Liposomal Irinotecan, Fluorouracil and Leucovorin in Treating Patients With Refractory Advanced High Grade Neuroendocrine Cancer of Gastrointestinal, Unknown, or Pancreatic Origin

PRIMARY OBJECTIVES:

I. To determine the objective response rate liposomal irinotecan (nanoliposomal irinotecan
[Nal-IRI]) + fluorouracil (5FU) and leucovorin in patients with refractory advanced high
grade neuroendocrine cancer of gastrointestinal (GI), unknown or pancreatic origin.

SECONDARY OBJECTIVES:

I. To determine overall survival, progression-free survival, time to treatment failure,
safety, clinical response and, quality of life (QOL) changes resulting from the combination
treatment of nanoliposomal irinotecan (Nal-IRI) + fluorouracil (5FU) and leucovorin.

EXPLORATORY OBJECTIVES:

I. Genetic profiling for mutations will be conducted on all pre-study tumor samples and
compared to changes in immune response.

OUTLINE:

Patients receive liposomal irinotecan intravenously (IV) over 90 minutes, leucovorin IV over
30 minutes, and fluorouracil IV over 46 hours on days 1 and 15. Courses repeat every 28 days
for in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, then every 2
months thereafter.

Inclusion Criteria:

- Participant must have a locally advanced and unresectable or metastatic
gastroenteropancreatic neuroendocrine carcinoma of the gastrointestinal (GI) tract, or
of unknown primary that has been previously treated with platinum etoposide or
temozolomide and capecitabine: Patients may have either progressed on therapy or
within 6 months of completing therapy, or be intolerant of therapy to be considered
eligible.

- Participant must have tissue available for central pathology review and, must have
pathologically/histologically confirmed high grade neuro endocrine defined as Ki-67
proliferative index of 20-100% or, must have evidence of at least 10 mitotic figures
per 10 high powered fields.

- Comprehensive Genomic Profiling will be performed on archival tissue available prior
to enrollment. If no archival tissue is available, then patient must have fresh biopsy
prior to treatment administration if clinically indicated.

- Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 - 2.

- Leukocytes >= 3,000/mm^3 .

- Absolute neutrophil count >= 1,500/mm^3.

- Hemoglobin >= 9 g/dL.

- Platelets >= 100,000/mm^3.

- Total bilirubin =< institutional upper limit of normal (ULN) or =< 1.5 x institutional
ULN (if the patient has liver metastases.

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN or (=< 5 x institutional ULN if the patient has liver
metastases).

- Serum creatinine =< 1.5 x institutional ULN or measured or calculated creatinine
clearance by Cockcroft Gault Equation >= 50ml/min for subjects with creatinine levels
> 1.5 x ULN.

- Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria present.

- Participant must have a life expectancy of >= 12 weeks as determined clinically by the
treating physician.

- Participants of child-bearing potential must agree to use adequate contraceptive
methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study
entry. Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately.

- A female of childbearing potential is any woman, regardless of sexual orientation
or whether they have undergone tubal ligation, who meets the following criteria:
1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months).

- Women of childbearing potential and sexually active males must be strongly
advised to use an accepted and effective method of contraception or to abstain
from sexual intercourse for the duration of their participation in the study.

- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure.

Exclusion Criteria:

- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Subjects with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging for at least four weeks prior to
the first dose of trial treatment and any neurologic symptoms have returned to
baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.

- Participants with known dihydropyrimidine dehydrogenase (DPD) deficiency.

- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

- Known hypersensitivity to any of the components of Nal-IRI, other liposomal products,
fluoropyrimidines or leucovorin.

- Investigational therapy administered within 4 weeks, or within a time interval less
than at least 5 half-lives of the investigational agent, whichever is longer, prior to
the first scheduled day of dosing in this study.

- Participants must NOT have previous or concurrent malignancy: exceptions are made for
patients who meet any of the following conditions:

- Non-melanoma skin cancer.

- In situ cervical cancer.

- Superficial bladder cancer.

- Breast cancer in situ.

- Prior malignancy completely excised or removed and patient has been continuously
disease free for > 5 years.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant or nursing female participants.

- Unwilling or unable to follow protocol requirements.

- Any condition which in the Investigator?s opinion deems the participant an unsuitable
candidate to receive study drug.