A Phase II Randomized Control Trial of Triapine Plus Lutetium Lu 177 Dotatate Versus Lutetium Lu 177 Dotatate Alone for Well-Differentiated Somatostatin Receptor-Positive Neuroendocrine Tumors.

Inclusion Criteria

- Patients must have metastatic, histologically confirmed well-differentiated

neuroendocrine tumor with positive gallium 68 DOTATATE or copper 64 DOTATATE scan.

Lesions on dotatate scan will be considered positive if the standardized uptake volume

maximum (SUVmax) of target lesion is > 2 times standardized uptake value (SUV) mean of

normal liver parenchyma. Patients with lung neuroendocrine tumors (NETs) are excluded

from the trial

- Patients must have progressive disease based on RECIST criteria, version 1.1 evidenced

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 Adverse Events

(CTCAE) 5.0

- Age >= 18 years

- Because no dosing or adverse event data are currently available on the use of

triapine in combination with lutetium Lu 177 dotatate in patients < 18 years of

age, 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 x 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 x institutional ULN. Creatinine > 1.5 ULN will require a

measured 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-retroviral

therapy with undetectable viral load within 6 months are eligible for this trial

- 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 treated brain metastases and off steroids are eligible if follow-up

brain imaging after central nervous system (CNS)-directed therapy shows no evidence of

progression for at least 4 weeks prior to enrollment in the study. Patients with a

history of brain metastases must have a head CT with contrast to document stable

disease prior to enrollment in the study

- 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

- 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 trial, patients should be class 2B or better

- Pregnancy precaution: Men and women should avoid pregnancy for seven months after the

date of their last treatment with lutetium Lu 177 dotatate. It is noteworthy that

beta-human chorionic gonadotropin (beta-HCG) may be secreted by a small percentage of

NETs, such that, in addition to being a pregnancy marker, it also is a tumor 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 pregnancy can be excluded by

lack of expected doubling of beta-HCG and negative pelvic ultrasound. Normally, in

pregnant subjects beta-HCG doubles every 2 days during the first 4 weeks of pregnancy

and every 3.5 days by weeks 6 to 7. Women of childbearing potential include any female

who has experienced menarche and who has not undergone successful surgical

sterilization (hysterectomy, bilateral tubal ligation, or bilateral ovariectomy) or is

not postmenopausal (defined as amenorrhea > 12 consecutive months, and for women on

hormone replacement therapy, only with a documented plasma follicle-stimulating

hormone [FSH] level > 35 mIU/mL). Even women who are using oral, implanted, or

injected contraceptive hormones, an intrauterine device (IUD), or barrier methods

(diaphragm, condoms, spermicidal) to prevent pregnancy, are practicing abstinence or

where the partner is sterile (e.g., vasectomy) should be considered to be of

childbearing potential. Postmenopausal women who have fertilized eggs implanted are

also considered to be of childbearing potential. Acceptable methods of contraception

may include total abstinence at the discretion of the Investigator in cases where the

age, career, lifestyle, or sexual orientation of the patient ensures compliance.

Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods)

and withdrawal are not acceptable methods of contraception. Reliable contraception

(hormonal or barrier method of birth control; abstinence) should be maintained

throughout the study and for 7 months after study treatment discontinuation. All men

and women of childbearing potential and male partners must use a double-barrier method

of birth control or practice continuous abstinence from heterosexual contact

throughout the study and for seven months after the end of the last treatment

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

- Patients who have not recovered from adverse events of previously administered

therapeutic 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 or biologic

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 ribonucleotide

reductase (RNR) inhibitor and lutetium Lu 177 dotatate is a peptide receptor

radionuclide therapy with the 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 triapine and lutetium Lu 177 dotatate,

breastfeeding should be discontinued if the mother is treated with triapine and

lutetium Lu 177 dotatate and for 2.5 months following the last treatment

- Inability to swallow oral medications or gastrointestinal disease limiting absorption

of oral agents

- Patients with any other significant condition, currently uncontrolled by treatment,

which may interfere with completion of the study