Inclusion Criteria:
1. Patients with functional or non-functional, well-differentiated, locally advanced
unresectable 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:
1. the patient has been on a stable dose of an somatostatin analogs for ≥12 weeks
and. 2. the patient has experienced disease progression while on stable somatostatin
analogs dose. 3. Patients must have 1 or more measurable target lesions by RECIST v1.1. 4. Age: 18 years or older. 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 or Karnofsky
Performance Status (KPS) ≥80. 6. Adequate liver function:
1. Total bilirubin ≤1.5 × upper limit of normal (ULN) (unless due to Gilbert's
syndrome or attributable to liver metastases, then ≤3 × ULN)
2. Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤2.5 × ULN (≤5 ×
ULN if attributable to liver metastases)
7. Adequate renal function: creatinine clearance ≥30 mL/min, Cockcroft-Gault creatinine
clearance = ((140-age) × weight[kg]) / (72 × serum creatinine [mL/min]) × 0.85, if
female.
8. Adequate hematologic parameters:
1. Absolute neutrophil count (ANC) ≥1.0 × 10^9/L (growth factor support allowed)
2. Platelet count ≥100,000/mm^3 (100 × 10^9/L) (transfusion and/or growth factor
support allowed)
3. Hemoglobin ≥8.0 g/dL (transfusion and/or growth factor support allowed)
9. Fasting serum triglyceride must be ≤300 mg/dL; fasting serum cholesterol must be less
than or equal to 350 mg/dL. 10. Minimum of 4 weeks since any major surgery, completion of radiation, and adequately
recovered from the acute toxicities of any prior therapy, including neuropathy, to
Grade ≤1. 11. Male or non-pregnant and non-breastfeeding female:
1. Females of childbearing potential must agree to use effective contraception or
abstinence without interruption from 28 days prior to starting study medication
throughout 3 months after last dose of study medication and have a negative serum
pregnancy test (beta human chorionic gonadotropin [β-hCG]) result at screening
and agree to ongoing pregnancy testing during the course of the study, and after
the EOS treatment. A second form of birth control is required even if she has had
a tubal ligation.
2. Male patients must agree not to donate sperm and must practice abstinence or
agree to use a condom during sexual contact with a pregnant female or a female of
childbearing potential while participating in the study and throughout 3 months
after last dose of study medication. A second form of birth control is required
even if he has undergone a successful vasectomy.
3. Sexual abstinence is considered a highly effective contraceptive method only if
defined as refraining from heterosexual intercourse from 28 days prior to
starting study medication throughout 3 months after last dose of study
medication. The reliability of sexual abstinence should be evaluated in relation
to the duration of the study and the preferred and usual lifestyle of the
patient.
12. The patient or the patient's legal guardian(s) understand(s) and sign(s) the informed
consent. 13. Willingness and ability to comply with scheduled visits, laboratory tests, and other
study procedures. 14. Patients with a known history of human immunodeficiency virus (HIV) infection are
eligible if:
1. There has been no acquired immunodeficiency syndrome (AIDS)-defining
opportunistic infection in 12 months prior to enrollment.
2. The patient has been receiving an antiretroviral therapy regimen for ≥4 weeks and
the HIV viral load is <400 copies/mL prior to enrollment.
3. Antiretroviral therapy regimen does not include strong cytochrome (CYP)3A4
inhibitors 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.) are
eligible to enroll in the study.
2. Patients with functional NETs who are experiencing uncontrolled symptoms attributed to
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-infective
treatment, either ongoing or completed ≤7 days prior to enrollment. 5. Patients who have any severe and/or uncontrolled medical or psychiatric conditions or
other conditions that could affect their participation including:
1. Known or suspected brain metastases. 2. Severe heart disease defined as unstable angina pectoris, NYHA Class III or IV
congestive heart failure, myocardial infarction ≤6 months prior to first study
treatment, serious uncontrolled cardiac arrhythmia or any other clinically
significant cardiac disease.
3. 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 performed
unless clinically indicated.)
4. Nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the treatment with the study therapy. 5. A history of malignancies other than the one under treatment unless the patient
is disease-free for more than 5 years from diagnosis. Controlled non-melanoma
skin cancers, carcinoma in situ of the cervix, resected incidental prostate
cancer, certain low-grade hematologic malignancies (eg, chronic lymphocytic
leukemia, follicular lymphoma, etc), or other adequately treated carcinoma in
situ may be eligible, after discussion with the medical monitor.
6. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic
blood pressure ≥100 mmHg)
7. Patients with history of interstitial lung disease and/or pneumonitis, or
pulmonary hypertension. 8. Active Hepatitis B and/or Hepatitis C infection and detectable viral load despite
antiviral therapy.
6. Required use of concomitant medications with strong CYP3A4 interactions (induction or
inhibition) should be discontinued (strong inhibitors include ketoconazole,
itraconazole, voriconazole, erythromycin, clarithromycin, telithromycin; strong
inducers include rifampin and rifabutin). These agents must be discontinued prior to
first dose of nab-sirolimus.
