.**

Effective 04/14/2021, Cohort #4 (Undifferentiated carcinoma of gastrointestinal (GI) tract) 

Effective 04/14/2021, Cohort #27 (Desmoid tumors)

Effective 11/17/2020, Cohort #35 (Vulvar cancer)

Effective 11/17/2020,  Cohort #48 (Gallbladder cancer)

Effective 07/29/2020, Cohort #51 (Angiosarcoma) 

Effective 04/09/2020, Cohort #45 (Clear cell cervical endometrial cancer)

Effective 03/11/2020, Cohort #22 Pancreatic neuroendocrine tumor (PNET)

Effective 02/19/2020- Cohort #39 (Apocrine tumors/Extramammary Paget’s Disease)

Effective 02/03/2020- Cohort #52 (High-grade neuroendocrine carcinoma)

Effective 02/03/2020- Cohort #26 (Carcinomas of pituitary gland, thyroid gland parathyroid gland and adrenal cortex)

Effective 01/15/2020- Cohort 24 (Pheochromocytoma, malignant)

Effective 10/22/19, Cohort #36 (MetaPLASTIC carcinoma of the breast)

Effective 10/02/19- Cohort #17 (Epithelial tumors of penis - squamous adenocarcinoma cell carcinoma with variants of penis)

Effective 09/01/19- Cohort #43 (Endometrial carcinosarcoma (malignant mixed Mullerian tumors)

Effective 08/15/19- Cohort #8 ( Rare pancreatic tumors including acinar cell carcinoma, mucinous cystadenocarcinoma or serous cystadenocarcinoma.

Effective 06/11/19- Cohort #44 ( Endometrial carcinosarcoma (malignant mixed Mullerian tumors).

Effective 06/11/19- Cohort #3 (Salivary gland type tumors of head and neck, lip, esophagus, stomach, trachea and lung, breast and other location. 

Effective 05/15/19 Cohort #16 (Cell Tumor of the Testes and Extragonadal Germ Tumors)
Effective 04/15/19 Cohort #14 (Trophoblastic tumor: A. Choriocarcinoma)
Effective 04/15/19 Cohort #15 (transitional cell carcinoma other
than that of the renal, pelvis, ureter, or bladder)
Effective 03/15/19 Cohort #33 ( Not Otherwise Categorized (NOC) Rare Tumors)

Effective 10/17/18- Cohort #6 (Squamous cell carcinoma with variants of GI tract (stomach, small intestine, colon, rectum, pancreas) 

Effective 09/26/18- Cohort #37 -(Gastrointestinal stromal tumor) 

Effective 09/19/18- Cohort #28- Peripheral nerve sheath tumors and NF1-related tumors

Effective 07/27/18-  Cohort #1 – Epithelial tumors of the nasal cavity, sinuses, nasopharynx

Effective 07/27/18-Cohort #20 – Adenocarcinoma with variants of GU system

Effective 07/27/18-  Cohort #22 – Endocrine carcinoma of pancreas and digestive tract

Effective 06/27/18- Cohort #31 (Adrenal cortical tumors)

Effective 05/10/18-Cohort #5 (Adenocarcinoma with variants of small intestine) 

Effective 03/20/18- Cohort #7 (Fibromixoma and low grade mucinous adenocarcinoma

(pseudomixoma peritonei) of the appendix and ovary Fibromixoma and low grade mucinous adenocarcinoma (pseudomixoma peritonei) of the appendix and ovary

Effective 03/20/18-Cohort #9- (Intrahepatic Cholangiocarcinoma),

Effective 03/20/18-Cohort  #10- Extrahepatic cholangiocarcinoma and bile duct tumors

Effective 03/30/18- Cohort #13 (Non-epithelial tumors of the ovary)

Effective 03/20/18- Cohort #2 (Epithelial tumors of major salivary glands)

Effective 12/19/17- Cohort #23 (Neuroendocrine carcinoma including carcinoid of the lung)

Effective 12/22/17-  Cohort #32 (Tumor of unknown primary, cancer of unknown primary)
-Effective 02/06/18 Cohort #34 (Adenoid cystic carcinoma)

-Patients must have histologically confirmed rare cancer and/or cancer of unknown  primary, identified in protocol section 18.1 that did not have a match to a molecularly -  

guided therapy on MATCH or who progressed on molecularly-matched therapy and have no further molecularly-matched treatment recommendations
-Patients who are determined to have a rare cancer with unknown primary site are eligible provided that there is histologic documentation of metastatic malignancy with no discernible primary site
-Patients must have measurable disease.
-Patients may have received either prior anti-CTLA4 or other prior anti-PD-1/anti-PD-L1 therapy, not both, provided that it is completed at least 4 weeks prior to registration

for monoclonal therapy, at least 8 weeks prior to registration if therapy involved immune stimulatory mAbs, and at least 28 days for all other immunotherapy
-Patients who had prior immune-related adverse event are not eligible.
-Patients must have a ECOG PS of 0-2.
-Patients must not have active autoimmune disease that has required systemic treatment in past 2 years

**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 substudy 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 FDAapproved 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.