Radiation Therapy and Capecitabine With or Without Curcumin Before Surgery in Treating Patients With Rectal Cancer

Study Overview
=================
Brief Summary
-----------------
This randomized phase II trial studies how well radiation therapy and capecitabine with or without curcumin before surgery works in treating patients with rectal cancer. Drugs such as curcumin may make tumor cells more sensitive to radiation therapy. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether chemotherapy and radiation therapy is more effective with or without curcumin when given before surgery in patients with rectal cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To evaluate the efficacy of a combination of capecitabine and radiation therapy with or without curcumin in locally advanced rectal cancer as assessed by pathological complete response rate. SECONDARY OBJECTIVES: I. To determine downstaging, local control, disease-free survival and overall survival rates. II. To determine serum and rectal tumor tissue pharmacology of curcumin and its metabolites in the above patients and its correlation with clinical response. III. To identify surrogate molecular markers for curcumin effects. IV. To correlate serum cytokine levels with quality of life in patients receiving this therapy. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients undergo radiation therapy 5 days a week for a total of 28 fractions. Patients also receive capecitabine orally (PO) twice daily (BID) on the days of radiation therapy and curcumin PO BID in weeks 1-11.5. ARM II: Patients undergo radiation therapy and receive capecitabine as in Arm I. Patients also receive placebo PO BID in weeks 1-11.5. After completion of study treatment, patients are followed up at 1 month.

Official Title
-----------------
A Randomized Double Blinded Study of Curcumin With Pre-operative Capecitabine and Radiation Therapy Followed by Surgery for Rectal Cancer

Conditions
-----------------
Rectal Mucinous Adenocarcinoma, Rectal Signet Ring Cell Adenocarcinoma, Recurrent Rectal Carcinoma, Stage IIA Rectal Cancer AJCC v7, Stage IIB Rectal Cancer AJCC v7, Stage IIC Rectal Cancer AJCC v7, Stage IIIA Rectal Cancer AJCC v7, Stage IIIB Rectal Cancer AJCC v7, Stage IIIC Rectal Cancer AJCC v7

Intervention / Treatment
-----------------
* Drug: Capecitabine
* Dietary Supplement: Curcumin
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Other: Placebo
* Other: Quality-of-Life Assessment
* Radiation: Radiation Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All patients must have clinical stage T3,4 N0,1,2 or T2N1,2 adenocarcinoma of the rectum; patients will be clinically staged using endorectal ultrasound, pelvic computed tomography (CT) or magnetic resonance imaging (MRI), and physical examination Histology must be confirmed with review by the Department of Pathology at MD Anderson Cancer Center (MDACC) All patients must have no distant metastatic disease in the liver, peritoneum, lungs, or paraaortic lymph nodes Patients must have a performance status (Karnofsky scale) of 70% or greater Absolute neutrophil count (ANC) > 1200 cells/mm^3 Platelets > 100,000/mm^3 Total serum bilirubin < 2 mg/dl Blood urea nitrogen (BUN) < 30 mg/dl Creatinine < 1.5 mg/dl or creatinine clearance > 50cc/min (estimated as calculated with Cockcroft-Gault equation) Patients must have signed informed consent indicating that they are aware of the investigational nature of the study, and are aware that participation is voluntary; patients must also agree to refrain from use of additional herbal supplements during the course of the study Patients will agree to continue contraception for 30 days from the date of the last study drug administration; sexually active males must practice contraception during the study Postmenopausal woman must have been amenorrheic for at least 12 months to be considered of non-childbearing potential Exclusion Criteria: Prior complete course up to 5 Gy of radiotherapy to the pelvis Pregnant or lactating woman; women of childbearing potential who have not undergone a hysterectomy with either a positive or no pregnancy test at baseline; women / men of childbearing potential not using a reliable and appropriate contraceptive method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) Treatment for other carcinomas within the last five years, except cured non-melanoma skin and treated in-situ cervical cancer Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or requiring IV antibiotics, cardiac disease New York Heart Association (NYHA) class III or IV, unstable angina pectoris, unstable cardiac arrhythmia or tachycardia (heart rate > 100 beats/minute), or psychiatric illness/ social situations that would limit compliance with the study requirements are excluded Other serious uncontrolled medical conditions that the investigator feels might compromise study participation Major surgery within 4 weeks of the start of study treatment Prior unanticipated severe reaction to fluoropyrimidine therapy or known hypersensitivity to 5-fluorouracil or capecitabine or curcumin Concurrent use of Coumadin other than low dose (1 mg) Coumadin used for line patency; patients on Coumadin must be changed to Lovenox at least 1 week prior to starting capecitabine Concurrent use of cimetidine, allopurinol, or aluminium hydroxide and magnesium hydroxide-containing antacids such as Maalox Sorivudine and brivudine use within 4 weeks of the start of study treatment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (curcumin)<br>Patients undergo radiation therapy 5 days a week for a total of 28 fractions. Patients also receive capecitabine PO BID on the days of radiation therapy and curcumin PO BID in weeks 1-11.5. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;Dietary Supplement: Curcumin<br>* Given PO<br>* Other names: Turmeric Yellow;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Optional correlative studies<br>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;|
| Active Comparator: Arm II (placebo)<br>Patients undergo radiation therapy and receive capecitabine as in Arm I. Patients also receive placebo PO BID in weeks 1-11.5. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Optional correlative studies<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;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;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pathologic Complete Response (pCR) Rate | Compared the rate of pCR between treatment arms with Fisher's exact test. | At time of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Curcumin Level in Tumor Tissue | A logistic regression model with pCR as the dependent variable will be used to assess the association between pCR and NF-kB activity and treatment. | Baseline to 11.5 weeks | 
| Change in Curcumin Level in Serum | Plasma levels were assessed pre and post curcumin/placebo administration. During week 2 (after at least 5 fractions of radiation therapy) of chemoradiation therapy: Optional endoscopic biopsy Optional blood collection for pharmacology (1 hour before and 1 hour after intake of curcumin or placebo) | assessed 1 hr pre/post curcumin administration on one of the days during week 2 of radiation therapy (fractions 6-10) | 
| Tumor Regression Grade | tumor regression grade (1= pCR, 2= near pCR, 3= partial response, 4= no response, 5=progression). | Baseline to 11.5 weeks | 
| Overall Survival (OS) | OS was calculated from start of CRT to date of death, censored at last follow-up. Estimated with the Kaplan-Meier method. | 5 years | 
| Progression Free Survival (PFS) | PFS was calculated from start of CRT to date of disease progression or death, censored at last endoscopy/imaging evaluation. | 5 years | 
| Number of Participants With Tumor Downstaging | Tumor downstaging (DS) is defined as a decrease in the T stage of the primary tumor by at least 1. | Baseline to 11.5 weeks |