Comparing Retreatment of 177Lu-DOTATATE PRRT Versus Everolimus in Patients With Metastatic Unresectable Midgut Neuroendocrine Tumors, NET RETREAT Trial

Eligibility Criteria

• * Patients must be at least \>= 18 years of age
• * Metastatic, histologically confirmed grade 1 or 2 well-differentiated midgut neuroendocrine tumours, including NETs of unknown primary thought to be of midgut origin, with positive Gallium-68 DOTATATE scan or Copper-64 DOTATATE scan within the last 12 months is recommended but within the last 36 months is allowed. Lesions on Gallium-68 or Copper-64 DOTATATE scan will be considered positive if the maximum standardized uptake value (SUVmax) of target lesion is \> SUV mean of normal liver parenchyma
• * Have received 3 or 4 cycles of PRRT using 177Lu-DOTATATE or a cumulative exposure of 22,200 MBq (600mCi) or 29,600 MBq (800 mCi) within a 52-week period. Previous therapy with everolimus for a maximum period of 1 month is permitted. No previous targeted alpha therapy is permitted. No previous alkylator therapy (i.e. Temodar) is permitted
• * Have had radiological progression per RECIST 1.1 after prior PRRT treatment and no sooner than 12 months from last scan performed post completion of initial PRRT where either stable disease, partial response, or complete response has been maintained throughout
• * Have not received any intervening therapy after initial PRRT
• * No ongoing toxicity from prior PRRT that is grade 3 or higher according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0
• * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
• * Hemoglobin \>= 80 g/L (\>= 8.0 g/dL) (measured within 28 days prior to enrollment)
• * Absolute neutrophil count \>= 1.0 x 10\^9/L (\>= 1000/mm\^3) (measured within 28 days prior to enrollment)
• * Platelets \>= 80 x 10\^9/L (\>= 80 x 10\^3/mm\^3) (measured within 28 days prior to enrollment)
• * Total bilirubin \< 1.5 x upper limit of normal (ULN) (upper limit of normal) (measured within 28 days prior to enrollment)
• * If confirmed Gilbert's, eligible providing =\< criteria x ULN
• * Creatinine clearance \> 50 mL/min (measured within 28 days prior to enrollment)
• * Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by Cockcroft and Gault equation
• * Prior or current use of somatostatin analogues is allowed for carcinoid syndrome control or in PRRT re-treatment patient population (Arm 1). Patients randomized to everolimus (Arm 2) will not be allowed to continue somatostatin analogues unless they have functional carcinoid syndrome
• * Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate
• * Patients of childbearing potential must have agreed to use a highly effective contraceptive method during protocol treatment and for 7 months after the last dose of protocol treatment. A woman is considered to be of "childbearing 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, or vasectomy/vasectomized partner. However, if at any point a previously celibate patient 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
• * Women of childbearing potential will have a pregnancy test to determine eligibility as part of the Pre-Study Evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. For example, when beta-human chorionic gonadotropin is high and partner is vasectomized, it may be associated with tumour production of human chorionic gonadotropin (hCG), as seen with some cancers. Patient will be considered eligible if an ultrasound is negative for pregnancy
• * Patients must be accessible for treatment, response assessment, and follow up. Patients enrolled on this trial must be treated and followed at the participating center. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up
• * Patients must agree to return to their primary care facility for any adverse events which may occur through the course of the trial
• * Patient must have access to everolimus. In the event that site/investigator is unable to provide access to the drug, patient will not be eligible for this trial
• * Human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• * 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
• * Major surgical procedures within 6 weeks from randomization date
• * Known brain metastases, unless these metastases have been treated, stabilized and off steroids for at least 4 weeks prior to enrollment in the study. Patients with a history of brain metastases must have a head CT and/or MRI with contrast to document stable disease prior to enrollment in the study
• * Uncontrolled congestive heart failure no worse than New York Heart Association Class (NYHA) IIB
• * Inability to swallow oral medications or gastrointestinal disease limiting absorption of oral agents
• * Patients with any other significant medical or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study
• * Pregnant women are excluded from this study because 177Lu-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 177Lu-DOTATATE, breastfeeding should be discontinued if the mother is treated with everolimus or 177Lu-DOTATATE and for 2.5 months following the last treatment