Safety of TAS-102 in Combination With Temozolomide for Metastatic Pancreatic NETs

The study is a two part phase 1B clinical trial consisting of three study periods: a
screening period of 14 days or less, a treatment period, and a safety follow-up period 30
days after treatment discontinuation.

Part 1 is a dose finding phase with the objective to assess the safety and tolerability of
the proposed drug combination and to identify the maximum tolerated dose (MTD) and a
recommended phase 2 dose.

Part 2 is an open-label expansion study, which will enroll patients with metastatic pNETs who
have not been previously treated with chemotherapy. Part 2 will obtain further safety data of
the proposed drug combination.

Inclusion Criteria:

- Part 1: Patients with histologically or cytologically confirmed metastatic or locally
advanced NETs of any origin and grade

- Part 1: Presence of evaluable OR measurable disease

- Part 2: Patients with histologically confirmed unresectable or metastatic pNETs of
grade 1 or 2.

- Part 2: Presence of measurable disease by RECIST 1.1 criteria

- Concurrent somatostatin analogues are allowed provided that the dose has been stable
(+/- 10mg) for at least 8 weeks

- Prior chemoembolization or radiation therapy (including Y90) must be performed at
least 2 weeks before study enrollment

- ECOG performance status 0-2

- Life expectancy more than 3 months

- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L

- Hemoglobin ≥ 9 g/dL

- Platelets ≥ 100 x 10^9/L

- AST/ALT ≤ 3 x ULN (≤5 x ULN in case of liver metastases)

- Total serum bilirubin of ≤ x institutional ULN (except for Grade 1 hyperbilirubinemia
solely due to a medical diagnosis of Gilbert's syndrome)

- Serum creatinine ≤ 1.5 x institutional ULN (Cockcroft and Gault formula)

- Ability to take oral medication (i.e. no feeding tube)

- Female patients of childbearing potential must have a negative pregnancy test (urine
or serum) within 14 days prior to the start of the study drug treatment and must agree
to use adequate birth control if conception is possible during the study and up to 6
months after discontinuation of study drug treatment

- Male patients must agree to use adequate birth control during the study and up to 6
months after discontinuation of study drug treatment

- Women who are nursing must discontinue breast feeding prior to the enrollment in the
trial

- Patient must be able and willing to comply with study procedures as per protocol

- Patient able to understand and willing to sign and date the written voluntary informed
consent form (ICF) at screening visit prior to any protocol-specific procedures

Exclusion Criteria:

- Part 2: Grade 3 tumors or tumors with small cell histology will be excluded

- Previous treatment with TAS-102 or TMZ

- History of partial or total gastrectomy

- Symptomatic CNS metastases requiring treatment

- Prior radiation therapy irradiating more than 10% of total bone marrow

- Other active malignancy requiring treatment within the last 2 years (except for
non-melanoma skin cancer, a non-invasive/in situ cancer, or indolent nonmetastatic
Gleason 6 prostate cancer)

- Pregnancy or breast feeding

- Active infection requiring treatment

- Known chronic infection with human immunodeficiency virus, hepatitis B, or hepatitis C

- Major surgery within prior 4 weeks (the surgical incision should be fully healed prior
to drug administration)

- Any anticancer therapy treatments, including other investigational agents within prior
2 weeks

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to TAS-102 or TMZ

- Extended field radiation within prior 4 weeks or limited field radiation within prior
2 weeks

- Psychological, familial, or sociological condition potentially hampering compliance
with the study protocol and follow-up schedule

- Ascites, pleural effusion or pericardial fluid requiring drainage in the last 4 weeks

- Uncontrolled diabetes mellitus

- Intestinal obstruction

- Pulmonary fibrosis

- Myocardial infarction within the last 12 months, severe/unstable angina, symptomatic
congestive heart failure NYHA class III or IV

- Gastrointestinal hemorrhage