Step 0 eligibility- see specific requirements for pathology:
-ECOG Performance Status must be 0 or 1
-Female and male patients must have histologically confirmed triple negative (ER-/PR-/HER2-) invasive breast cancer, clinical stage II-III at diagnosis. Note: patients that originally present with synchronous bilateral tumors are eligible provided both tumors are TNBC, and at least one of them fulfills the remainder eligibility criteria of the protocol.
-Must have completed neoadjuvant taxane +/- anthracycline. Patients must NOT have received cisplatin or carboplatin or capecitabine as part of their neoadjuvant treatment.
-Must have completed definitive resection of primary tumor with negative margins (or have received RT and no further surgery is possible).
-Post neoadjuvant chemotherapy, patients must have residual cancer in the breast at the time of definitive surgery.  ***Please note: pathology must comment on cellularity- residual cancer must be more than minimum cellularity, preferably > 20%**
-Post-mastectomy RT is required for all patients with:
--Primary tumor greater than or equal to 5 cm or involvement of 4 or more lymph nodes at the time of definitive surgery.
-RT is required for patients who underwent breast-conserving therapy
-Must NOT have stage IV disease
-Must NOT have neuropathy greater than grade 1.
-Surgical tissue must be submitted for PAM50 analysis 

Step 1 Eligibility:
-Must have central PAM50 analysis by digital mRNA quantitation on residual disease
-Patients must have completed adjuvant radiotherapy greater than or equal to 2 weeks prior to randomization for protocol therapy, if applicable.
-Patients must be randomized within 24 weeks of surgery

EA1131 Arm 3 Capecitabine ARIA ordering Guide in Documents Library (SJMAA, SMML)

SJMH-Ann Arbor is the only participating site

-Women at least 45 years old and less than 75 years old
-Must be scheduled or have intent to schedule a screening mammogram
-Must not have symptoms or signs of benign or malignant breast disease
-Must not have had a screening mammogram within the last 11 mo
-Must not have previous personal history of breast cancer, including DCIS
-Must not have breast enhancements
-To be eligible for the annual screening regimen patients must meet one of the following additional criteria:
--pre-menopausal OR
-- post-menopausal aged 45-69 with risk factor: dense breasts, family history or positive genetic testing, currently on hormone therapy OR
--post-menopausal ages 70-74 with ether dense breasts or currently on hormone therapy

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

CURRENT SITES CREDENTIALED: St. Alphonsus

Eligibility Criteria:

3.1.1 Patient must be ≥ 18 years of age.

3.1.2 Patients must have an ECOG performance status of 0 or 1.

3.1.3 Patient must have histologically confirmed HER2-positive primary invasive breast carcinoma, determined by local testing. The tumor must have either HER2 IHC result of 3+ or HER2/CEP17 ratio > 2 with > 4.0 HER2 signals per cell by ISH. Tumors with HER2/CEP17 ISH ratio < 2 are ineligible, even if HER2 copy number is > 6, unless HER2 IHC result is 3+.

3.1.4 Patients hormone receptor (ER and PR) status must be known and will be determined by local testing. Patients with either hormone receptor–positive or hormone receptor- negative HER2-positive breast cancer are eligible.

3.1.5 Patients must have AJCC 8th Edition stage II or IIIa according to anatomic staging table at diagnosis.

• Patients without nodal involvement (cN0) are eligible if T size >2.0 cm (T2-3)  

NOTE: Cohort for patients with 2-3 cm, ER+ and node negative HER2-positive/ER-positive disease closed on July 27, 2022.

• Patients with HER2-positive/ER-negative disease without nodal involvement (cN0) are eligible if T size > 2.0 cm (T2-3) NOTE: Cohort for HER2-postive/ER-negative patients closed on May 18, 2023.

• Patients with HER2-positive/ER-positive disease without nodal involvement (cN0) are eligible if T size > 3.0 cm

• Patients with nodal involvement (cN1-2) are eligible if T1-3

• Patients with clinical T4 or N3 disease are not eligible 

3.1.6 Patient must be willing and able (i.e., have no contraindication) to receive standard adjuvant therapy, consisting of HER2-directed therapy, radiation (if indicated) and endocrine therapy (if ER+) if achieving pCR at surgery.

3.1.7 Patient with bilateral invasive breast cancers are eligible if both cancers are HER2-positive (as defined in 3.1.3) at least one meets protocol eligibility and neither cancer renders the patient ineligible (i.e., per eligibility 3.1.5).

3.1.8 Patients with multiple ipsilateral invasive tumors are eligible as long as all tumors are HER2-positive, and at least one tumor focus meets eligibility criteria (per eligibility 3.1.5). Multiple lesions that appear part of the same index tumor do not require additional biopsy/HER2 testing.However, even if biopsy is not deemed necessary, consideration must be given to placing a clip in any lesion that is 1 cm or further from the primary tumor to ensure that all tumor is removed at surgery AND that the pathologist can locate all primary sites of tumor to assess pathologic response at surgery.

3.1.9 Patients must not have impaired decision-making capacity.

3.1.10 Patient must not have a history of any prior (ipsilateral or contralateral) invasive breast cancer. One exception: a patient with a history of T1N0 triple negative breast cancer diagnosed more than 10 years earlier, who remains disease free is eligible. 

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

-Patients must have a locally advanced and unresectable or metastatic gastroenteropancreatic neuroendocrine carcinoma of the GI tract.
-Patients must have pathologically/histologically confirmed tumor of non-small cell histology.
-Patients must have a Ki-67 proliferative index of 20-100%
-Patients must have evidence of at least 10 mitotic figures per 10 high powered fields
-Patients must have measurable disease
-Patients may not have had any prior treatment for this malignancy.
-Patients must have an ECOG performance status of 0-2.
-Patients may not be receiving Coumadin while on treatment. Other anticoagulants are allowed.
-Patients with brain metastases (either remote or current) or presence of carcinomatous meningitis are not eligible

Step 1

-Patients must have histologically proven stage II (T3N0 only), IIIA, or IIIB invasive anal squamous cell carcinoma.

-For patients registering to Arm T, patients must not have received prior chemoradiotherapy for anal cancer.
-Patients must have ECOG performance status of 0-2.

-Patients with an allogenic bone marrow/stem, cell or solid organ transplant are excluded.

-Patients will be excluded if they have a T1, T2N0 or M1 cancer.

-Patients must not have had prior potentially curative surgery (abdominal, peritoneal resection) for carcinoma of the anus.
-Patient must not have active autoimmune disease that has required systemic treatment in past 2 years
Step 2
-Patients will be registered no sooner than 4 weeks following completion of standard chemoradiation for anal cancer.

-Patients must have histologically proven stage II (T3N0 only), IIIA, or IIIB invasive anal (anal margin) squamous cell carcinoma.

-Patients must not have received less than 54 Gy of radiation for the treatment of the anal cancer.

-Patients must have ECOG performance status of 0-2.

Current sites credentialed: SJMH (AA, Brighton, Canton, Chelsea), GenHur, LVHN, Sparrow, St. John, Macomb, SJMO, Livonia, Saginaw,

SJMH - not participating in diffuse weighted MRI sub-study

Eligibility Criteria

- Patients must be age ≥ 18 years.

- Patients must have histologically confirmed T1N1-3M0 or T2-3N0-2M0 esophageal or gastroesophageal junctional adenocarcinoma (Siewert I and II).

- Patients must have an ECOG Performance Status 0-1.

- Patents must be deemed a surgical candidate by a thoracic surgeon, surgical oncologist, or surgeon who is qualified to perform an esophagectomy.

- Patients must have normal organ and marrow function as definded below within less than or equal to 14 days prior to randomization:

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total bilirubin ≤ institutional upper limit of normal (ULN).

-AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional

- Serum creatinine ≤ 1.5 X institutional ULN

- Hgb ≥ 9 g/dL

- Leukocytes ≥ 3,000/mm3

- Patients may not have received prior chemotherapy or radiation therapy for management for this malignancy.

- Patients may not have received prior immunotherapy for management of this malignancy or for any other past malignancy.

- Patients must have no contraindication to receiving either carboplatin or paclitaxel chemotherapy.

- Patients must have no contraindication to receiving radiation therapy

-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, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain\u0002Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, connective tissue disease, 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. Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren’s syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.

- Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event). - Patient must NOT have previous or concurrent malignancy. Exceptions are made for patients who meet any of the following conditions:

· Non-melanoma skin cancer, in situ cervical cancer, superficial bladder cancer, or breast cancer in situ OR

· Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years.

OR

· Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years.

· Date of last evidence of disease:

- Patients must not have a condition requiring systemic treatment with either corticosteroids (>10 mg/day prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses ≤ 10 mg/day prednisone equivalents are permitted in the absence of active autoimmune disease.

- Adequate cardiac function including EKG and echocardiogram for any patient with a history of CHF or at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs.

- For patients with evidence of CHF, MI, cardiomyopathy, or myositis, cardiac evaluation including lab tests and cardiology consultations including EKG, CPK, troponin, and echocardiogram.

- Patients must not have a positive test result for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection. Testing should be conducted to determine eligibility.

-Patients with a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) must have no detectable viral load on a stable anti\u0002viral regimen.

- Patients must not be receiving any other investigational agents.

-Patients with an uncontrolled intercurrent illness such as ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements will be excluded.

- Women must not be pregnant or breast-feeding due to potential harm to the fetus from carboplatin, paclitaxel, or nivolumab. All females of childbearing potential must have a blood test or urine study done within 2 weeks prior to registration to rule out pregnancy. Those enrolled on Arm B with nivolumab must agree to have a pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours of starting nivolumab to rule out pregnancy.

-A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at east 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

-Women of childbearing potential (WOCBP) and sexually active males must either abstain from sexual intercourse for the duration of their participation in the study or agree to use both double barrier contraception and birth control pills or implants for at least one month (female patients) or one week (male patients) prior to the start of the study drug and continuing for 5 months after the last dose of study drug (for female patients) and for 7 months after the last dose of study drug (for male patients who are sexually active with WOCBP). Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy.

- If patient says ‘Yes’ to “I choose to take part in the imaging study and will have the diffusion weighted MRI scans”: patients must be able to tolerate MRI scans:

-No history of untreatable claustrophobia.

- No MR incompatible implants/devices or metallic foreign bodies.

- Weight compatible with limits imposed by the MRI scanner table.

Eligibility Criteria: Step 2

-Patient registration must not exceed 12 weeks from time of esophagectomy.

- Patients must have a post-operative ECOG performance status of 0- 2.

-Patients must have normal organ and marrow function as definded below within less than or equal to 14 days prior to randomization:

-Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total bilirubin ≤ institutional upper limit of normal (ULN).

- AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional ULN

- Serum creatinine ≤ 1.5 X institutional ULN

- Patients must be disease free following esophagectomy as is demonstrated by having no evidence of disease on a post-surgical CT scan. Patients must also have a negative surgical margin (R0 resection).

Patients must not have an active, known or suspected autoimmune disease or a condition requiring treatment with steroids or immunosuppressive agents. Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.

- Patients must not have a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalents) or other immunosuppressive medications with 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg/day prednisone equivalents are permitted in the absence of active autoimmune disease.

- Patients must not be receiving any other investigational agents.

- Patients with an uncontrolled intercurrent illness such as ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements will be excluded.

-Women must not be pregnant or breast-feeding due to potential harm to the fetus from nivolumab or ipilimumab. All females of childbearing potential must have a blood test or urine study done (minimum sensitivity 25 IU/L or equivalent units of HCG) within 2 weeks prior to registration to rule out pregnancy. All patients must also agree to have a pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours of starting nivolumab to rule out pregnancy. Those enrolled on Arm D with ipilimumab must agree to have pregnancy tests within 72 hours of each ipilimumab administration to rule out pregnancy.

- Women of childbearing potential (WOCBP) and sexually active males must either abstain from sexual intercourse for the duration of their participation in the study or agree to use both double barrier contraception and birth control pills or implants for at least one month (female patients) or one week (male patients) prior to the start of the study drug and continuing for 5 months after the last dose of study drug (for female patients) and for 7 months after the last dose of study drug (for male patients who are sexually active with WOCBP). Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy.

*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, LVHN, Sparrow, St. John, Macomb, Holy Cross, Saginaw

Eligibility Criteria:

• Patient must have inoperable, recurrent, or metastatic disease (tumor resectability should be assessed by a local surgeon or a multidisciplinary team) not amenable to curative therapy.
• Patient must have histological or cytological confirmation of anal squamous cell carcinoma (includes basaloid and cloacogenic lesions) from the primary tumor or a newly diagnosed recurrent/metastatic lesion.
• Patient must be = 18 years of age.
• Patient must have ECOG Performance Status = 0-1.
• Patients must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 and based on radiologic assessment performed <4 weeks prior to randomization.
• Patient receiving palliative (limited-field) radiation therapy is allowed, as long as the lesion treated for palliation is not a target lesion.
• Patients with brain metastasis are eligible if patient is asymptomatic and if treatment ended > 3 months prior to randomization. Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression within 4 weeks prior to randomization.

• Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used
• All females of childbearing potential must have a blood test or urine study with a minimum sensitivity of 25 IU/L or equivalent units of BCG, within 14 days prior to randomization to rule out pregnancy.
• A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

Female of child bearing potential? ______ (Yes or No)

Date of blood test or urine study: ___________

• Women of childbearing potential and sexually active males must not expect to conceive or father children by using accepted and effective method(s) of contraception or to abstain from sexual intercourse for at least one week prior to the start of treatment, and continue for 5 months after the last dose of protocol treatment for women of childbearing potential and 7 months after the last dose of protocol treatment for males who are sexually active with WOCBP.
• Patient must have adequate organ and marrow function as defined below , obtained < 14 days prior to randomization:

Leukocytes = 3,000/mcL

Leukocytes:__________ Date of Test:__________

Absolute neutrophil count = 1,500/mcL

ANC:__________ Date of Test:__________

Platelets = 100,000/mcL

Platelet:__________ Date of Test:__________

Hemoglobin (Hb) = 9 g/dL for males and = 9 g/dL for females

Hgb:__________ Date of Test:__________

Total bilirubin = 1.5 X institutional upper limit of normal (ULN)

Bilirubin:__________ Institutional ULN:_________

Date of Test:__________

AST(SGOT) /ALT(SGPT) = 5 × institutional ULNALT:_______

Institutional ULN:_________

Date of Test:_______

AST:_______Institutional ULN:_________

Date of Test:_______

Creatinine = 1.5 X institutional ULN

OR

Creatinine clearance (CrCl) =50 mL/min (if using the Cockcroft-Gault formula below):

• Female CrCl = (140 - age in years) x weight in kg x 0.85

• • 72 x serum creatinine in mg/dL

• Male CrCl = (140 - age in years) x weight in kg x 1.00

• • 72 x serum creatinine in mg/dL

• Human immunodeficiency virus (HIV)-infected patients on effective Anti-Retroviral Therapy (ART) with undetectable viral load are eligible
• All HIV+ patients should be under the care of an Infectious Diseases specialist. If a relationship with an Infectious Diseases specialist is not established, an Infectious Disease specialist should be consulted. Records of all viral counts and peripheral T-cell counts should be documented in order to follow these values over the course of treatment.
• All patients must be willing to undergo testing for HIV testing if not tested within the past 12 months.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• 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, they are eligible if they have an undetectable HCV viral load.
• Patients with known history or current symptoms of cardiac disease, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. Patients with a history of CHF or who are at risk because of underlying cardiovascular disease or exposure to cardiotoxic drugs must be willing to undergo evaluation of cardiac function including EKG and ECHO as clinically indicated.
• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible.
• Patient must not have had previous use of systemic chemotherapy or other investigational drugs for the treatment of inoperable recurrent or metastatic anal cancer (Previous use of radiotherapy or chemoradiotherapy in this setting is not an exclusion criterion if: 1) non-irradiated target tumor lesions are present at randomization for the purpose of tumor response assessment or 2) in the absence of non-irradiated target tumor lesions, progression of the irradiated tumor lesions according to the RECIST criteria version 1.1 is documented). Patient must not have current or recent (within 30 days prior to randomization) treatment with another investigational drug or participation in another investigational study.
• Patient must not have had prior immunotherapy.
• Patient must not have a history of known hypersensitivity reaction to any platinum or taxane-based chemotherapy or monoclonal antibody.
• Patient must not have active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including chronic prolonged systemic corticosteroids (defined as corticosteroid use of duration one month or greater). 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, and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or anti-phospholipid syndrome. Patients with any of these are ineligible because of the risk of recurrence or exacerbation of disease.
• Patient must not have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids and adrenal replacement doses <10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Physiologic replacement doses of systemic corticosteroids are permitted, even if <10 mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted.
• Patient must not have had major surgery performed = 28 days prior to randomization.
• Patient must not have a history of interstitial lung disease (e.g., pneumonitis or pulmonary fibrosis) or evidence of interstitial lung disease on baseline chest CT scan.
• Patient must not have a serious active infection requiring IV antibiotics at time of randomization.
• Patient must not have other primary malignancy within the last 3 years, except for adequately treated carcinoma in situ of the cervix or squamous carcinoma of the skin, or adequately controlled limited basal cell skin cancer, or any other cancer from which the patient has been disease-free for at least 3 years.
• Patient must not have known peripheral neuropathy > grade 1 at the time of randomization (absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible).
• Patients must agree to not receive live vaccines while on this study.

Eligibility Criteria:

- Newly diagnosed untreated metastatic adenocarcinoma of the pancreas. However, previous surgery, adjuvant chemotherapy and/or radiation therapy will be allowed, provided radiation therapy is completed at least 2 weeks prior to registration and adjuvant therapy was administered more than 6 months prior to registration. Patients with the following histology are excluded: Acinar cell; Adenosquamous carcinoma.

- Patient must be = 70 years of age.

- Patient must have an ECOG Performance status 0-2

- Patient is an English speaker with the ability to understand and complete the informed consent and questionnaires

- Patient must have adequate organ and marrow function as defined below, with results obtained within 4 weeks prior to registration:

- Leukocytes = 3,000/mcL

- Absolute neutrophil count = 1,500/mcL

- Platelets = 100,000/mcL

-

Total bilirubin = institutional upper limit of normal (ULN)

- AST(SGOT)/ALT(SGPT) = 2.5 × institutional ULN

- Creatinine = institutional ULN and glomerular filtration rate (GFR) = 40 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2.

-Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this protocol. HIV (+) patients who are on ritonavir or/and cobicistat-based regimen must be switched to alternative ART.

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

- 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, they are eligible if they have an undetectable HCV viral load.

- Male patients must agree not to father children while on study.

-Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this protocol, patients should be class 2B or better.

-Patient must have measurable disease as defined in Section 6.1.2 and scans must be done within 4 weeks prior to registration.

-Patients classified to have mild-moderate abnormalities in any of the domains evaluated in the screening geriatric assessment (as outlined in the table in Section 10.1) and are classified as "vulnerable" are eligible.

Patients classified without any abnormalities ("fit") or with severe cognitive/functional impairment or high co-morbidity score ("frail") on the screening geriatric assessment are ineligible.

- Patient must agree not to take any medications or substances that are strong inhibitors or inducers of CYP3A4. Those who are randomized to liposomal irinotecan treatment arm should avoid drugs that are UGT1A1 inhibitors.