Testing the Effectiveness of an Anti-cancer Drug, Triapine, When Used With Targeted Radiation-based Treatment (Lutetium Lu 177 Dotatate), Compared to Lutetium Lu 177 Dotatate Alone for Metastatic Neuroendocrine Tumors

Inclusion Criteria:

• Patients must have metastatic, histologically confirmed well-differentiatedneuroendocrine tumor with positive gallium 68 DOTATATE or copper 64 DOTATATE scan.Lesions on dotatate scan will be considered positive if the standardized uptakevalue maximum (SUVmax) of target lesion is > 2 times standardized uptake value (SUV)mean of normal liver parenchyma. Patients with lung neuroendocrine tumors (NETs) areexcluded from the trial

• Patients must have progressive disease based on RECIST criteria, version 1.1evidenced with CT scans/MRI obtained within 24 months from enrollment

• Patients must have measurable disease per RECIST 1.1

• Failure of at least one prior systemic cancer treatment with somatostatin analogs

• No prior exposure to peptide receptor radionuclide therapy

• Recovered from adverse events of previously administered therapeutic agents (i.e.,to grade 2 or less toxicity) according to Common Terminology Criteria for AdverseEvents (CTCAE) 5.0

• Age >= 18 years

• Because no dosing or adverse event data are currently available on the use oftriapine in combination with lutetium Lu 177 dotatate in patients < 18 years ofage, children are excluded from this study

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

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

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN

• Serum creatinine =< 1.5 institutional ULN. Creatinine > 1.5 ULN will require ameasured creatinine clearance (CrCl) > 50 ml/min to qualify

• Hemoglobin > 5.0 mmol/L (> 8.0 g/dL)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

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

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with treated brain metastases and off steroids are eligible if follow-upbrain imaging after central nervous system (CNS)-directed therapy shows no evidenceof progression for at least 4 weeks prior to enrollment in the study. Patients witha history of brain metastases must have a head CT with contrast to document stabledisease prior to enrollment in the study

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

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Pregnancy precaution: Men and women should avoid pregnancy for seven months afterthe date of their last treatment with lutetium Lu 177 dotatate. It is noteworthythat beta-human chorionic gonadotropin (beta-HCG) may be secreted by a smallpercentage of NETs, such that, in addition to being a pregnancy marker, it also is atumor marker. Consequently, NET female patients with positive beta-HCG (> 5 mIU/mL)at baseline can be eligible to enter the study and receive treatment if pregnancycan be excluded by lack of expected doubling of beta-HCG and negative pelvicultrasound. Normally, in pregnant subjects beta-HCG doubles every 2 days during thefirst 4 weeks of pregnancy and every 3.5 days by weeks 6 to 7. Women of childbearingpotential include any female who has experienced menarche and who has not undergonesuccessful surgical sterilization (hysterectomy, bilateral tubal ligation, orbilateral ovariectomy) or is not postmenopausal (defined as amenorrhea > 12consecutive months, and for women on hormone replacement therapy, only with adocumented plasma follicle-stimulating hormone [FSH] level > 35 mIU/mL). Even womenwho are using oral, implanted, or injected contraceptive hormones, an intrauterinedevice (IUD), or barrier methods (diaphragm, condoms, spermicidal) to preventpregnancy, are practicing abstinence or where the partner is sterile (e.g.,vasectomy) should be considered to be of childbearing potential. Postmenopausalwomen who have fertilized eggs implanted are also considered to be of childbearingpotential. Acceptable methods of contraception may include total abstinence at thediscretion of the Investigator in cases where the age, career, lifestyle, or sexualorientation of the patient ensures compliance. Periodic abstinence (e.g., calendar,ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptablemethods of contraception. Reliable contraception (hormonal or barrier method ofbirth control; abstinence) should be maintained throughout the study and for 7months after study treatment discontinuation. All men and women of childbearingpotential and male partners must use a double-barrier method of birth control orpractice continuous abstinence from heterosexual contact throughout the study andfor seven months after the end of the last treatment

• Ability to understand and the willingness to sign a written informed consentdocument

Exclusion Criteria:

• Patients who have not recovered from adverse events of previously administeredtherapeutic agents (i.e., have residual toxicities > grade 2) according to CTCAE 5.0, with the exception of alopecia

• Patients who are receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to triapine or lutetium Lu 177 dotatate

• Patients with uncontrolled intercurrent illness

• Uncontrolled congestive heart failure (New York Heart Association [NYHA] III, IV)

• Pregnant women are excluded from this study because triapine is a ribonucleotidereductase (RNR) inhibitor and lutetium Lu 177 dotatate is a peptide receptorradionuclide therapy with the potential for teratogenic or abortifacient effects.Because there is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with triapine and lutetium Lu 177 dotatate,breastfeeding should be discontinued if the mother is treated with triapine andlutetium Lu 177 dotatate and for 2.5 months following the last treatment

• Inability to swallow oral medications or gastrointestinal disease limitingabsorption of oral agents

• Patients with any other significant condition, currently uncontrolled by treatment,which may interfere with completion of the study