TAS-102 and Radiation Therapy in Treating Patients With Rectal Cancer That Is Locally Recurrent, Metastatic, or Cannot Be Removed by Surgery

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of trifluridine/tipiracil hydrochloride combination agent TAS-102 (TAS-102) when given together with radiation therapy in treating patients with rectal cancer that has come back, spread to other places in the body, or cannot be removed by surgery. Drugs used in chemotherapy, such as TAS-102, 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. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving TAS-102 with radiation therapy may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose and dose-limiting toxicity of TAS-102 when administered in combination with concurrent radiation therapy in patients with locally recurrent or metastatic rectal cancer. SECONDARY OBJECTIVES: I. To determine the overall response rate (ORR) to concurrent TAS-102 and radiation therapy in patients with locally recurrent or metastatic rectal cancer. II. To determine the progression-free survival (PFS) in patients with locally recurrent or metastatic rectal cancer who receive concurrent TAS-102 and radiation therapy. III. To determine the overall survival (OS) in patients with locally recurrent or metastatic rectal cancer who receive combined TAS-102 and radiation therapy. IV. To determine quality of life (QoL) among patients with locally recurrent or metastatic rectal cancer who receive concurrent TAS-102 and radiation therapy. V. To determine the number of patients who are able to undergo surgical resection following concurrent treatment with TAS-102 and radiation therapy. Of this subset of patients, the investigators will assess rates of pathologic complete response (pCR), tumor regression grade (TRG) and rates of R0 resection. OUTLINE: This is a dose-escalation study of trifluridine/tipiracil hydrochloride combination agent TAS-102. Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally (PO) twice daily (BID) and undergo radiation therapy in 10 fractions on days 1-5 and 8-12 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 4-6 weeks, and at 3 and 6 months.

Official Title
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Phase I Trial of TAS-102 and Concurrent Radiation Therapy for Patients With Locally Recurrent, Unresectable or Metastatic, Rectal Cancer

Conditions
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Rectal Adenocarcinoma, Recurrent Rectal Carcinoma, Stage IV Rectal Cancer AJCC v7, Stage IVA Rectal Cancer AJCC v7, Stage IVB Rectal Cancer AJCC v7

Intervention / Treatment
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* Other: Quality-of-Life Assessment
* Radiation: Radiation Therapy
* Drug: Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological confirmation of locally recurrent or metastatic rectal adenocarcinoma Note: Patients with locally recurrent/persistent disease within the pelvis after primary therapy (chemotherapy, surgery, and/or radiotherapy) are eligible Note: Patients who have had prior pelvic radiotherapy with a total dose of =< 54 Gy are eligible Note: Patients with or without metastatic disease (excluding untreated central nervous system [CNS] metastasis), with primary pelvic disease or pelvic recurrence are eligible Note: Patients with pelvic disease that is potentially resectable or unresectable are eligible Measurable disease Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 Expected life expectancy >= 12 weeks Obtained =< 14 days prior to registration: Absolute neutrophil count (ANC) >= 1500/mm^3 Obtained =< 14 days prior to registration: Platelet count >= 100,000/mm^3 Obtained =< 14 days prior to registration: Hemoglobin >= 9.0 g/dL Obtained =< 14 days prior to registration: Total bilirubin =< 1.5 x upper limit of normal (ULN) (in patients with well-documented Gilbert's syndrome and the total bilirubin is grade 1, then direct bilirubin value must be =< 1.0 mg/dL) Obtained =< 14 days prior to registration: Aspartate transaminase (AST) =< 2 x ULN (=< 5 x ULN for patients with liver involvement) Obtained =< 14 days prior to registration: Alanine aminotransferase (ALT) =< 2 x ULN (=< 5 x ULN for patients with liver involvement) Obtained =< 14 days prior to registration: Alkaline phosphatase =< 3 x ULN Obtained =< 14 days prior to registration: Creatinine =< 1.5 x ULN OR Obtained =< 14 days prior to registration: Calculated creatinine clearance must be >= 45 ml/min using the Cockcroft-Gault formula Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only; Note: patients must agree to adequate birth control during the study and for up to 6 months after discontinuation of study medication Patients must be able to take medications orally (i.e. no feeding tube) Provide written informed consent Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) Able to complete questionnaires by themselves or with assistance Exclusion Criteria: Primary resectable rectal cancer Prior treatment with TAS-102 Chemotherapy or immunotherapy =< 28 days prior to registration Radiation therapy =< 28 days prior to registration; Note: patients with prior pelvic radiation therapy > 54 Gy are ineligible Failure to fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment Other concurrent chemotherapy, immunotherapy, or any ancillary antitumor therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) Untreated CNS or leptomeningeal metastasis Note: CNS or leptomeningeal disease must be stable for >= 3 months prior to registration History of seizure disorder Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Ascites, pleural effusion, or pericardial fluid requiring drainage in the last 4 weeks prior to registration Intestinal obstruction, uncontrolled gastrointestinal hemorrhage, pulmonary fibrosis, renal failure, liver failure, or cerebrovascular disorder Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or hepatitis B or C Patients with autoimmune disorders or history of organ transplantation who require immunosuppressive therapy History of myocardial infarction =< 12 months prior to registration, severe/unstable angina, systematic congestive heart failure (CHF) New York Heart Association classification III or IV or CHF requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias Major surgery =< 4 weeks prior to registration (the surgical incision should be fully healed prior to drug administration or radiation therapy) Any of the following: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (TAS-102, radiation therapy)<br>Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 PO BID and undergo radiation therapy in 10 fractions on days 1-5 and 8-12 in the absence of disease progression or unacceptable toxicity. | Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Drug: Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102<br>* Given PO<br>* Other names: Trifluridine/Tipiracil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | Defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients. | Up to 28 days |