TAS102 in Combination With NAL-IRI in Advanced GI Cancers

PRIMARY OBJECTIVES:

I. Determine the recommended phase II dose for the combination of TAS-102 and nanoliposomal
irinotecan (nanoliposomal [nal]-IRI). (Phase I)

II. Evaluate the activity of the combination of TAS102 and nal-IRI in previously treated
patients with metastatic colorectal cancer and pancreatic cancer. (Phase II)

SECONDARY OBJECTIVES:

I. Define the toxicity profile of the combination of TAS-102 and nal-IRI.

II. Evaluate the response duration, progression free, and overall survival of the combination
of TAS-102 and nal-IRI in previously treated patients with metastatic colorectal cancer and
pancreatic cancer.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive nanoliposomal irinotecan intravenously (IV) over 90 minutes on day 1 and
trifluridine/tipiracil hydrochloride combination agent TAS-102 orally (PO) twice daily (BID)
on days 1-5. Courses repeat every 2 weeks in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 8 or
12 weeks thereafter.

Inclusion Criteria:

- Subjects must have histologic or cytological confirmation of a malignancy that is
advanced (metastatic and/or unresectable) with measurable disease per Response
Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1

- In the dose escalation phase, the trial will be open for patients with stage IV or
locally advanced unresectable gastrointestinal adenocarcinomas (gastric,
cholangiocarcinoma, pancreatic, colorectal) who have failed at least one prior
therapy; subjects must have received, and then progressed or been intolerant to, at
least 1 standard treatment regimen in the advanced or metastatic setting

- In the dose expansion phase, Arm A will be open for 25 patients with pancreatic
adenocarcinoma; patients must have histologic diagnosis and either locally advanced
unresectable or metastatic disease and have not received prior irinotecan; patients
must have received at least one prior line of standard treatment for locally advanced
or metastatic disease

- In dose expansion phase, Arm B will be open for 25 patients with colorectal
adenocarcinoma; patients must have histologic diagnosis and metastatic disease and
have not received prior irinotecan; patients must have received at least one prior
line of standard treatment for locally advanced or metastatic disease

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1

- Adequate organ function

- Recovered from the effects of any prior surgery, radiotherapy or other antineoplastic
therapy

Exclusion Criteria:

- History of any second malignancy in the last 5 years; subjects with prior history of
in-situ cancer or basal or squamous cell skin cancer are eligible; subjects with other
malignancies are eligible if they have been continuously disease free for at least 5
years

- Severe arterial thromboembolic events (myocardial infarction, unstable angina
pectoris, stroke) less than 6 months before inclusion

- New York Heart Association (NYHA) class III or IV congestive heart failure,
ventricular arrhythmias or uncontrolled blood pressure

- 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

- 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

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

- Inability to take oral medications

- Homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) only for the phase I part;
heterozygotes for UGT1A1*28 (UGT1A11 7/6 genotype) will be allowed to enroll on the
trial

- Patients who are not appropriate candidates for participation in this clinical study
for any other reason as deemed by the investigator

- Patients with history of positive dihydropyrimidine dehydrogenase (DPD) deficiency

Other protocol defined inclusion/exclusion criteria could apply