TAS-OX for Refractory Metastatic Colon Cancer

TAS-102 is an oral agent, which consists of a combination of a novel antimetabolite
5-trifluorothymidine (FTD) and a thymidine phosphorylase inhibitor (TPI) that prevents
degradation of FTD. It has demonstrated activity in chemorefractory metastatic colorectal
cancer (mCRC) patients. In the Japanese randomized phase II trial, TAS-102 improved medial
overall survival when compared to placebo (9.0 vs.6.6 months, Hazard Ratio (HR) 0.56) in
patients with mCRC refractory to 5-fluorouracil (5-FU), irinotecan and oxaliplatin.
Subsequently, a randomized phase III study conducted in 13 countries (RECOURSE trial)
confirmed this benefit on overall survival when compared to placebo (7.1 months vs. 5.3
months, HR 0.68) in patients with refractory metastatic colorectal cancer (CRC) 5.

Oxaliplatin is a third generation platinum compound, which is active when used together with
5-FU in the treatment of mCRC (FOLFOX). FOLFOX chemotherapy, which is frequently combined
with anti-angiogenic agent Bevacizumab, is widely accepted as the preferred first-line
regimen in the treatment of this disease in the US. Oxaliplatin is also frequently
reintroduced in more advanced settings. Reintroduction is seen after progression on
maintenance therapy, after resolution of previous treatment limiting neuropathy, after
disease recurrence post adjuvant treatment or post metastasectomy. In the control arm of a
randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced
colorectal cancer (OPTIMOX1 study), oxaliplatin was reintroduced in 27% of patients. Although
patients derive clinical benefit when oxaliplatin is reintroduced, the response rates are not
as robust as during initial exposures. Decreased efficacy may be at least in part due to
prolonged exposure and resultant resistance to 5-FU, which is a backbone in maintenance and
in oxaliplatin containing regimens. Hence, the investigators propose exploring the safety and
efficacy of oxaliplatin in combination with an alternative anti-metabolite TAS-102 (TAS-OX).

TAS-102 has demonstrated activity in 5-FU refractory mCRC, so the investigators hypothesize
that TAS-OX may serve as an alternative drug combination for patients who have progressed or
recurred after FOLFOX, and who are candidates for additional oxaliplatin therapy.

This is a 2-part clinical trial with TAS-102 in combination with oxaliplatin. The first part
will be a dose-finding run-in phase and will enroll 3-18 patients. The second part, the focus
of this study, will be a single arm cohort , which will further evaluate the safety, as well
as efficacy, of TAS-OX in the treatment of mCRC. The subjects in part 2 will be treated with
the drug doses determined in Part 1 of the trial. Up to 50 patients will be enrolled in part
2. Anticipated enrollment may be as high as 68 patients. Maximum potential enrollment is
listed under anticipated enrollment, below.

Inclusion Criteria:

1. Histologically confirmed stage IV colon cancer (AJCC 7th edition) that has progressed
after standard therapy that included 5-FU, irinotecan and oxaliplatin. Patients who
could not tolerate standard agents because of unacceptable, but reversible, toxicity
necessitating their discontinuation will be allowed to participate.

2. Patients who had received adjuvant chemotherapy and had recurrence during or within 6
months of completion of the adjuvant chemotherapy will be allowed to count the
adjuvant therapy as one chemotherapy regimen.

3. Progression of disease must be documented on the most recent scan.

4. Presence of measurable disease (not required for Phase 1 portion of the trial).

5. Retrovirus-associated DNA sequences (RAS) mutation and mismatch repair (MMR) status
must be determined (or tissue availability for testing if not already determined)

6. Age 18 years or older.

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

8. Life expectancy of at least 3 months.

9. Patient with adequate organ function:

1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

2. Hemoglobin ≥ 9 g/dL

3. Platelets (PLT) ≥ 75 x 109/L

4. Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) ≤ 5 x Upper limit
of normal (ULN)

5. Total serum bilirubin of ≤1.5 mg/dL (except for Grade 1 hyperbilirubinemia due
solely to a medical diagnosis of Gilbert's syndrome).

6. Albumin ≥ 2.5 g/dL

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

10. Adequate contraception if applicable.

11. Women who are nursing must discontinue nursing prior to enrollment in the program.

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

13. Patient able and willing to comply with study procedures as per protocol.

14. 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:

1. Patients who have previously received TAS-102.

2. Grade 2 or higher peripheral neuropathy.

3. Symptomatic Central nervous system (CNS) metastases requiring treatment.

4. Other active malignancy within the last 3 years (except for non-melanoma skin cancer
or a non-invasive/in situ cancer).

5. Pregnancy or breast feeding.

6. Current therapy with other investigational agents.

7. Active infection with body temperature ≥38°C due to infection.

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

9. Any anticancer therapy within prior 3 weeks of first dose of study drug.

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

11. Current therapy with other investigational agents or participation in another clinical
study or any investigational agent received within prior 4 weeks.

12. Grade 3 or higher hypersensitivity reaction to oxaliplatin, or grade 1-2
hypersensitivity reaction to oxaliplatin not controlled with pre-medication.

13. Unresolved toxicity of greater than or equal to Common Terminology Criteria for
Adverse Events (CTCAE) Grade 2 attributed to any prior therapies (excluding anemia,
alopecia, skin pigmentation, and platinum-induced neurotoxicity).

14. Extended field radiation within prior 4 weeks of first dose of study drug or limited
field radiation within prior 2 weeks of first dose of study drug.

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

16. Involvement in the planning and/or conduct of the study.

17. Previous enrollment in the present study.