Trial of Nab-sirolimus in Patients With Well-differentiated Neuroendocrine Tumors (NETs) of the Gastrointestinal Tract, Lung, or Pancreas Who Have Not Received Prior Treatment With mTOR Inhibitors

Inclusion Criteria:

1. Patients with functional or non-functional, well-differentiated, locally advancedunresectable or metastatic NETs of the GI tract, lung, or pancreas who have received 2 or less prior lines of therapy excluding somatostatin analogs

2. Patients with functional NETs may enroll if:

3. the patient has been on a stable dose of an somatostatin analogs for ≥12 weeksand

4. the patient has experienced disease progression while on stable somatostatinanalogs dose

5. Patients must have 1 or more measurable target lesions by RECIST v1.1

6. Age: 18 years or older

7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 or KarnofskyPerformance Status (KPS) ≥80

8. Adequate liver function:

9. Total bilirubin ≤1.5 × upper limit of normal (ULN) (unless due to Gilbert'ssyndrome or attributable to liver metastases, then ≤3 × ULN)

10. Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤2.5 × ULN (≤5 × ULN if attributable to liver metastases)

11. Adequate renal function: creatinine clearance ≥30 mL/min, Cockcroft-Gault creatinineclearance = ((140-age) × weight[kg]) / (72 × serum creatinine [mL/min]) × 0.85, iffemale.

12. Adequate hematologic parameters:

13. Absolute neutrophil count (ANC) ≥1.0 × 10^9/L (growth factor support allowed)

14. Platelet count ≥100,000/mm^3 (100 × 10^9/L) (transfusion and/or growth factorsupport allowed)

15. Hemoglobin ≥8.0 g/dL (transfusion and/or growth factor support allowed)

16. Fasting serum triglyceride must be ≤300 mg/dL; fasting serum cholesterol must beless than or equal to 350 mg/dL

17. Minimum of 4 weeks since any major surgery, completion of radiation, and adequatelyrecovered from the acute toxicities of any prior therapy, including neuropathy, toGrade ≤1

18. Male or non-pregnant and non-breastfeeding female:

19. Females of childbearing potential must agree to use effective contraception orabstinence without interruption from 28 days prior to starting study medicationthroughout 3 months after last dose of study medication and have a negativeserum pregnancy test (beta human chorionic gonadotropin [β-hCG]) result atscreening and agree to ongoing pregnancy testing during the course of thestudy, and after the EOS treatment. A second form of birth control is requiredeven if she has had a tubal ligation.

20. Male patients must agree not to donate sperm and must practice abstinence oragree to use a condom during sexual contact with a pregnant female or a femaleof childbearing potential while participating in the study and throughout 3months after last dose of study medication. A second form of birth control isrequired even if he has undergone a successful vasectomy.

21. Sexual abstinence is considered a highly effective contraceptive method only ifdefined as refraining from heterosexual intercourse from 28 days prior tostarting study medication throughout 3 months after last dose of studymedication. The reliability of sexual abstinence should be evaluated inrelation to the duration of the study and the preferred and usual lifestyle ofthe patient.

22. The patient or the patient's legal guardian(s) understand(s) and sign(s) theinformed consent

23. Willingness and ability to comply with scheduled visits, laboratory tests, and otherstudy procedures

24. Patients with a known history of human immunodeficiency virus (HIV) infection areeligible if:

25. There has been no acquired immunodeficiency syndrome (AIDS)-definingopportunistic infection in 12 months prior to enrollment.

26. The patient has been receiving an antiretroviral therapy regimen for ≥4 weeksand the HIV viral load is <400 copies/mL prior to enrollment.

27. Antiretroviral therapy regimen does not include strong cytochrome (CYP)3A4inhibitors or inducers

Exclusion Criteria:

1. Prior treatment with mTOR inhibitors including nab-sirolimus Note: Patients who have previously received locoregional or liver-directed therapies (radiofrequency or microwave ablation, transarterial chemoembolization, etc.) areeligible to enroll in the study.

2. Patients with functional NETs who are experiencing uncontrolled symptoms attributedto hormones and other vasoactive substances secreted by the tumor

3. Patients with inactivating TSC1 or TSC2 alterations (based on tissue or liquid NGS)

4. Severe (Grade ≥3) ongoing infection requiring parenteral or oral anti-infectivetreatment, either ongoing or completed ≤7 days prior to enrollment

5. Patients who have any severe and/or uncontrolled medical or psychiatric conditionsor other conditions that could affect their participation including:

6. Known or suspected brain metastases

7. Severe heart disease defined as unstable angina pectoris, NYHA Class III or IVcongestive heart failure, myocardial infarction ≤6 months prior to first studytreatment, serious uncontrolled cardiac arrhythmia or any other clinicallysignificant cardiac disease.

8. Severe lung disease defined as a diffusing capacity for carbon monoxide that is ≤50% of normal predicted value and/or an O2 saturation ≤88% at rest on room air (Note: Spirometry and pulmonary function tests are not required to be performedunless clinically indicated.)

9. Nonmalignant medical illnesses that are uncontrolled or whose control may bejeopardized by the treatment with the study therapy

10. A history of malignancies other than the one under treatment unless the patientis disease-free for more than 5 years from diagnosis. Controlled non-melanomaskin cancers, carcinoma in situ of the cervix, resected incidental prostatecancer, certain low-grade hematologic malignancies (eg, chronic lymphocyticleukemia, follicular lymphoma, etc), or other adequately treated carcinoma insitu may be eligible, after discussion with the medical monitor.

11. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolicblood pressure ≥100 mmHg)

12. Patients with history of interstitial lung disease and/or pneumonitis, orpulmonary hypertension

13. Active Hepatitis B and/or Hepatitis C infection and detectable viral loaddespite antiviral therapy.

14. Required use of concomitant medications with strong CYP3A4 interactions (inductionor inhibition) should be discontinued (strong inhibitors include ketoconazole,itraconazole, voriconazole, erythromycin, clarithromycin, telithromycin; stronginducers include rifampin and rifabutin). These agents must be discontinued prior tofirst dose of nab-sirolimus.