** Lutetium LU177 credentialing requirements**

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

CURRENT SITES CREDENTIALED:

Eligibility Criteria:

3.2 Pre-Registration Eligibility Criteria

3.2.1 Documentation of Disease

• Pathologic Documentation: Well- or moderately differentiated neuroendocrine tumor(s) of bronchial origin (i.e. carcinoid) as assessed by local pathology. The pathology report must state ONE of the following: 1) well- or moderately differentiated neuroendocrine tumor, 2) low- or intermediate-grade neuroendocrine tumor, or 3) carcinoid tumor (including typical or atypical carcinoid tumors). Documentation of histology from a primary or metastatic site is allowed. Functional (evidence of peptide hormones and/or bioactive substances associated with a clinical hormone syndrome such as carcinoid syndrome or Cushing’s syndrome) or nonfunctional tumors are allowed. Patients with poorly-differentiated or high-grade neuroendocrine carcinoma (i.e. large cell neuroendocrine carcinoma of lung, small cell lung cancer) or mixed tumors (i.e. adenocarcinoid tumor) are not eligible. • Stage: Recurrent or locally-advanced/unresectable or metastatic disease.

• Tumor Site: Neuroendocrine tumor of bronchial (i.e. lung) primary site.

• Radiologic Evaluation: Lesions must have shown radiological evidence of disease progression in the 12 months prior to pre-registration. Tumor must have shown somatostatin receptor (SSTR) positivity on 68Ga\u0002DOTATATE PET or other SSTR-PET scan in the 12 months prior to pre-registration; however, documentation of SSTR positivity in the 6 months prior to pre-registration is preferred. SSTR positivity is defined as uptake greater than background liver in all measurable lesions. 

3.2.2 Measurable Disease Patients must have measurable disease per RECIST v1.1 by computer tomography (CT) scan or magnetic imaging (MRI); see Section 11.0. Any lesions which have undergone percutaneous therapies or radiotherapy should not be considered measurable unless the lesion has clearly progressed since the procedure. Lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 1 cm with CT or MRI (or ≥ 1.5 cm for lymph nodes). Non-measurable disease includes disease smaller than these dimensions or lesions considered truly non-measurable including: leptomeningeal disease, bone metastases, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung. See Section 11.0 for additional details.  

3.3 Registration Eligibility Criteria 

3.3.1 Disease Status Confirmation of SSTR positivity by Alliance ICL at IROC Ohio central radiographic review.

3.3.2 Prior Treatment Patients with treatment-naïve or previously treated disease are allowed. Patients with previously-treated disease must have demonstrated radiographic disease progression on the prior therapy. No prior treatment with peptide receptor radionuclide therapy (PRRT) (e.g. lutetium Lu 177 dotatate). No prior treatment with mammalian target of rapamycin (mTOR) inhibitors (e.g. deforolimus, everolimus, sirolimus, temsirolimus, etc.). Prior treatment with hepatic artery embolization (including bland embolization, chemoembolization, and selective radioembolization) or ablative therapies (i.e. cryoablation, radiofrequency ablation, etc.) is allowed if measurable disease remains outside of the treated area or if there is documented disease progression in a treated site. Prior liver-directed or other ablative treatment must be completed at least 28 days prior to registration. Prior treatment with 90-Yttrium radioembolization must be completed at least 3 months prior to registration. Radiation therapy to the lung and/or mediastinum must be completed at least 14 days prior to registration for stereotactic ablative and at least 28 days prior to registration for conventional fractionation. Prior treatment with systemic anticancer therapy must be completed at least 28 days prior to registration (except for somatostatin analogs in patients with functional tumors). Continuation of treatment with somatostatin analogs while on protocol therapy is allowed provided that the patient: 1) has functional tumors (evidence of peptide hormones and/or bioactive substances associated with a clinical hormone syndrome such as carcinoid syndrome or Cushing’s syndrome), and 2) has previously demonstrated radiographic disease progression while on somatostatin analog therapy. Patients must have completed any major surgery at least 28 days prior to registration. Complete wound healing from major surgery should occur prior to registration. Patients should have improvement of any toxic effects of prior therapy (except alopecia, fatigue, and other non-reversible toxic effects such as neuropathy from cisplatin) to NCI CTCAE, version 5.0, grade 1 or less.  

**PLEASE SEE 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: Trinity Health- SJMH (Ann Arbor, Brighton, Chelsea, Canton), Livonia, Genesys, Hurley, Lehigh

Eligibility Criteria:

Pre-Registration (Step 0) Eligibility Criteria

Pre-registration for central tumor testing will occur after colon resection. Pre-registration can occur at any time after surgery through a five week period after completion of standard adjuvant therapy.

3.2.1 BRAF Mutation Testing BRAF V600 mutational status may be determined either locally or by central testing. This testing is mandatory prior to registration to determine eligibility.

3.3 Registration (Step 1) Eligibility Criteria

 3.3.1 Documentation of Disease Histologically-proven stage III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk (pT4) stage II colon adenocarcinoma. Tumors must be deemed to originate in the colon including tumors that extend into/involve the small bowel (e.g. those at the ileocecal valve) and must have been completely resected. BRAF V600E mutation. MMR proficient (pMMR) or microsatellite stable (MSS) tumor. Histologic Documentation: adenocarcinoma Stage: III (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C) or high-risk II (pT4) Tumor Site: colon

3.3.2 Prior Treatment Patients must have received at least 3 months of adjuvant chemotherapy with either FOLFOX (minimum of 5 cycles) or CAPOX (minimum of 3 cycles). Adjuvant therapy must be completed at most 8 weeks prior to registration. No other prior medical therapy (chemotherapy, immunotherapy, biologic, or targeted therapy) or radiation therapy for the current colon cancer is permitted. 

3.3.3 Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 days prior to registration is required.

3.3.4 Age ≥ 18 years

3.3.5 ECOG Performance Status: 0-2 

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

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:

Pre-Registration Eligibility Criteria (see Section 3.2)

- Histologically-confirmed metastatic colorectal adenocarcinoma

- No known microsatellite instable tumor

- No known BRAF V600E mutation

- No known brain metastases

- No known peritoneal and/or omental metastases

- Primary tumor is already resected OR primary tumor is surgically amenable to resection, (See Sec 3.2.1). Patients with unresectable primary tumors are not eligible.

- Four or fewer apparent sites of metastatic disease based on review by local medical team of baseline radiographic imaging obtained prior to initiation of systemic therapy; (See Sec 3.2.1)

- Patients must have measurable disease per RECIST v1.1

- A maximum of 16 weeks (4 months) of systemic therapy may be administered prior to pre-registration Registration Eligibility Criteria (see Section 3.3)

- Patients must have no overt evidence of disease progression during systemic therapy prior to registration

- Not eligible for hepatic artery infusion pump (HAIP) therapy or benefit of HAIP therapy is undefined.

- Patients must have measurable disease per RECIST v1.1

- Patients must be receiving (or have received) first-line systemic therapy for metastatic disease for a minimum of 16 weeks (4 months) and a maximum of 24 weeks (6 months).

- Prior definitive therapy must have been completed at least 12 months prior to diagnosis of metastatic disease

- Not pregnant and not nursing (See Sec 3.3.4)

- Age ≥ 18 years

- ECOG Performance Status: 0-2

- Patients with known HIV are eligible (See Sec 3.3.8)

- No other planned concurrent investigational agents while on study 

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

Eligibility Criteria 

Required Initial Laboratory Values

• HER2 negative gastroesophageal adenocarcinoma with known PD-L1 CPS ANC ≥ 1500/mm3

• Measurable disease or non-measurable but evaluable disease as defined by RECIST 1.1 Platelet count: ≥ 100,000/mm3

• No prior treatment for metastatic disease (see Section 3.2 for prior neoadjuvant and/or adjuvant therapy parameters) Creatinine: ≤ 1.5 x upper limit of normal (ULN) OR

• Not pregnant and not nursing Calc. creatinine ≥ 30 mL/min

• Age ≥ 18 years clearance

• ECOG performance status 0 or 1

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

• No allogeneic tissue/organ transplant Total bilirubin: AST/ALT: ≤ 1.5 x ULN ≤ 3 x ULN (< 5 x ULN if clearly attributable to liver metastases)

• No known Gilbert’s Syndrome or known homozygosity for UGAT1A1*28 polymorphism

• No grade ≥ 2 peripheral neuropathy, neurosensory toxicity, or neuromotor toxicity per CTCAE v5.0 regardless of causality

• No medical condition such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.

• No active autoimmune disease requiring systemic treatment with disease modifying agents or immunosuppressive drugs within 6 months.

• No history of noninfectious pneumonitis requiring steroid

**SEE CURRENT PROTOCOL FOR COMPLETE ELIGIBILITY LIST***  

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

Eligibility Criteria:

Eligibility Criteria (see Section 3.2)

• Clinical stage II or III rectal adenocarcinoma defined as T4N0, or any T with node positive disease (any T, N+); also T3N0 requiring APR or coloanal anastomosis

• No prior systemic chemotherapy, targeted therapy, or immunotherapy; or radiation therapy administered as treatment for colorectal cancer within the past 5 years

• Not pregnant and not nursing

• Age ≥ 18 years

• ECOG Performance Status 0-1

• No upper rectal tumors (distal margin of tumor > 12 cm from the anal verge)

• No recurrent rectal cancer; prior transanal excision, prior distal sigmoid cancer with a low anastomosis

• No known mismatch repair deficient rectal adenocarcinoma

**See most current version of the protocol for full eligibility list**

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

*DTL Required- Physicians must sign toxicity grid CREDENTIALING REQUIRED. Please check your site's credentialing status.

-Histologically confirmed muscle-invasive urothelial carcinoma of the bladder or upper tract.
-Patient must fit into one of the following three categories:
--Patients who received neoadjuvant chemotherapy and pathologic stage at surgical resection is ? pT2 and/or N+
--Patients who are not cisplatin-eligible
--Patients that decline adjuvant cisplatin-based or other systemic chemotherapy based on an informed discussion with the physician and pathologic stage at surgical resection is ? pT3 or pN+
-Patient must have had radical surgical resection of their bladder cancer ?4 weeks but ? 16 weeks prior to pre-registration.
-No invasive cancer at the surgical margins
-No evidence of residual cancer or metastasis after surgery
-No metastatic disease on cross-sectional imaging
-No postoperative/adjuvant systemic therapy.
-No prior treatment with any therapy on the PD-1/PD-L1 axis.
-ECOG Performance Status ? 2

Step 1:

-Histologically confirmed muscle-invasive urothelial carcinoma of the bladder.
-Clinical stage T2-T4aN0/xM0 disease
-Medically appropriate candidate for radical cystectomy as assessed by surgeon
-No concomitant multifocal carcinoma in situ; a single focus is allowed
-One focus of muscle-invasive bladder cancer and/or a tumor less than 5 cm in size
-No locally advanced or metastatic disease
-No prior anti-PD-1, anti-PD-L1 therapies, or systemic chemotherapy
-No prior radiation to the bladder
-ECOG PS must be 0-1
-No pre-existing sensory neuropathy grade 2 or greater

Step 2:
-Must have completed 4 or more cycles of protocol-directed chemotherapy

Step 3:
-Deleterious alteration within 1 or more of 9 pre-defined DDR genes within the pre-treatment TURBT DNA 

**Effective 08/12/21, A031702 Cohort F (Sarcomatoid Renal Cell Carcinoma Cohort) is Temporarily Closed to Accrual

**Effective 03/12/2020, Cohort E is Temporarily Closed to Accrual

**Effective 07/20/2020, Cohort G is Temporarily Closed to Accrual

**Effective 06/16/2021, Cohort B (Adenocarcinoma of the Bladder) is Temporarily Closed. **Effective 06/23/2021, Cohort I (Renal Medullary Carcinoma Cohort) is Temporarily Closed. .**Effective 01/16/2025, Cohort K-Renal Collecting Duct Carcinoma is Temporarily Closed to Accrual

*DTL Required- Physicians must sign toxicity grid CREDENTIALING REQUIRED. Please check your site's credentialing status. CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Canton, Chelsea), GenHur, Sparrow, Livonia, Saginaw, St. John, Macomb, LVHN, Holy Cross

Eligibility Criteria:

Metastatic disease defined as new or progressive lesions on cross-sectional imaging or bone scan. Patients must have at least:

-One measurable site of disease as per RECIST v1.1

-One bone lesion on bone scan (tec99 or NaF PET/CT, CT or MRI) for the bone-only cohort.

Histologically confirmed diagnosis of one of the following metastatic cohorts:

- Small cell/ neuroendocrine carcinoma of the bladder - All urothelial carcinomas with any amount of neuroendocrine differentiation (including small cell differentiation) will be included. If the tumor is purely neuroendocrine, metastasis from another site of origin should be clinically excluded.

-Adenocarcinoma of the bladder, or urachal adenocarcinoma, or bladder/urethra clear cell adenocarcinoma - must be pure (per WHO definition), (i.e. urothelial carcinoma with glandular differentiation is not considered a pure adenocarcinoma.

-Squamous cell carcinoma of the bladder - must be pure (i.e. urothelial carcinoma with squamous differentiation is not considered a pure squamous cell carcinoma).

-Plasmacytoid urothelial carcinoma - Tumor should show predominantly > or equal ~50% plasmacytoid histology (including all types of discohesive growth, such as tumors with signet-ring and/or rhabdoid features as well).

-Any penile cancer

-Sarcomatoid renal cell carcinoma - Tumor should be predominantly sarcomatoid ~50% (including rhabdoid differentiation) is also unclassified RCCs: all (assuming they are high grade with metastasis) malignant angiomyolipomas are allowed.

-Sarcomatoid urothelial carcinoma - Tumor should show predominantly ~ 50% sarcomatoid differentiation.

-Renal medullary carcinoma - Per WHO definition, ideally confirmed with immunostains.

-Renal Collecting Duct Carcinoma - Per WHO definition (medullary involvement, predominant tubular morphology, desmoplastic stromal reaction, high grade cytology, infiltrative growth pattern, and absence of other renal cell carcinoma subtype or urothelial carcinoma).

-Bone only urothelial carcinoma or other non-prostate GU tumor

-Urethra carcinoma- May be of any histology but if urothelial carcinoma then must be isolated to the urethra and not have metachronous or synchronous urothelial carcinoma of the bladder.

-Other miscellaneous histologic variants of the urothelial carcinoma, such as, but not limited to : micropapillary (Tumor should show predominantly > or equal 50% micropapillary architecture), giant cell, lipid-rich, clear cell and nested variants (Tumor should predominantly > or equal 50% show these features), large cell neuroendocrine carcinoma, lymphoepithelioma-like carcinoma and mixed patterns will be considered, as well as small cell neuroendocrine prostate cancer (Only treatment-naïve primary small cell of prostate with any amount of small cell component allowed. Post-treatment small cell prostatic carcinomas are not allowed), Malignant testicular Sertoli or Leydig cell tumors, and papillary and chromophobe RCC.

Note: Translocation positive renal cell carcinoma patients are eligible. However, AREN1721 should be considered before this trial.

H&E slides from diagnostic tumor tissue for retrospective central pathology review (See Section 6.3).

-Patients may have received up to 2 systemic anti-cancer treatments or be treatment naïve. Patients with small cell carcinoma should have received a platinum-based combination regimen either as neoadjuvant, adjuvant or first-line treatment). Patients in the bone-only cohort may be urothelial carcinoma histology but must receive standard cisplatin-based chemotherapy (if cisplatin- eligible).

-Age =18 years

-Patients must be able to swallow oral formulation of the tablets.

-Karnofsky performance status =80%.

-Required Laboratory Values:

• Absolute Neutrophil Count (ANC) =1,000/mcL
• Platelet Count =75,000/mcL
• Total Bilirubin =1.5 × ULN. For subjects with known Gilbert’s disease or similar syndrome with slow conjugation of bilirubin, total bilirubinp = 3.0 mg/dL
• AST/ALT =3.0 × institutional upper limit of normal (ULN) (or =5 x ULN for patients with liver metastases or Gilbert’s disease)
• Creatinine = 1.5 x upper limit of normal (ULN)

OR

• creatinine clearance = 40 mL/min/1.73 m2 (calculated using the CKD-EPI equation or Cockroft-Gault formula) for patients with creatinine levels above institutional normal
• hemoglobin =9 g/dL (transfusion of PRBCs allowed)
• serum albumin =3.2g/dL
• lipase and amylase =2.0 × ULN and no radiologic (on baseline anatomical imaging) or clinical evidence of

pancreatitis

-Prior treatment with MET or VEGFR inhibitors is allowed. However, prior cabozantinib will not be allowed. Also, patients that have received both prior MET or VEGF and prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are also not allowed.

-Prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA- 4/CTLA-4 inhibitors is allowed, either in the perioperative or in the metastatic setting. However, patients that have received both prior MET or VEGF and prior PD-1/PD- L1/CTLA-4 (sequentially or in combination) are not allowed.

-HIV-positive patients are eligible if on stable dose of highly active antiretroviral therapy (HAART) and no clinically significant drug-drug interactions are anticipated with the current HAART regimen, CD4 counts are greater than 350 and viral load is undetectable.

- Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjögren’s syndrome and psoriasis controlled with topical medication only and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies etc. are eligible but should be considered for rheumatologic evaluation for the presence of target organ involvement and potential need for systemic treatment.

- Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones or medications (eg thyrodidits managed with PTU or methamizole) including physiologic oral corticosteroids are eligible.

-Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess, and GI obstruction, within 12 months are not eligible.

- Women of childbearing potential must have a negative pregnancy test = 7 days prior to registration.

Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post menopause is defined as amenorrhea =12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason.

- Pregnant women may not participate in this study because with cabozantinib, nivolumab, and ipilimumab have potential for teratogenic or abortifacient effects.

Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cabozantinib, nivolumab, and ipilimumab, breastfeeding should be discontinued if the mother is treated with these agents.

- The patient has received no cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 2 weeks before the first dose of study treatment.

- The patient has received no radiation therapy:

• To the lungs and mediastinum or abdomen within 4 weeks before the first dose of study treatment, or has ongoing complications, or is healing from prior radiation therapy.
• To brain metastasis within 3 weeks for WBXRT, and 2 weeks for SBRT before the first dose of study treatment.
• To the abdomen within 4 weeks before the first dose of study treatment, or has ongoing complications, or is healing from prior radiation therapy.
• To any other site(s) within 2 weeks before the first dose of study treatment.

- The patient has received no radionuclide treatment within 6 weeks of the first dose of study treatment.

- The patient has received no prior treatment with a small molecule kinase inhibitor within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment.

- The patient has received no prior treatment with hormonal therapy within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment. Subjects receiving Gonadotropin-releasing hormone (GnRH) agonists and antagonists are allowed to participate.

- The patient has not received any other type of investigational agent within 14 days before the first dose of study treatment.

- The patient must have recovered to baseline or CTCAE = Grade 1 from toxicity due to all prior therapies except alopecia, neuropathy and other non-clinically significant AEs defined as lab elevation with no associated symptoms or sequelae.

- The patient may not have active brain metastases or epidural disease. Patients with brain metastases previously treated with whole brain radiation or radiosurgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility.

- No concomitant treatment with warfarin. Aspirin (up to 325 mg/day), thrombin or factor Xa inhibitors, low-dose warfarin (=1 mg/day), prophylactic and therapeutic low molecular weight heparin (LMWH) are permitted.

- No chronic concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s Wort) or strong CYP3A4 inhibitors.

Because the lists of these agents are constantly changing, it is important to regularly consult medical reference texts such as the Physicians’ Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.

- The patient has not experienced any of the following:

Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment.

Hemoptysis of = 0.5 teaspoon (2.5 mL) of red blood per day within 1 months before the first dose of study treatment.

Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment.

- The patient has no tumor invading any major blood vessels.

- The patient has no evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib. Patients with rectal tumor masses are not eligible.

- The patient has no uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

• Cardiovascular disorders including:
• Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening.
• Concurrent uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment.

The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms within 28 days before randomization. Note: if initial QTcF is found to be > 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is =500 ms, the subject meets eligibility in this regard.

- Any history of congenital long QT syndrome.

- Any of the following within 6 months before registration of study treatment:

• unstable angina pectoris clinically-significant cardiac arrhythmias (patients with atrial fibrillation are eligible)
• stroke (including TIA, or other ischemic event)
• myocardial infarction
• cardiomyopathy

-No significant gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

• Any of the following that have not resolved within 28 days before the first dose of study treatment:
• Active peptic ulcer disease
• Acute diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or malabsorption syndrome

-None of the following within 2 years before the first dose of study treatment:

• abdominal fistula or genitourinary fistula
• gastrointestinal perforation
• bowel obstruction or gastric outlet obstruction
• intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 2 years before the first dose of study treatment.

-Disorders associated with a high risk of fistula formation including PEG tube placement are not eligible.

- No other clinically significant disorders such as:

• severe active infection requiring IV systemic treatment within 14 days before the first dose of study treatment
• serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
• history of organ or allogeneic stem cell transplant
• concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment (for asymptomatic patients with an elevated TSH, thyroid replacement may be initiated if clinically indicated without delaying the start of study treatment)

-No history of major surgery as follows:

• Major surgery within 3 months of the first dose of cabozantinib; however, if there were no wound healing complications, patients with rapidly growing aggressive cancers, may start as soon as 6 weeks if wound has completely healed post- surgery.
• Minor surgery within 1 month of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications excluding core biopsies and mediport placement.
• Complete wound healing from prior surgery must be confirmed before the first dose of cabozantinib irrespective of the time from surgery.

- No history of severe hypersensitivity reaction to any monoclonal antibody.

- No evidence of active malignancy, requiring systemic treatment within 2 years of registration.

- No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, nivolumab, ipilimumab or other agents used in study.

- No positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection. If HBV sAG is positive, subsequent RNA PCR must be negative.

- No patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. These include, but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease.

**Step 1 Closed to Patient Accrual Effective 05/15/2024** *DTL Required- Physicians must sign toxicity grid CREDENTIALING REQUIRED. Please check your site's credentialing status. CURRENT SITES CREDENTIALED: SJMH (AA, Brighton, Chelsea, Canton), LVHN, Sparrow, St. John. Macomb, GenHur, Saginaw, Livonia, SJMO, Holy Cross Fatigue/uniscale assesssment to be done after reg prior to C1

Ages Eligible for Study:

18 Years and older (Adult, Older Adult)

Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No