Combination of Oxaliplatin, Capecitabine, and Celecoxib With Concurrent Radiation for Rectal Cancer

A Phase II Trial Using a Combination of Oxaliplatin, Capecitabine, and Celecoxib With Concurrent Radiation for Patients With Newly Diagnosed Resectable Rectal Cancer

A combination of chemotherapy and radiation is often used to treat rectal cancer patients before surgery in an effort to shrink the tumor and make it easier to remove as well as to help increase the chances of sphincter-sparing surgery. Many previous clinical studies have suggested that rectal cancer patients may survive longer if the surgery results in a pathological complete response - that is, the absence of any tumor cells in the surgical specimen. However, there is still controversy over this. This study attempts to start to answer this question by treating rectal cancer patients with a combination of chemotherapy drugs (oxaliplatin and capecitabine), a cyclooxygenase-2 (COX-2) enzyme inhibitor and radiation before surgery. The rates of pathologic complete response, sphincter-sparing surgery, and disease-free survival are some of the therapeutic endpoints that will be studied.

Study Overview

• Status: Terminated
• Conditions: Rectal Cancer
• Intervention / Treatment: Other: Chemotherapy, Celecoxib, and Radiation

Detailed Description

Improved regional control as demonstrated by a lower incidence of local recurrence after concurrent chemoradiation delivered either pre-operatively or post-operatively for resectable rectal cancer is supported by clinical trial data but the impact on overall survival with either approach remains controversial. An ideal regimen for preoperative chemoradiation in locally advanced rectal cancer would include agents that are both potent radio-sensitizers and effective in treating micro-metastatic disease without excessive toxicity. The cyclooxygenase-2 (COX-2) enzyme is over expressed in colorectal cancer, but the exact role of this over expression in tumorigenesis remains an active area of research. The area with the most potential in using cyclooxygenase-2 inhibitors in cancer treatment may be to use them as an adjunct to other modalities of treatment.

Taking into consideration all the above, a previous pilot trial of neoadjuvant therapy with combined oxaliplatin, capecitabine, celecoxib (a COX-2 inhibitor), and radiation was conducted in four patients with operable rectal cancer. Promising results, including pain relief and downstaging of cancer, were observed.

Therefore, this single-arm phase II trial of preoperative concurrent chemoradiation for patients with T3-4N0-2M0 rectal cancer was initiated to assess patient outcomes and explore the relationship between COX-2 expression in surgical specimens and therapeutic endpoints.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Cancer Center
    • Albuquerque, New Mexico, United States, 87106
      • Hematology Oncology Associates
    • Santa Fe, New Mexico, United States, 87505
      • New Mexico Cancer Care Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All patients 18 years of age or older, with biopsy proven T3-4N0-2M0 rectal cancer are eligible.
• Life expectancy of at least 2 years.
• Zubrod performance status of 0-2.
• Patients must be able to sign an informed consent.
• Adequate bone marrow function: peripheral granulocyte count of > 1,500 cells/mm3 and platelet count >100,000/mm3, hemoglobin > 10 gm/dl and absence of a regular red blood cell transfusion requirement.
• Adequate hepatic function with a total serum bilirubin < 1.5 x ULN; alkaline phosphatase, alanine aminotransferase (ALAT), and aspartate aminotransferase (ASAT) < 2.5 x the upper limit of normal (ULN); and adequate renal function as defined by a calculated creatinine clearance > 50 ml/min [Cockroft-Gault].
• Other initial cancer diagnosis more than five years ago without evidence of residual or recurrent disease
• Prior diagnosis of squamous or basal cell carcinoma of skin,no active disease at the time of enrollment.

Exclusion Criteria:

• Known metastases
• Pregnant or lactating women. Women/men of childbearing potential not using a reliable and appropriate contraceptive method.
• May receive no other concurrent chemotherapy or radiation therapy during this trial.
• Severe medical problems such as uncontrolled diabetes mellitus or cardiovascular disease or active infections
• Prior pelvic radiation
• Known active inflammatory bowel disease, Crohn's disease or ulcerative colitis.
• Medical conditions that would preclude the patient from definitive surgery at the end of concurrent chemoradiation
• Serious, uncontrolled, concurrent infection(s).
• Prior severe reaction to fluoropyrimidine therapy, or known hyper-sensitivity to 5-fluorouracil or known dihydropyrimidine dehydrogenase (DPD) deficiency.
• Treatment for other carcinomas within the last five years, except cured non-melanoma skin and treated in-situ cervical cancer.
• Participation in any investigational drug study within 4 weeks preceding the start of study treatment.
• Clinically significant cardiac disease or myocardial infarction within the last 12 months.
• History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake.
• Other serious uncontrolled medical conditions that the investigator feels might compromise study participation.
• Major surgery <4 weeks of the start of study treatment, without complete recovery.
• Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome.
• Known, existing uncontrolled coagulopathy

• Any of the following laboratory values:

  • Abnormal hematologic values (neutrophils < 1.5 x 10^9/L, platelet count < 100 x 10^9/L, hemoglobin < 10 gm/dl)
  • Impaired renal function (estimated creatinine clearance <50 ml/min as calculated with Cockroft-Gault equation.
  • Serum total bilirubin > 1.5 x upper normal limit.
  • ALAT, ASAT > 2.5 x upper normal limit (or > 5 x upper normal limit in the case of liver metastases).
  • Alkaline phosphatase > 2.5 x upper normal limit (or > 5 x upper normal limit in the case of liver metastases or > 10 x upper normal limit in the case of bone disease).
• Unwillingness to give written informed consent.
• Unwillingness to participate or inability to comply with the protocol for the duration of the study.
• History of allergic reactions, hypersensitivity reactions to aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), or sulfonamides

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Chemotherapy, Celecoxib, and Radiation; Oxaliplatin weekly at 50 mg/m2 given intravenously over two hours for the duration of radiation. Capecitabine: on the days of radiation at 850 mg/m2 orally twice a day [1700 mg/m2/day] (Monday through Friday during radiation therapy). Celecoxib at 200 mg orally twice a day throughout the duration of radiation without a break.	Other: Chemotherapy, Celecoxib, and Radiation; Enrolled rectal cancer patients are treated with concurrent chemoradiation and celecoxib pre-operatively for at least 14 days. Definitive surgery is performed within 6 weeks from the end of treatment.; Other Names: Oxaliplatin = Eloxatin; Capecitabine = Xeloda; Celecoxib = Celebrex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Complete Response (PCR)	The pathologic complete response (PCR) rate will be calculated as the proportion of patients who achieve complete response out of all evaluable patients. PCR is defined as the total absence of residual tumor cells by microscopic examination of the resected surgical specimen, including all of the sampled lymph nodes.	At surgery (up to 6 weeks after end of treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity	All toxicities encountered during the study will be evaluated according to the grading system (0-5) NCI CTCAE (Common Terminology Criteria for Adverse Events) version 3.0. Toxicity will be reported as the proportion of subjects experiencing Grades 3,4, and 5 adverse events (AEs) out of all evaluable patients	Up to 3 years
Progression-free Survival (PFS)	The Response Evaluation Criteria In Solid Tumors (RECIST) guidelines (Version 1.0) will be used to determine tumor response and progression. Progressive disease (PD) for target lesions: >= 20% increase in the sum of diameters of the target lesions taking as reference the smallest sum on study, and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered . PD for non-target lesions is defined as unequivocal appearance of one or more new malignant lesions or unequivocal progression of existing non-target lesions. Time to progression will be measured from the time of surgery or clinically documented down staging if surgery for whatever reason is not carried in the subject until there is evidence of PD. Progression-free survival is reported as the percentage of patients who have not experienced progression of disease at three years post-surgery	3 years after surgery
Incidence of Sphincter-sparing Surgery	Incidence of sphincter-saving surgery is defined as the proportion of subjects who do not have permanent colostomy at the final follow-up out of all evaluable patients.	At surgery (up to 6 weeks after end of treatment)
Surgical Downstaging Rate	Downstaging rate after neoadjuvant treatment with combination oxaliplatin, capecitabine, celecoxib and concurrent radiation is defined as the proportion of patients whose pathological stage (stage at surgery) is different from their clinical stage (stage at baseline)	At surgery (up to 6 weeks after treatment)
Pelvic Local Control Rate	Pelvic local control rate is defined as the proportion of subjects who have no evidence of pelvic recurrence (by standard clinical assessment, including CT scan and clinical examination) at the final follow-up evaluation, out of all evaluable patients	Up to 3 years after surgery

Collaborators and Investigators

• Sponsor: New Mexico Cancer Care Alliance

Publications and helpful links

General Publications

• Araujo-Mino EP, Patt YZ, Murray-Krezan C, Hanson JA, Bansal P, Liem BJ, Rajput A, Fekrazad MH, Heywood G, Lee FC. Phase II Trial Using a Combination of Oxaliplatin, Capecitabine, and Celecoxib with Concurrent Radiation for Newly Diagnosed Resectable Rectal Cancer. Oncologist. 2018 Jan;23(1):2-e5. doi: 10.1634/theoncologist.2017-0474. Epub 2017 Nov 20.

Helpful Links

• University of New Mexico Cancer Center
• New Mexico Cancer Care Alliance

Study record dates

Study Major Dates

• Study Start: April 1, 2005
• Primary Completion (ACTUAL): December 1, 2012
• Study Completion (ACTUAL): May 1, 2015

Study Registration Dates

• First Submitted: November 4, 2005
• First Submitted That Met QC Criteria: November 4, 2005
• First Posted (ESTIMATE): November 8, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): September 1, 2015
• Last Update Submitted That Met QC Criteria: August 3, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: Cancer; Neoadjuvant; Radiation; Rectum; Resectable Rectal Cancer; GI - Colorectal Neoadjuvant
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Cyclooxygenase 2 Inhibitors; Capecitabine; Oxaliplatin; Celecoxib
• Other Study ID Numbers: 3304C; NCI-2011-02685 (REGISTRY: NCI CTRP)