Clinical Trials /

TAS-OX for Refractory Metastatic Colon Cancer



This study will examine the safety and effectiveness of oxaliplatin in combination with TAS-102 (TAS-OX) for treatment of patients with metastatic colorectal cancer whose cancer has progressed or recurred after FOLFOX chemotherapy.

Related Conditions:
  • Colon Carcinoma
Recruiting Status:



Phase 1/Phase 2

Trial Eligibility



  • Brief Title: TAS-OX for Refractory Metastatic Colon Cancer
  • Official Title: TAS-102 and Oxaliplatin (TAS-OX) for Refractory Metastatic Colon Cancer

Clinical Trial IDs

  • ORG STUDY ID: 1605017852
  • NCT ID: NCT02848079


  • Colorectal Neoplasms


combined TAS-102 and TAS-OXcombined TAS-102 and oxaliplatin


This study will examine the safety and effectiveness of oxaliplatin in combination with TAS-102 (TAS-OX) for treatment of patients with metastatic colorectal cancer whose cancer has progressed or recurred after FOLFOX chemotherapy.

Detailed Description

      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.

Trial Arms

combined TAS-102 and oxaliplatinExperimentalCombination treatment with TAS-102 and oxaliplatin. Combination treatment with TAS-102 and oxaliplatin. TAS-102 is an oral medication; oxaliplatin (TAS-OX) is given by infusion. In Part 1 treatments were started at level 1 doses, which were based on prior clinical experience with the medications studied. Dose escalation followed a traditional "3+3" design. The subjects in Part 2 were treated with dose level 3. Oxaliplatin infusion was given on day 1 of each cycle. TAS-102 was taken twice daily on days 1-5 of each cycle.
  • combined TAS-102 and TAS-OX

Eligibility Criteria

        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.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:up to 30 days following discontinuation of treatment
Safety Issue:
Description:Overall Response Rate was measured by Response Evaluation Criteria In Solid Tumor (RECIST) 1.1 criteria. Tumors were assessed with CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.".

Secondary Outcome Measures

Measure:Progression Free Survival
Time Frame:from the date of start of treatment to the date of first documented progression or any cause of death assessed up to 12 months.
Safety Issue:
Description:Progression Free Survival was assessed according to RECIST criteria version 1.1. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Measure:Overall Survival
Time Frame:from the date of start of treatment to the date of any cause of death assessed up to 24 months.
Safety Issue:
Description:Overall Survival was assessed by the time to death from start of study.


Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Yale University

Last Updated

July 20, 2021