TAS102 in Combination With NAL-IRI in Advanced GI Cancers
TAS102 in Combination With NAL-IRI in Advanced GI Cancers
This phase I/II trial studies the best dose and how well trifluridine/tipiracil hydrochloride
 combination agent TAS-102 (TAS-102) and nanoliposomal irinotecan work in treating patients
 with gastrointestinal cancers that have spread to other places in the body (metastatic) or
 cannot be removed by surgery. Drugs used in the chemotherapy, such as trifluridine/tipiracil
 hydrochloride combination agent TAS-102 and nanoliposomal irinotecan, work in different ways
 to stop the growth of tumor cells, either by killing the cells, by stopping them from
 dividing, or by stopping them from spreading.
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. Cycles 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; acquisition of existing
 formalin fixed paraffin embedded (FFPE) tumor tissue by study investigators is not
 mandatory for enrollment on the trial; patients without previous histologic/cytologic
 confirmation must have freshly obtained biopsy for routine pathologic evaluation
 before enrolment on the study

 -  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

 -  Presence of measurable disease based on RECIST 1.1; subjects with lesions in a
 previously irradiated field as the sole site of measurable disease will be permitted
 to enroll provided the lesion(s) have demonstrated clear progression and can be
 measured accurately

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

 -  Adequate renal function as evidenced by a serum creatinine ≤ 1.5 x upper limit of
 normal (ULN)

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

 -  Able to understand and sign an informed consent (or have a legal representative who is
 able to do so)

 -  Female subject of childbearing potential should have a negative urine or serum
 pregnancy within 72 hours prior to receiving the first dose of study medication; if
 the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
 will be required

 -  Female subjects of childbearing potential must be willing to use an adequate method of
 contraception; Note: abstinence is acceptable if this is the usual lifestyle and
 preferred contraception for the subject

 -  Male subjects of childbearing potential must agree to use an adequate method of
 contraception; Note: abstinence is acceptable if this is the usual lifestyle and
 preferred contraception for the subject

 -  Absolute neutrophil count (ANC) ≥ 1,500/ul without the use of hematopoietic growth
 factors (within 14 days of treatment initiation)

 -  Platelets ≥ 100,000/ul (within 14 days of treatment initiation)

 -  Hemoglobin ≥ 8 g/dL (blood transfusions are permitted for patients with hemoglobin
 levels below 8 g/dL) (within 14 days of treatment initiation)

 -  Serum creatinine ≤ 1.5 X upper limit of normal (ULN) OR measured or calculated
 creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
 creatinine or creatinine clearance [CrCl]) ≥ 50 mL/min for subject with creatinine
 levels > 1.5 X institutional ULN (within 14 days of treatment initiation)

 * Creatinine clearance should be calculated per institutional standard

 -  Serum total bilirubin within normal range for the institution (biliary drainage is
 allowed for biliary obstruction) (within 14 days of treatment initiation)

 -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
 alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 X
 ULN OR ≤ 5 X ULN for subjects with liver metastases (within 14 days of treatment
 initiation)

 -  Albumin ≥ 3.0 g/dL (within 14 days of treatment initiation)

 -  International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 X ULN unless
 subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
 time (PTT) is within therapeutic range of intended use of anticoagulants (within 14
 days of treatment initiation)

 -  Activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN unless subject is receiving
 anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
 of anticoagulants (within 14 days of treatment initiation)

 Exclusion Criteria:

 -  Prior therapy with irinotecan (for expansion phase II only)

 -  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

 -  Active infection or an unexplained fever > 38.5 degrees Celsius (C) during screening
 visits or on the first scheduled day of dosing (at the discretion of the investigator,
 patients with tumor fever may be enrolled), which in the investigator's opinion might
 compromise the patient's participation in the trial or affect the study outcome

 -  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

 -  Any other medical or social condition deemed by the investigator to be likely to
 interfere with a patient's ability to sign informed consent, cooperate and participate
 in the study, or interfere with the interpretation of the results

 -  Pregnant or breast feeding; females of child-bearing potential must test negative for
 pregnancy at the time of enrollment based on a urine or serum pregnancy test; both
 male and female patients of reproductive potential must agree to use a reliable method
 of birth control, during the study and for 3 months following the last dose of study
 drug

 -  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