Arm 2 is Closed to Accrual as of 02/15/2024

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

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

Eligibility Criteria:

Disease Related Criteria

a. Participant must have predominant histologically and cytologically proven urothelial carcinoma in a metastatic site.

b. Participant must have evidence of metastatic urothelial carcinoma based on CT or MRI within 28 days prior to registration.

c. Participant must have had progression of disease following prior therapy at the discretion of the treating investigator.

d. Participants must not require immediate CNS-specific treatment, in the opinion of the treating investigator if they have active brain metastases (defined as new or progressive brain metastases) or leptomeningeal disease. 

Prior/Concurrent Therapy Criteria

a. Participant must have received previous treatment for metastatic urothelial carcinoma with either a platinum-based chemotherapy regimen, systemic PD1/PDL1 immunotherapy, antibody conjugate, or enfortumab. There is no limit to the number of prior regimens patient may have received for urothelial carcinoma.

• If participant is a candidate for a platinum-based chemotherapy, then participant must have previously received a platinum-based chemotherapy.

• If participant is a candidate for immunotherapy, then participant must have previously received immunotherapy. If participant is not a candidate for immunotherapy, then participant either: (a) must have had prior anti PD1/PDL1 antibody therapy; OR (b) must have not been a candidate for anti PD1/PDL1 antibody therapy in the opinion of the treating physician.

• Participant is eligible if platinum based chemotherapy and/or anti PDL/PDL1 antibody therapy was provided in perioperative setting before or after radical cystectomy and if there is evidence of progression to metastatic disease within 12 months of the last dose of therapy. For instance, a patient treated with ddMVAC in neoadjuvant setting, then radical cystectomy followed by adjuvant pembrolizumab on AMBASSADOR trial will meet the requirement for prior/concurrent therapy if progression of disease occurs within 12 months of discontinuation of pembrolizumab.

b. Participant must have received any planned surgery prior to registration.

c. Participant must not have progressed within 3 months following last dose of gemcitabine. 

d. Participant must not have unresolved toxicities from prior surgeries or radiation therapy > Grade 1 at the time of registration to registration.

Clinical/Laboratory Criteria

a. Participant must be ≥ 18 years of age.

b. Participant must have Zubrod Performance Status 0-2 (see Section 10.0).

c. Participant must have history and physical examination within 28 days prior to registration.

d. Participant must have complete blood count (CBC), complete metabolic panel including liver function tests, and LDH obtained within 28 days prior to registration.

e. Participant must have adequate kidney function as evidenced by measured or calculated creatinine clearance ≥ 50 mL/min within 28 days prior to registration. Calculated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 72 x creatinine (mg/dl)

f. Participant must have adequate hepatic function documented by either AST or ALT ≤ 3 x IULN within 28 days prior to registration. If both AST and ALT are performed, both must be ≤ 3 x IULN. For participants with liver metastases, AST or ALT must be ≤ 5 x IULN.

g. Participant must be on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration if they are known to have human immunodeficiency virus (HIV)-infection.

h. Participants must have undetectable HBV viral load within 28 days prior to registration if participant has known chronic hepatitis B virus (HBV) infection.

i. Participants with a known history of hepatitis C virus (HCV) infection must have an undetectable HCV viral load within 28 days prior to registration.

j. Participants may have a prior or concurrent malignancy provided the natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen per the opinion of the treating investigator. 

k. Participants must not be planning to take strong or moderate CYP3A or CYP2C8 inhibitors or inducers if randomized to Arm 1 and SOC regimen chosen is Paclitaxel or Docetaxel. Participants receiving strong or moderate CYP3A or CYP2C8 inducers must discontinue use at least 2 weeks prior to randomization.

l. Participant must not have a known history of QTc prolongation.

m. Participants must not be pregnant or nursing due to the risk of harm to a fetus or nursing infant. Women and men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study and 6 months (females) or 3.5 months (males) after the last dose.. 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.

Specimen Submission Criteria

a. Participants must be offered the opportunity to participate in specimen banking as outlined in Section 15.1. 

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

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

Eligibility Criteria: 

Disease Related Criteria

a. Patient must have a histologic or cytologic diagnosis of pancreatic adenocarcinoma. Patients with neuroendocrine tumors, acinar cell and adenosquamous carcinomas are excluded. All disease must be assessed and documented on the Baseline Tumor Assessment Form.

b. Patients must have one of the following mutations: germline mutation in BRCA 1 or 2 that was tested in a CLIA certified lab defined as positive and/or deleterious (that is, pathogenic or likely pathogenic variant). (NOTE: Patients with tumor somatic mutations are not eligible). The Germline Testing Report must be submitted per Section 14.4a.

c. Patient must have metastatic disease and received first line platinum-based chemotherapy (i.e. FOLFIRINOX, FOLFOX, or gemcitabine + cisplatin)

d. Patients must have had a CT or MRI showing stable or responding disease on first line platinum-based chemotherapy within 30 days prior to registration.

e. Patients with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration.

f. Patients with history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 30 days prior to registration.

g. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment must have an undetectable HCV viral load within 30 days prior to registration.  

Prior/Concurrent Therapy Criteria

a. Patients must have received at least 16 weeks but no more than 24 weeks of first line platinum-based therapy for metastatic disease.

b. Patients’ last chemotherapy treatment must be within 30 days prior to registration.

c. Patients must have resolved or stable ≤ Grade 1 toxicity from prior administration of another investigational drug and/or prior anti-cancer treatment, excluding neuropathy and alopecia

d. Patients must not have a known hypersensitivity to olaparib or any of the excipients of the product.

e. Patients must not be planning to receive strong or moderate CYP3A inhibitors or inducers (See Section 3.2c.3) while on olaparib treatment. Patients receiving strong or moderate CYP3A inhibitors must discontinue use at least 2 weeks prior to receiving olaparib. Patients receiving strong or moderate CYP3A inducers must discontinue use at least 5 weeks prior to receiving olaparib. Medications should be checked using a frequently updated medical reference for a list of drugs to avoid.

f. Patients must not have received live vaccines within 42 days prior to randomization and must not be planning to receive live virus or live bacterial vaccines while receiving study treatment and during the 30 day follow up period. 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.

g. Patients must not have had prior therapy with an anti-PD-1, anti-PD-L1, or antiPD-L2 agent, or any other immune checkpoint inhibitors.

h. Patients must not have had prior therapy with PARP inhibitors.

i. Patients must not have had a prior diagnosis of immunodeficiency or receiving systemic steroid therapy (defined as > 10 mg prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 

Clinical/Laboratory Criteria

a. Zubrod performance status of 0-1.

b. Patients must be ≥ 18 years old.

c. Patients must have a complete medical history and physical exam within 28 days prior to registration. d. Patients must have adequate organ and marrow function within 14 days of registration, as defined below:

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

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

- AST/ALT ≤3 × institutional ULN

- creatinine ≤ 1.5 mg/dl

- Albumin ≥3.0 - Hemoglobin ≥9.0 g/dL

e. Patients must have CA19-9 obtained within 42 days prior to registration.

f. Patients must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of the study medication.

g. Participants with a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial provided it does not require concurrent therapy.

h. Participants must not be pregnant or nursing due to the possibility of harm to the fetus or nursing infant from this treatment regimen. Women/men of reproductive potential must have agreed to use an effective contraceptive method for the course of the study through 6 months after the last dose of study medication. 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. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

i. Patients must not have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.

j. Patients must not have an active infection requiring systemic therapy.

k. 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. 

Specimen Submission Criteria

a. Patients must be offered the opportunity to participate in specimen banking of FFPE tissue and whole blood as outlined in Section 15.1. If a patient is unable to submit archival tissue, should the patient need to undergo a standard of care biopsy per NCCN guidelines, patients must then be offered the opportunity to submit the fresh tumor tissue from that biopsy. With participant consent, specimens must be collected and submitted via the SWOG Specimen Tracking System as outlined in Section 15.1. 

*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, Saginaw

Eligibility Criteria:

Registration Step 1: Initial Registration/Randomization Disease Related Criteria

a. Participants must have had a confirmed diagnosis of Waldenström’s macroglobulinemia (WM)/Lymphoplasmacytic Lymphoma (LPL). Participants must have measurable disease as determined by IgM protein quantification (see Section 10.1a). Testing to establish baseline disease status must be performed within 28 days prior to registration.

b. Participants must have at least one of the criteria to require therapy for WM including anemia, thrombocytopenia, neuropathy related to WM, symptomatic hyperviscosity or serum viscosity levels greater than 4.0 centipoises, WM associated glomerulonephritis or renal disease, bulky disease, or constitutional symptoms. Constitutional symptoms can be described as unintentional weight loss ≥10% within the previous 6 months prior to Screening; Fevers higher than 100.5°F or 38.0°C for 2 or more weeks prior to Screening without evidence of infection; Night sweats for more than 1 month prior to Screening without evidence of infection; Clinically relevant fatigue which is not relieved by rest due to WM.

Prior/Concurrent Therapy Criteria

c. Participants who require ongoing use or received a moderate or strong CYP3A inducer, moderate or strong CYP3A inhibitor, P-gp inihibitor within 7 days prior to the first dose of study drug will be excluded from the study. If such participants can be safely switched to an alternative agent, then the participants will be eligible to enroll.

d. Participants must not have had prior systemic therapy. Prior therapy with rituximab will be allowed as long as the last rituximab dose was at least 12 months prior to registration.

Clinical/Laboratory Criteria

e. Participants must be ≥ 18 years of age.

f. Participants must have history and physical exam within 28 days prior to registration.

g. Participants must have Zubrod Performance Status ≤ 2 (see Section 10.7).  

h. Participants must not be intolerant to rituximab.

i. Participants must have evidence of adequate renal function, as defined by creatinine clearance (CrCl) ≥ 30 mL/min. Values must be obtained within 14 days prior to registration. 

j. Participants must have adequate hepatic function defined by the following within 14 days prior to registration:

1. Total bilirubin ≤1.5 x IULN (institutional upper limit of the norm).

AND

2. AST, ALT and alkaline phosphatase ≤ 3 x IULN

k. Participants must have adequate bone marrow function defined by the following without transfusion or growth factor support within 14 days prior to registration:

1. Platelet count ≥ 50,000 cells/mm3 and

AND

2. Hemoglobin ≥ 7.0 g/dL AND

3. Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3

l. Participants must not have known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) 4 weeks prior to registration.

m. Participants with known human immunodeficiency virus (HIV)-infection are eligible providing they are on effective anti-retroviral therapy and have undetectable viral load at their most recent viral load test and within 6 months prior to registration.

n. Participants must not be seropositive for hepatitis C (except in the setting of sustained virologic response, defined as undetectable viral load at least 12 weeks after completion of antiviral therapy). HCV testing is only required if clinically indicated or if the participant has a history of HCV.  

o. Participants must be able to take and swallow oral medication (capsules) whole. Participants may not have any known impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection.)

p. Participants must not consume grapefruit, Seville oranges or starfruit within 3 days prior to the first dose of venetoclax.

q. Participants must not be pregnant or nursing because venetoclax has not been studied in pregnant or nursing women and the mechanism of action is expected to cause fetal harm. 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" e.g., implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence, or sterilized partner) and a barrier method (e.g., condom, cervical ring, sponge, etc.). This 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 throughout the study and for at least 30 days after competition of therapy.

r. No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the participant is currently in complete remission, or any other cancer from which the participant has been disease free for two years or watchful waiting is appropriate in the opinion of the treating physician. Also, malignancy that in the opinion of the Investigator, is considered cured with minimal risk of recurrence within 5 years, is permissible consideration of eligibility for this trial. Specimen Submission Criteria

s. Participants must be offered the opportunity to participate in specimen banking as outlined in Section 15.1.  

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Canton, Chelsea), Livonia, St. John, Macomb, Genesys, Hurley, Oakland, Saginaw, Lehigh

Eligibility Criteria:

Disease Related Criteria

a. Participants must be female and have Stage I, II, or III hormone receptor positive breast cancer based on clinical or pathologic evaluation (See Section 4.0).

b. Participants must have been pre- or peri-menopausal at the time of breast cancer diagnosis by satisfying one of the following:

1. had a menstrual period (by self-report) within the 12 months before breast cancer diagnosis, or

2. had a serum or plasma estradiol and/or FSH concentration consistent with premenopausal status (based on institutional standards) within the 12 months before breast cancer diagnosis or when checked after breast cancer diagnosis.

c. Participants must not have distant metastatic breast cancer.  

Prior/Concurrent Therapy Criteria

a. Participants must have started initial treatment with standard of care oral endocrine therapy (ET) (i.e., tamoxifen, anastrozole, exemestane, or letrozole; see Section 7.1 for details) within 14 days prior to randomization or be planning to start initial treatment with standard of care oral ET (+/- GnRHa injection) within 14 days after randomization.

NOTE: For participants who will be starting GnRHa injection followed by initiation of oral ET after achieving ovarian suppression, participants must be planning to start initial treatment with standard of care GnRHa therapy within 14 days after randomization.

b. Participants who currently have ovarian function (estradiol above the postmenopausal range) must be planning to undergo ovarian suppression or ablation (see Section 7.1) concomitantly with oral ET medication, starting before or at the same time as oral ET initiation. 

*** Please see the current version of protocol for full eligibility list**

*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, Hurley, St. John, Macomb, Holy Cross

Eligibility Criteria:

Disease Related Criteria

a. Participants must have histologically-confirmed (local site pathological confirmation sufficient) extrapulmonary poorly differentiated, small cell neuroendocrine carcinoma (NEC) as defined in Section 4.0 that is metastatic.

b. Participants must have radiologically evaluable disease, measurable or nonmeasurable, per RECIST 1.1 criteria. All measurable and non-measurable lesions must be assessed by CT scan within 28 days prior to registration. For patients who received one cycle of platinum + etoposide prior to registration, at least 21 days must have elapsed between Day 1 of platinum + etoposide and the preregistration CT scan. All known sites of disease must be assessed and documented on the Baseline Tumor Assessment Form.

c. Participants must have brain MRI (or CT head with contrast if there is contraindication to MRI brain) within 28 days prior to registration. Participants with asymptomatic central nervous system (CNS) metastases are eligible if one or more of the following apply:

• Participants who have received treatment for brain metastases must have:

o No evidence of radiological progression (by MRI brain or CT head with contrast if there is contraindication to MRI brain) within 28 days prior to registration

o Discontinued all corticosteroids at least 14 days prior to registration

• Participants with treatment-naïve brain lesions must have:

o No lesion measuring >2.0 cm in size in any axis

o MRI brain or CT head with contrast (if there is contraindication to MRI brain) demonstrating no evidence for mass effect, edema, or other impending neurological compromise within 28 days prior to registration.

o No evidence of radiological progression (by MRI brain or CT head with contrast if there is contraindication to MRI brain) within 28 days prior to registration

o No need for >2 mg of dexamethasone (or equivalent of >10 mg prednisone) per day at time of registration.

d. Participants must not have symptomatic central nervous system (CNS) metastases.

e. Participants must not have known or suspected leptomeningeal disease.

f. Participants must not have small cell NEC mixed with urothelial carcinomas. 

Prior/ Concurrent Therapy Criteria

a. Participants with prior history of non-metastatic (localized/locally advanced disease) extrapulmonary poorly differentiated small cell NEC may have had prior platinum-based therapy ± radiation ± surgery provided that all therapy was completed ≥ 6 months prior to registration.

b. Participants must discontinue denosumab prior to study registration and plan to replace with a bisphosphonate while on the study.

c. Participants must not have had prior treatment for metastatic disease EXCEPT one cycle of platinum (carboplatin/cisplatin) + etoposide is allowed prior to registration. Other chemotherapy regimens are not allowed.  

d. Participants must not have had prior treatment with an anti-PD-1, anti-PD-L1, antiPD-L2, CD137 agonists, anti-CTLA-4 agent, or any other immune checkpoint inhibitors for any neuroendocrine neoplasm. Immune checkpoint inhibitors given for other cancer indications are allowed provided last therapy was given at least 12 months prior to study registration.

e. Participants must not have received treatment with systemic immunostimulatory agents including, but not limited to, interferon and interleukin2 [IL-2] within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to registration.

f. Participants must not have had history of known severe allergy, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies, including to Chinese hamster ovary cell products or to any component of the atezolizumab formulation, cisplatin, carboplatin, or etoposide.

g. Participants must not be on active systemic therapy for another cancer with the exception of hormonal therapy including androgen deprivation therapy (e.g., gonadotropin-releasing hormone (GnRH) agonists or antagonists), which can be continued while participants are receiving protocol therapy. Use of enzalutamide or apalutamide is permitted after completion of chemotherapy; however, glucocorticoid-containing regimens, including abiraterone, are not permitted. 

Clinical/ Laboratory Criteria

a. Participants must be ≥ 18 years of age.

b. Participants must have a Zubrod Performance Status of ≤ 2 (see Section 10.4) within 28 days prior to registration.

c. Participants must have a complete medical history and physical exam within 28 days prior to registration.

d. Participants must have adequate marrow function as defined below. These results must be obtained within 14 days prior to registration. For participants who received a cycle of chemotherapy prior to registration, at least 21 days must have elapsed between Day 1 of platinum + etoposide and performance of these tests.

• Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L

• Hemoglobin ≥ 9.0 g/dl

• Platelet count ≥ 100 x 109/L e. Participants must have adequate organ function as defined below. These results must be obtained within 14 days prior to registration. For participants who received a cycle of chemotherapy prior to registration, at least 21 days must have elapsed between Day 1 of platinum + etoposide and performance of these tests.

• Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x institutional upper limit of normal (ULN)

• Serum total bilirubin ≤ 1.5 x ULN

• Measured creatinine clearance (CL) >50 mL/min or Calculated creatinine CL>50 mL/min by the Cockcroft-Gault formula as below (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance. 

f. Participants must not have uncontrolled or symptomatic hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium >ULN) within 14 days prior to registration. Participants who have asymptomatic hypercalcemia are eligible provided that medical therapy to treat the hypercalcemia is planned.

g. Participants must not have a diagnosis of immunodeficiency nor be receiving systemic steroid therapy (equivalent of > 20 mg of hydrocortisone per day) or any other form of immunosuppressive therapy within 14 days prior to registration.

h. Participants must not have active or history of autoimmune disease or immune deficiency, including, but not limited to myasthesia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener grandulomatosis, Sjögren syndrome, Guillian-Barré syndrome, or multiple sclerosis with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study

. • Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:

o Rash must cover < 10% of body surface area

o Disease is well controlled at baseline and requires only lowpotency topical corticosteroids

o No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or highpotency or oral corticosteroids within the previous 12 months

i. Participants must not have history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. NOTE: History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

j. Participants must not have significant cardiovascular disease, such as New York Heart Association Class II or greater cardiac disease (refer to Section 18.2), myocardial infarction within 3 months prior to registration, unstable arrythmias, or unstable angina.

k. Participants must not have had a major surgical procedure other than for diagnosis within 28 days prior to registration. Participant must not plan to receive a major surgical procedure during the course of protocol treatment. NOTE: Patient port placement is not considered a major surgery. 

l. Participants must not have severe infections (i.e., CTCAE Grade ≥2) at time of registration, including but not limited to hospitalization for complications for infection, bacteremia, or severe pneumonia.

m. Participants must not have active tuberculosis 

n. Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load, with testing performed as clinically indicated.

o. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with active HCV infection who are currently on treatment must have an undetectable HCV viral load, with testing performed as clinically indicated.

p. Participants with known HIV-infection must be on effective anti-retroviral therapy at time of registration and have undetectable HIV viral load within 6 months of registration.

q. Participants must not have prior allogeneic bone marrow transplantation or solid organ transplant.

r. Participants must not have received administration of a live, attenuated vaccine (e.g., FluMist®) within 28 days prior to initiation of study treatment, during treatment with atezolizumab, and not plan to receive for 5 months after the last dose of atezolizumab.

s. Participants must not be pregnant due to the possibility of harm to the fetus. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method (with details provided as a part of the consent process) during the treatment period and for 5 months after the final dose of atezolizumab. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen. 

Specimen Submission Criteria

a. Participants must be offered the opportunity to participate in specimen banking as outlined in Section 15.1. With participant consent, specimens must be collected and submitted via the SWOG Specimen Tracking System as outlined in Section 15.1. 

**Cohort 1 is Closed to Accrual Effective 11/15/2024

Cohort 2 is re-activated for patient accrual Effective 11/15/2024**

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

Eligibility Criteria 

5.1 Disease Related Criteria

a. Participants must be planning to receive ICI-based therapy for a solid tumor malignancy. This therapy must be given according to NCCN guidelines at Category 1 or 2A and not in the context of a clinical trial. See Section 18.1 for ICI-based therapies.

5.2 Prior/Concurrent Therapy Criteria

a. Participants who have received prior ICI-based therapy must have completed ICI based therapy at least 180 days prior to registration.

b. Participants must not have discontinued any prior ICI-based therapy (if applicable) because of irAE. c. Participants must not have received chemotherapy, biologic, or targeted-therapy within 14 days prior to registration. Hormonal therapy is allowed. 

d. Participants must have recovered from side effects of prior therapy to the following standards per treating physician’s discretion:

• < = Grade 1 for any non-hematologic side effects (excluding neuropathy and alopecia); lab-related parameters of liver and renal function will be considered at the discretion of the treating physician)

• < = Grade 2 for neuropathy and/or alopecia

• Grade 3 or less for any hematologic side effects

e. Participants must be planning to begin standard of care ICI-based therapy within 7 calendar days after registration.

f. Participants must not be planning to receive ICI-based therapy in combination with chemotherapy or any other non-ICI therapy for treatment of their cancer. Palliative radiation is allowed. 

5.3 Clinical/Laboratory Criteria a. Participants must be at least 18 years of age.

b. Participants must complete their history and physical examination within 28 days prior to registration.

c. Participants who can complete the S2013 Feasibility Questionnaire in English or Spanish must participate at the scheduled assessments.

d. Participants must be able to complete Patient-Reported Outcome (PRO) instruments in English, Spanish, or French and must be planning to complete PROs at all scheduled assessments.

e. Participants must complete the pre-registration (baseline) PRO forms within 14 days prior to registration.  

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

*DTL Required- Physicians must sign toxicity grid

CREDENTIALING REQUIRED. Please check your site's credentialing status.
CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Chelsea, Canton), St. Mary's Livonia. Genesys, Hurley, Sparrow

Eligibility Criteria: 

Step 1 – Specimen Submission

a. Disease Related Criteria

1. Participants must have histologically confirmed melanoma that is Stage III or IV, unresectable, recurrent, or metastatic non-uveal melanoma according to criteria in Section 4.1.

OR Participants must have histologically confirmed squamous cell carcinoma of the head and neck (HNSCC) that is either locally recurrent and nonamendable to curative therapy (e.g., radiation, surgery) or metastatic. The primary tumor location must be the oropharynx, oral cavity, hypopharynx, or larynx. Primary tumor site of nasopharynx (any histology) or unknown primary tumor are not eligible.

Note: For participants with primary oropharyngeal cancer, HPV or p16 status must be known prior to Step 1 registration.

2. Participants must have disease presentation consistent with measurable disease. Note: Current disease measurements will not be required until Step 2 registration.

3. Participants must have had documented progression within 12 weeks after the last dose of PD-1 checkpoint inhibition-based therapy. Participants must have been receiving checkpoint inhibition for a minimum of 6 weeks prior to progression. Participants who recur during adjuvant anti-PD1 treatment or within 12 weeks of completion of adjuvant anti-PD1 treatment are eligible if they have measurable disease and considered unresectable. 4. Participants with known human immunodeficiency virus (HIV)-infection must be receiving anti-retroviral therapy and have an undetectable viral load test within 6 months prior to Step 1 registration.

5. Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 28 days prior to Step 1 registration.

6. Participants with a history of hepatitis C virus (HCV) infection must have no detectable viral load within 28 days prior to Step 1 registration.

7. Participants must not have an active infection requiring systemic therapy (except HBV, HCV or HIV as mentioned above)  

Prior/Concurrent Therapy Criteria

1. Participants must have recovered to baseline or ≤ Grade 1 CTCAE v5 toxicities related to any prior treatments, unless adverse events are deemed clinically nonsignificant by the treating investigator or stable on supportive therapy.

2. Participants must not have received surgery, chemotherapy, radiation therapy, biologic agents, or steroids within 14 days prior to Step 1 registration.

3. Participants must not have received more than one prior primary radiotherapy regimen, curative or adjuvant, to the head and neck, with the additional following criteria.  

Clinical/Laboratory Criteria

1. Participants must be ≥ 18 years of age.

2. Participants must have a Zubrod Performance Status 0 or 1. See Section 10.4. 

***Please see the most recent version of the protocol for complete eligibility list**

*DTL Required- Physicians must sign toxicity grid

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

Eligibility Criteria 

Disease Related Criteria 

a. Participants must have a histologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum. The date of diagnosis will be determined according to the pathologic date of diagnosis.

b. Participants must have measurable disease according to RECIST1.1 criteria. CT scans or MRIs used to assess measurable disease (as defined in Section 10.1) must have been completed within 28 days prior to registration. CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form. c. Participants must have documented unresectable and/or metastatic disease on CT or MRI imaging. All disease must be assessed and documented on the Baseline Tumor Assessment Form.

d. Participants must have BRAFV600E mutated colorectal cancer as tested in a CLIAcertified laboratory.

e. Participants must have proficient mismatch repair (pMMR) or Microsatellite Stable (MSS) status as tested in a CLIA-certified laboratory and documented by the treating clinician. Proficient mismatch repair status can be determined by intact expression by immunohistochemistry of all 4 mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2). Microsatellite instability can be determined by polymerase chain reaction (PCR).

f. Participants with brain metastases must have completed surgery or radiation therapy ≥ 28 days prior to registration. These participants must have a CT or MRI of the brain showing no new or enlarging lesions within 42 days prior to registration. These participants must also be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to registration. Metastatic brain parenchymal disease must have been treated and participant must be off steroids for 7 days prior to registration. The presence of leptomeningeal disease (LMD) is not considered stable disease, and participants with LMD are not eligible for this study.

g. Participants must not have a known positive serology for human immunodeficiency virus (HIV). Encorafenib is contraindicated with concomitant use of nonnucleoside analog reverse transcriptase inhibitors like efavirenz and etravirine. In addition, it is recommended in the Investigator Brochure of encorafenib to avoid using encorafenib with protease inhibitors. Therefore, because all participants on this study would receive encorafenib for either randomized arm of treatment, participants with HIV who receive these components of highly active antiretroviral therapy (HAART) would be at high risk for complications of drug-drug interaction.

h. Participants with known evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load on suppressive therapy within 28 days prior to registration.

i. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to registration.  

Clinical/Laboratory Criteria

a. Participants must be of age ≥ 18 years at the time of informed consent.

b. Participants must have a Zubrod performance status of 0 or 1 

**See Protocol for full eligibility criteria list*** 

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

**Canton will not be participating** 

***Registering MD is also the Treating Investigator***

Eligibility Criteria:

Recruitment Center Definition and Eligibility Criteria Recruitment Centers must have completed the S2108CD Recruitment Center Application and be approved for participation in the study. Eighteen Recruitment Centers will be selected to participate in the study based on the eligibility criteria listed below.

a. A Recruitment Center is defined as an outpatient clinic, or group of clinics, belonging to the same NCORP or MU-NCORP, that will be contributing physicians and patient participants to the study.

b. Participating Recruitment Centers must meet the following requirements:

1. Recruitment Centers must be part of an NCORP or MU-NCORP site with CCDR funding. Each clinic included in the Recruitment Center must be associated with CTEP site ID.

2. Recruitment Centers must order large panel next generation sequencing genomic tests on at least 10 unique patients per month.

3. Recruitment Centers must have at least 4 practicing oncologists (including medical, gynecologic, or neuro-oncologists) at the site willing to participate in the study and register within three months of study activation.

4. Recruitment Centers must be willing to register a total of 66 patients (over 2 years) to the study.

5. Recruitment Centers must be able to send at least one member of the clinical team to attend the Recruitment Center’s cases presented to the S2108CD Genomic Tumor Board, should the Recruitment Center be randomized to the intervention arm.

6. Recruitment Centers must be willing and able to document the number of unique patients for whom GTT were ordered at the Recruitment Center and submit this monthly via Rave®.

7. Recruitment Centers must not have an existing Genomic Tumor Board. For the purposes of this study, a Genomic Tumor Board is defined as an interdisciplinary team of clinicians and scientists that reviews genomic testing results and provides guidance on treatment options based primarily on genomic data to the treating physician. The existence of a general multidisciplinary tumor board that addresses all aspects of patient care and treatment is not considered an exclusion criterion. A general multidisciplinary tumor board is defined as an interdisciplinary team of clinicians that primarily discusses all aspects of cancer care, including diagnostic aspects (pathology and radiology), therapeutic options (surgical, radiation and medical) as well as palliative and psychosocial support options.

Physician Participant Criteria

a. Physician participant must be a registering investigator of the Recruitment Center that is participating in the study. If the physician is a registering investigator at more than one Recruitment Center, he/she must choose one Recruitment Center to identify with and enroll patients from.

b. Physician participants must be board-eligible or board-certified in Medical Oncology, Gynecologic Oncology, or Neurology with certification or eligible for certification in Neuro-oncology.

c. Physician participants must be willing to offer participation in the study to all eligible patients under their care for the duration of the study. A single physician may enroll multiple patients on the study.

d. Physician participants must be willing to complete all study questionnaires and, as part of the implementation objective, participate in interviews if invited.

e. Physician participants must complete all baseline questionnaires prior to registration.

f. Physician participants at a Recruitment Center randomized to the intervention arm must be willing to participate in the educationally enhanced GTB (EGTB).

Patient Participant Criteria

a. Disease Related

1. Patient participants must have a solid tumor malignancy that is either recurrent, relapsed, refractory, metastatic, or newly diagnosed Stage III or Stage IV.

2. Patient participants must be under the care of a physician enrolled on the study.

3. Patient participants must not be going on hospice care at the time of registration.

b. Prior/Concurrent Therapy Criteria

1. Patient participants may have started anti-cancer treatment for the current diagnosis.

2. The treating physician anticipates that the patient will start a new anticancer treatment (either first or subsequent lines) within 6 months after registration 

3. Patient participants are allowed to be co-enrolled on other clinical trials including non-treatment studies and studies that include investigational drugs. Patients may be enrolled on genome-informed therapeutic trials, such as LungMAP, MATCH, or TAPUR.

c. Clinical/Laboratory Criteria

1. Patient participant must have a genomic tumor test (GTT) ordered prior to registration with results pending. The genomic testing may be a commercially available panel (such as FoundationOne, Caris, or Tempus) or a non-commercial tumor panel performed at an academic medical center.

NOTE: Qualifying GTTs are defined as a genomic test conducted on the tumor tissue, tumor cells, or cellfree DNA (cfDNA). They must be CLIAcertified NGS tissue or liquid biopsy panels, including hotspot, whole gene, or DNA and RNA (including expression data) panels. Fluorescence-in-situ hybridization (FISH) and immunohistochemistry test results assessing cancer-relevant proteins (e.g. Her2/neu, ALK, MET) and immune parameters (e.g. PD-L1 tests) are also permissible if performed in the context of a larger panel that includes NGS or expression profiling. These tests can come from any commercial or academic laboratory within the US and they should be ordered with the intent to influence genome-informed treatment decision. Oncotype DX and other panels used for making treatment decisions based on a prognostic read-out (e.g. liquid biopsy minimal residual disease (MRD)) are not permitted.

2. Patient participants must be at least 18 years of age.

3. Patient participants must have a Zubrod performance status of 0-2.

4. Patient participants with tests assessing cancer-risk defining germline variants only (“germline test”) are not eligible. 

*DTL Required- Physicians must sign toxicity grid

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

CURRENT SITES CREDENTIALED: SJMH (Ann Arbor, Brighton, Chelsea, Canton), St. Mary's Livonia, GenHur, Hurley, Sparrow, Saginaw

Eligibility Criteria:

Disease Related Criteria

a. Participants must have a histologically confirmed diagnosis of metastatic papillary renal cell carcinoma (PRCC), either type 1 or type 2. (NOTE: A designation of type 1 or type 2 should be made by the local pathologist if possible but is not required). Mixed histologies which contain type 1 or type 2 along with any other RCC histology/histologies will be allowed provided that they contain a papillary component.

b. Participants must have measurable disease per RECIST 1.1 criteria (see Section 10.1). All measurable lesions must be assessed by CT or MRI within 28 days prior to registration. All non-measurable lesions must be assessed by CT or MRI, or nuclear medicine bone scan within 42 days prior to registration. 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 S2200 Section 10.1.c. If there is clinical suspicion for bone metastases at the time of enrollment (at the discretion of the investigator), bone scan must be performed at baseline (within 42 days prior to registration).

c. Participants with new or progressive brain metastases (active brain metastases) must not require immediate CNS specific treatment at the time of study registration or anticipated during the first cycle of therapy. Patients with leptomeningeal disease are excluded from enrolling.

d. Participants with measurable disease, per RECIST v1.1, must be present outside the CNS.

e. Participants must have no history of intracranial hemorrhage or spinal cord hemorrhage.

f. Participants must not have undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment.

g. Participants must not have ongoing requirements for corticosteroids as therapy for CNS disease.

h. Participants, if needed, must receive a stable dose of anti-convulsant therapy.

i. Participants must not have cavitating pulmonary lesions. 

Prior/Concurrent Therapy Criteria

a. Participants must not have had major surgery within 28 days prior to registration, and participants must have recovered from any adverse effects of surgery.

b. Participants must not have had prior treatment with cabozantinib for any reason.

c. Participants must not have had prior treatment or adjuvant therapy with PD-1/PDL1 checkpoint inhibitors for any reason within the past 6 months.

d. Participants must not have received more than one prior systemic therapy for advanced or metastatic renal cell carcinoma with the exception of another VEGF inhibitor FDA-approved for advanced RCC

e. (i.e., pazopanib, bevacizumab, sorafenib or axitinib).  

Participants must not take within 14 days prior to registration, nor plan to take while on protocol treatment, any strong CYP3A4 inhibitors 

g. Participants must complete all prior radiation therapy at least 14 days prior to registration.

Clinical/Laboratory Criteria

a. Participants must be ≥ 18 years of age.

b. Participants must have a complete physical examination and medical history within 28 days prior to registration.

c. Participants must have a Zubrod performance status of 0-2 (see Section 10.6).

d. Participants must have adequate hematologic function within 28 days prior to registration.

***Please see the current version of the protocol for the complete eligibility criteria list**