Bevacizumab, Radiation Therapy, and Combination Chemotherapy in Treating Patients Who Are Undergoing Surgery for Locally Advanced Nonmetastatic Rectal Cancer

Rectal Adenocarcinoma Clinical Trial

Official title:

Phase II Study of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin and Bevacizumab Followed by Surgery and Postoperative 5-FU, Leucovorin, Oxaliplatin (FOLFOX) and Bevacizumab in Patients With Locally Advanced Rectal Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00321685
• Other study ID #: NCI-2009-01081
• Secondary ID: NCI-2009-01081CD
• Status: Completed
• Phase: Phase 2
• Start date: July 25, 2006
• Est. completion date: February 11, 2019

Study information

• Verified date: March 2019
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well giving bevacizumab, radiation therapy, and combination chemotherapy works in treating patients who are undergoing surgery for locally advanced nonmetastatic rectal cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs, such as capecitabine, may make tumor cells more sensitive to radiation therapy. Drugs used in chemotherapy, such as capecitabine, oxaliplatin, fluorouracil, and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with radiation therapy and combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bevacizumab together with combination chemotherapy after surgery may kill any tumor cells that remain after surgery.

Description:

PRIMARY OBJECTIVES:

I. To evaluate the pathological complete response rate in patients with T3 and T4 rectal cancers when treated preoperatively with capecitabine, oxaliplatin, bevacizumab, and concurrent radiotherapy (XRT).

II. To evaluate the resection rate for T3 and T4 rectal cancers and the expected versus actual type of resection (abdominoperinal resection [APR] vs. low anterior resection [LAR] vs. LAR/coloanal anastomosis).

III. To make preliminary observations of patient survival and patterns of recurrence for this treatment combination.

IV. To gain additional experience regarding the toxicity and tolerability of this preoperative and postoperative regimen.

OUTLINE:

PREOPERATIVE CHEMORADIOTHERAPY: Patients undergo radiotherapy (total dose to the tumor bed was 5040 cGy) once daily (QD) 5 days a week and receive capecitabine 825 mg/m^2 orally (PO) twice daily (BID) 5 days a week for 5.5 weeks. Patients also receive oxaliplatin 50 mg/m^2 intravenously (IV) over 2 hours on days 1, 8, 15, 22, and 29 and bevacizumab 5 mg/kg IV over 30-90 minutes on days 1, 15, and 29 during radiotherapy.

SURGERY: Approximately 6-8 weeks after completion of chemoradiotherapy, patients undergo surgical resection. Patients whose tumors are not completely resected or who have metastatic disease discontinue protocol therapy.

POSTOPERATIVE CHEMOTHERAPY: Approximately 4-12 weeks after surgery, patients receive oxaliplatin IV over 2 hours, leucovorin calcium 400 mg/m^2 IV over 2 hours, and bevacizumab 5 mg/kg IV over 30-90 minutes on day 1. Patients also receive fluorouracil 2400 mg/m^2 IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 9 courses in the absence of disease progression or unacceptable toxicity. Patients then receive up to 3 additional courses of leucovorin calcium, fluorouracil, and bevacizumab.

After completion of study treatment, patients are followed up periodically for 10 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: February 11, 2019
• Est. primary completion date: August 12, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have histologically confirmed, locally advanced, non-metastatic primary T3 or T4 adenocarcinoma of the rectum

• Patients must not have evidence of tumor outside of the pelvis including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy

• Patients must not have intra-operative radiotherapy (IORT) or brachytherapy treatment to the pelvis

• The distal border of the tumor must be at or below the peritoneal reflection, defined as within 12 centimeters of the anal verge by proctoscopic examination

• Transmural penetration of tumor through the muscularis propria must be demonstrated by either of the following: computed tomography (CT) scan plus endorectal ultrasound, or a magnetic resonance imaging (MRI); an endorectal coil or pelvic MRI is allowed

• For the patient to be eligible, the surgeon must prospectively define the tumor as either initially resectable or potentially resectable after pre-operative chemoradiation; clinically resectable tumors are defined as completely resectable with negative margins based on routine examination of the non-anesthetized patient; patients whose tumors are not resectable are not eligible; before pre-operative (op) treatment, the surgeon should estimate and record the type of resection anticipated: pelvic exenteration, posterior pelvic exenteration, APR, LAR, or LAR/coloanal anastomosis

• Patients with tumors that are clinically fixed, clinical stage T4N0-2, M0 are eligible if it is believed that their tumors are potentially resectable after chemoradiation; based on the following:

• Clinically fixed tumors on rectal examination with tumor adherent to the pelvic sidewall or sacrum

• Sciatica attributed to sacral root invasion with CT scan/MRI evidence of the lack of clear tissue plane will be considered evidence of fixation

• Hydronephrosis on CT scan or intravenous pyelogram (IVP) or ureteric or bladder invasion as documented by cystoscopy and cytology or biopsy, or invasion into prostate

• Vaginal or uterine involvement

• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• A surgical evaluation must confirm patient's ability to tolerate the proposed surgical procedure

• Patients must have a caloric intake > 1500 kilocalories/day (d)

• Within 4 weeks prior to registration, the patient's absolute neutrophil count (ANC) level must be >= 1,500/mm^3

• Within 4 weeks prior to registration, the patients platelet level must be >= 100,000/mm^3

• Within 4 weeks prior to registration, serum creatinine must be < 1.5 X upper limit of normal (ULN); if serum creatinine > 1.5 x ULN, then creatinine clearance must be >= 50 mL/mm

• Within 4 weeks prior to registration, serum bilirubin must be =< 1.5 X ULN

• Within 4 weeks prior to registration, alkaline phosphatase (alk phos) must be < 2 x ULN

• Within 4 weeks prior to registration, serum glutamic oxaloacetic transaminase (SGOT) must be < 2 x ULN

• Carcinoembryonic antigen (CEA) must be determined prior to initiation of therapy

• Within 4 weeks prior to registration, urine protein/creatinine (UPC) ratio must be < 1; patients with a ratio of >= 1 must undergo a 24-hour urine collection which must be an adequate collection and must demonstrate < 1 gram (gm) of protein in order to participate

• Within 4 weeks prior to registration, albumin must be >= 2 gm/dl

• Absence of clinical evidence of high-grade (lumen diameter < 1 cm) large bowel obstruction, unless diverting colostomy has been performed

• Eligible patients of reproductive potential (both sexes) must agree to use an accepted and effective method of contraceptive during study therapy and for at least 6 months after the completion of bevacizumab

• Women must not be pregnant or breast-feeding; all females of childbearing potential must have a serum pregnancy test to rule out pregnancy within 2 weeks of registration

• Patients must have had no prior chemotherapy for rectal cancer or pelvic irradiation therapy

• Patients with prior malignancies, including pelvic cancer, are eligible if they have been disease free for > 5 years; patients with prior in situ carcinomas are eligible provided there was complete removal

• Patients must have no active inflammatory bowel disease or other serious medical illness or disease that might limit the patient's ability to receive protocol therapy

• Patients with a history of cerebrovascular accident (CVA)/transient ischemic attack (TIA) at any time, or myocardial infarction/unstable angina within 12 months of study entry are not eligible

• Patients with > grade 1 peripheral neuropathy are not eligible

• Patients must have urine protein/creatinine (UPC) ratio of < 1.0; patients with a UPC ratio >= 1.0 must undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate < 1 gm of protein in order to participate

• Patients with a history of hypertension must measure < 150/90 mmHg and be on a stable regimen of anti-hypertensive therapy

• Patients with clinically significant peripheral vascular disease are not eligible

• Patients must not have any of the following:

• Unstable angina (within 12 months of study entry)

• New York Heart Association (NYHA) grade II or higher congestive heart failure

• Evidence of bleeding diathesis/coagulopathy

• Serious non-healing wound or bone fracture

• Patients with a history of the following within 28 days prior to registration are not eligible:

• Abdominal fistula

• Gastrointestinal perforation

• Intrabdominal abscess

• Patients with a history of the following within 28 days prior to day 0 (first treatment day) are not eligible:

• Major surgical procedure

• Open biopsy

• Significant traumatic injury

• Patients must not have core biopsy within 7 days prior to day 0 (first treatment day)

• Patients with prothrombin time (PT) (international normalized ratio [INR]) > 1.5 are not eligible, unless the patient is on full-dose anticoagulants; if so, the following criteria must be met for enrollment:

• The subject must have an in-range INR (usually between 2 and 3), be on a stable dose of warfarin or on a stable dose of low molecular weight heparin

• The subject must not have active bleeding or a pathological condition that is associated with a high risk of bleeding

Related Conditions & MeSH terms

• Adenocarcinoma
• Rectal Adenocarcinoma
• Rectal Neoplasms
• Stage II Rectal Cancer AJCC v7
• Stage III Rectal Cancer AJCC v7

Intervention

Biological:
• Bevacizumab
Given IV

Drug:
• Capecitabine
Given PO
• Fluorouracil
Given IV
• Leucovorin Calcium
Given IV
• Oxaliplatin
Given IV

Radiation:
• Radiation Therapy
Undergo radiotherapy

Procedure:
• Therapeutic Conventional Surgery
Undergo surgical resection

Locations

Country	Name	City	State
United States	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Rush - Copley Medical Center	Aurora	Illinois
United States	Summa Barberton Hospital	Barberton	Ohio
United States	Mary Rutan Hospital	Bellefontaine	Ohio
United States	MacNeal Hospital and Cancer Center	Berwyn	Illinois
United States	Constantinou, Costas L MD (UIA Investigator)	Bettendorf	Iowa
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Wakefield Campus	Bronx	New York
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Hematology and Oncology Associates	Chicago	Illinois
United States	Jesse Brown Veterans Affairs Medical Center	Chicago	Illinois
United States	Mercy Hospital and Medical Center	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	Presence Saint Joseph Hospital-Chicago	Chicago	Illinois
United States	Swedish Covenant Hospital	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Doctors Hospital	Columbus	Ohio
United States	Grant Medical Center	Columbus	Ohio
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Mercy Fitzgerald Hospital	Darby	Pennsylvania
United States	Atlanta VA Medical Center	Decatur	Georgia
United States	Grady Memorial Hospital	Delaware	Ohio
United States	Pocono Medical Center	East Stroudsburg	Pennsylvania
United States	Fairview-Southdale Hospital	Edina	Minnesota
United States	Saint Anthony Memorial Hospital	Effingham	Illinois
United States	Ephrata Cancer Center	Ephrata	Pennsylvania
United States	Unity Hospital	Fridley	Minnesota
United States	Hematology Oncology Associates of Illinois-Highland Park	Highland Park	Illinois
United States	Hinsdale Hematology Oncology Associates Incorporated	Hinsdale	Illinois
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	Joliet Oncology-Hematology Associates Limited	Joliet	Illinois
United States	Midwest Center for Hematology Oncology	Joliet	Illinois
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Fairfield Medical Center	Lancaster	Ohio
United States	NorthShore Hematology Oncology-Libertyville	Libertyville	Illinois
United States	Saint Rita's Medical Center	Lima	Ohio
United States	Nebraska Cancer Research Center	Lincoln	Nebraska
United States	Meeker County Memorial Hospital	Litchfield	Minnesota
United States	Medical Center of Central Georgia	Macon	Georgia
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Saint John's Hospital - Healtheast	Maplewood	Minnesota
United States	Marietta Memorial Hospital	Marietta	Ohio
United States	Riddle Memorial Hospital	Media	Pennsylvania
United States	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana
United States	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Virginia Piper Cancer Institute	Minneapolis	Minnesota
United States	Garneau, Stewart C MD (UIA Investigator)	Moline	Illinois
United States	Porubcin, Michael MD (UIA Investigator)	Moline	Illinois
United States	Sharis, Christine M MD (UIA Investigator)	Moline	Illinois
United States	Spector, David MD (UIA Investigator)	Moline	Illinois
United States	Stoffel, Thomas J MD (UIA Investigator)	Moline	Illinois
United States	Trinity Medical Center	Moline	Illinois
United States	Vigliotti, Antonio, P.G. M.D. (UIA Investigator)	Moline	Illinois
United States	Virtua Memorial	Mount Holly	New Jersey
United States	DuPage Medical Group-Ogden	Naperville	Illinois
United States	The Hospital of Central Connecticut	New Britain	Connecticut
United States	Licking Memorial Hospital	Newark	Ohio
United States	Illinois Cancer Specialists-Niles	Niles	Illinois
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Missouri Valley Cancer Consortium	Omaha	Nebraska
United States	Aria Health-Torresdale Campus	Philadelphia	Pennsylvania
United States	Einstein Medical Center Philadelphia	Philadelphia	Pennsylvania
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	Saint Joseph's Hospital - Healtheast	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Hematology and Oncology Associates of North East Pennsylvania	Scranton	Pennsylvania
United States	Saint Francis Regional Medical Center	Shakopee	Minnesota
United States	Mercy Medical Center-Sioux City	Sioux City	Iowa
United States	Saint Luke's Regional Medical Center	Sioux City	Iowa
United States	Siouxland Regional Cancer Center	Sioux City	Iowa
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Avera McKennan Hospital and University Health Center	Sioux Falls	South Dakota
United States	Medical X-Ray Center	Sioux Falls	South Dakota
United States	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Edward H Kaplan MD and Associates	Skokie	Illinois
United States	Hematology Oncology Associates of Illinois - Skokie	Skokie	Illinois
United States	Sparta Cancer Treatment Center	Sparta	New Jersey
United States	Springfield Regional Medical Center	Springfield	Ohio
United States	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma
United States	Associates In Hematology Oncology PC-Upland	Upland	Pennsylvania
United States	Carle Cancer Center	Urbana	Illinois
United States	Virtua Voorhees	Voorhees	New Jersey
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Saint Ann's Hospital	Westerville	Ohio
United States	Inspira Medical Center Woodbury	Woodbury	New Jersey
United States	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota
United States	Woodwinds Health Campus	Woodbury	Minnesota
United States	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pathologic Complete Response Rate	Pathologic complete response to preoperative therapy was determined at the time of surgical resection. Pathologic complete response (pCR) is defined as no evidence of invasive cells on pathologic examination of the primary rectal cancer (or tissue from the area where the tumor had been if there is a complete clinical response). Pathologic complete response rate is calculated as number of patients achieving pathologic complete response divided by all eligible and treated patients	Assessed at surgery time
Secondary	Resection Rate for T3 Rectal Cancers	Resection rate is defined as number of patients with T3 rectal cancer who underwent curative surgical resection among all eligible and treated patients with T3 rectal cancers	Assessed at surgery time
Secondary	Resection Rate for T4 Rectal Cancers	Resection rate is defined as number of patients with T4 rectal cancer who underwent curative surgical resection among all eligible and treated patients with T4 rectal cancers	Assessed at surgery time
Secondary	5-year Overall Survival Rate	Overall survival is defined as time from registration to death from any cause. 5-year overall survival rate is estimated using Kaplan-Meier method.	survival follow-up began after post-operative chemotherapy, assessed every 3 months for patients 3-5 years from registration, every 6 months for patients 5-10 years from registration and every 12 months for patients 10 years from registration
Secondary	5-year Recurrence-free Survival Rate	Recurrence free survival is defined as time from surgery to disease recurrence or death without recurrence (whichever occurred first) among resected patients. 5-year recurrence-free survival rate is estimated using Kaplan-Meier method, with 90% confidence interval calculated using Greenwood's formula.	recurrence follow-up began after post-operative chemotherapy, assessed every 3 months for patients 3-5 years from registration, every 6 months for patients 5-10 years from registration and every 12 months for patients 10 years from registration