RANDOMIZED PHASE II TRIAL OF LUTETIUM LU 177 DOTATATE VERSUS EVEROLIMUS IN SOMATOSTATIN RECEPTOR POSITIVE BRONCHIAL NEUROENDOCRINE TUMORS

This phase II trial studies the effect of lutetium Lu 177 dotatate compared to the usual
treatment (everolimus) in treating patients with somatostatin receptor positive bronchial
neuroendocrine tumors that have spread to other places in the body (advanced). Radioactive
drugs, such as lutetium Lu 177 dotatate, may carry radiation directly to tumor cells and may
reduce harm to normal cells. Lutetium Lu 177 dotatate may be more effective than everolimus
in shrinking or stabilizing advanced bronchial neuroendocrine tumors.

Inclusion Criteria:

- PRE-REGISTRATION: 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:

- Well- or moderately-differentiated neuroendocrine tumor,

- Low- or intermediate-grade neuroendocrine tumor, or

- Carcinoid tumor (including typical or atypical carcinoid tumors)

- PRE-REGISTRATION: Documentation of histology from a primary or metastatic site is
allowed

- PRE-REGISTRATION: 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

- PRE-REGISTRATION: 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

- PRE-REGISTRATION: Recurrent or locally-advanced/unresectable or metastatic disease

- PRE-REGISTRATION: Neuroendocrine tumor of bronchial (i.e. lung) primary site

- PRE-REGISTRATION: 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-DOTATATE
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

- PRE-REGISTRATION: Patients must have measurable disease per Response Evaluation
Criteria in Solid Tumors (RECIST) version (v)1.1 by computer tomography (CT) scan or
magnetic imaging (MRI). Any lesions which have undergone percutaneous therapies or
radiotherapy should not be considered measurable unless the lesion has clearly
progressed since the procedure

- PRE-REGISTRATION: 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

- REGISTRATION: Confirmation of SSTR positivity by Alliance Imaging Core Lab (ICL) at
Imaging and Radiation Oncology Core (IROC) Ohio central radiographic review

- REGISTRATION: Patients with treatment-naive or previously-treated disease are allowed.
Patients with previously-treated disease must have demonstrated radiographic disease
progression on the prior therapy

- REGISTRATION: No prior treatment with peptide receptor radionuclide therapy (PRRT)
(e.g. lutetium Lu 177 dotatate)

- REGISTRATION: No prior treatment with mammalian target of rapamycin (mTOR) inhibitors
(e.g. deforolimus, everolimus, sirolimus, temsirolimus, etc.)

- REGISTRATION: 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

- REGISTRATION: Prior treatment with 90-Yttrium radioembolization must be completed at
least 3 months prior to registration

- 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

- REGISTRATION: 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:

- 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

- Has previously demonstrated radiographic disease progression while on
somatostatin analog therapy

- REGISTRATION: 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

- 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 National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE), version 5.0, grade 1 or less

- REGISTRATION: Not pregnant and not nursing, because this study involves:

- An investigational agent whose genotoxic, mutagenic, and teratogenic effects on
the developing fetus and newborn are unknown, and

- An agent that has known genotoxic, mutagenic, and teratogenic effects

- Therefore, for women of childbearing potential only, a negative pregnancy test
done =< 14 days prior to registration is required

- REGISTRATION: Age >= 18 years

- REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- REGISTRATION: Hemoglobin >= 8.0 g/dL

- REGISTRATION: Platelet count >= 75,000/mm^3

- REGISTRATION: Absolute neutrophil count (ANC) >= 1,500/mm^3

- REGISTRATION: Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated creatinine
clearance >= 40 mL/min

- Calculated by the Cockcroft-Gault equation

- REGISTRATION: Total bilirubin =< 2.0 x ULN

- In patients with Gilbert's syndrome, if total bilirubin is > 2.0 x ULN, then
direct bilirubin must be =< 2.0 x ULN

- REGISTRATION: Albumin >= 2.8 g/dL

- REGISTRATION: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x
ULN

- REGISTRATION: No known central nervous system metastases unless treated and clinically
stable for at least 14 days prior to registration. Patients on steroid support must be
clinically stable on weaning doses of steroids

- REGISTRATION: No other currently active malignancy that requires therapy or is
expected to require therapy during the study (excluding non-melanoma skin cancers or
in situ carcinomas, such as breast or cervical)

- REGISTRATION: No known active hepatitis B (defined as hepatitis B surface antigen
[HbsAg] reactive) or known active hepatitis C virus (defined as hepatitis C virus
[HCV] ribonucleic acid [RNA] viral load detected). The exception is for patients with
known active hepatitis B virus (defined as HbsAg reactive) infection, where the HBV
viral load must be undetectable on suppressive therapy for patient to be eligible

- REGISTRATION: Patients with known human immunodeficiency virus (HIV) infections on
effective anti-retroviral therapy with undetectable viral load within 6 months of
registration are eligible for this trial

- REGISTRATION: No known active or uncontrolled infections requiring ongoing antifungals
or antibiotics in the 3 days prior to registration

- REGISTRATION: No receipt of live attenuated vaccines in the 7 days prior to
registration

- REGISTRATION: No known decompensated liver cirrhosis

- REGISTRATION: No known prior drug-induced pneumonitis that was symptomatic or required
treatment

- REGISTRATION: No known medical condition causing an inability to swallow and no known
impairment of gastrointestinal function that may significantly alter the absorption of
an oral agent

- REGISTRATION: No known hypersensitivity to everolimus or other rapamycin analogs (e.g.
sirolimus, temsirolimus, etc.)

- REGISTRATION: Concurrent somatostatin analog use while on protocol therapy is allowed
provided that the patient: 1) has a functional tumor (evidence of peptide hormones
and/or bioactive substances associated with a clinical hormone syndrome such as
carcinoid syndrome or Cushing's syndrome), 2) has previously demonstrated radiographic
disease progression while on somatostatin analog therapy

- REGISTRATION: Chronic concomitant treatment with P-gp and strong CYP3A4 inhibitors
and/or inducers is not allowed on the everolimus treatment arm of this study. Given
that the study is randomized, all patients on P-gp and strong CYP3A4 inhibitors and/or
inducers must discontinue the drug(s) 7 days prior to registration

- RE-REGISTRATION: Confirmation of disease progression by RECIST v1.1 by real-time
Alliance ICL at IROC Ohio central radiographic review

- RE-REGISTRATION: Not pregnant and not nursing

- Therefore, for women of childbearing potential only, a negative pregnancy test
done =< 14 days prior to re-registration is required

- RE-REGISTRATION: ECOG performance status 0-2

- RE-REGISTRATION: Hemoglobin >= 8.0 g/dL

- RE-REGISTRATION: Platelet count >= 75,000/mm^3

- RE-REGISTRATION: Absolute neutrophil count (ANC) >= 1,500/mm^3

- RE-REGISTRATION: Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated
creatinine clearance >= 40 mL/min

- Calculated by the Cockcroft-Gault equation

- RE-REGISTRATION: Total bilirubin =< 2.0 x ULN

- In patients with Gilbert's syndrome, if total bilirubin is > 2.0 x ULN, then
direct bilirubin must be =< 2.0 x ULN

- RE-REGISTRATION: Albumin >= 2.8 g/dL

- RE-REGISTRATION: AST/ALT =< 3.0 x ULN