Clinical trial NCT00321685: Bevacizumab, Radiation Therapy, and Combination Chemotherapy in Treating Patients Who Are Undergoing Surgery for Locally Advanced Nonmetastatic Rectal Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Rectal Adenocarcinoma
Stage II Rectal Cancer AJCC v7
Stage III Rectal Cancer AJCC v7
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2006-05-04
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Pathologic Complete Response Rate
timeFrame: Assessed at surgery time
Secondary outcomes:
measure: Resection Rate for T3 Rectal Cancers
timeFrame: Assessed at surgery time
measure: Resection Rate for T4 Rectal Cancers
timeFrame: Assessed at surgery time
measure: 5-year Overall Survival Rate
timeFrame: 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
measure: 5-year Recurrence-free Survival Rate
timeFrame: 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
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Cancer Center
state: Alabama
city: New Britain
country: United States
facility: The Hospital of Central Connecticut
state: Connecticut
city: Atlanta
country: United States
facility: Emory University Hospital/Winship Cancer Institute
state: Georgia
city: Decatur
country: United States
facility: Atlanta VA Medical Center
state: Georgia
city: Macon
country: United States
facility: Medical Center of Central Georgia
state: Georgia
city: Aurora
country: United States
facility: Rush - Copley Medical Center
state: Illinois
city: Berwyn
country: United States
facility: MacNeal Hospital and Cancer Center
state: Illinois
city: Chicago
country: United States
facility: Hematology and Oncology Associates
state: Illinois
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Jesse Brown Veterans Affairs Medical Center
state: Illinois
city: Chicago
country: United States
facility: Mercy Hospital and Medical Center
state: Illinois
city: Chicago
country: United States
facility: Swedish Covenant Hospital
state: Illinois
city: Chicago
country: United States
facility: Presence Saint Joseph Hospital-Chicago
state: Illinois
city: Effingham
country: United States
facility: Saint Anthony Memorial Hospital
state: Illinois
city: Highland Park
country: United States
facility: Hematology Oncology Associates of Illinois-Highland Park
state: Illinois
city: Hinsdale
country: United States
facility: Hinsdale Hematology Oncology Associates Incorporated
state: Illinois
city: Joliet
country: United States
facility: Midwest Center for Hematology Oncology
state: Illinois
city: Joliet
country: United States
facility: Joliet Oncology-Hematology Associates Limited
state: Illinois
city: Libertyville
country: United States
facility: NorthShore Hematology Oncology-Libertyville
state: Illinois
city: Moline
country: United States
facility: Garneau, Stewart C MD (UIA Investigator)
state: Illinois
city: Moline
country: United States
facility: Porubcin, Michael MD (UIA Investigator)
state: Illinois
city: Moline
country: United States
facility: Sharis, Christine M MD (UIA Investigator)
state: Illinois
city: Moline
country: United States
facility: Spector, David MD (UIA Investigator)
state: Illinois
city: Moline
country: United States
facility: Stoffel, Thomas J MD (UIA Investigator)
state: Illinois
city: Moline
country: United States
facility: Trinity Medical Center
state: Illinois
city: Moline
country: United States
facility: Vigliotti, Antonio, P.G. M.D. (UIA Investigator)
state: Illinois
city: Naperville
country: United States
facility: DuPage Medical Group-Ogden
state: Illinois
city: Niles
country: United States
facility: Illinois Cancer Specialists-Niles
state: Illinois
city: Skokie
country: United States
facility: Edward H Kaplan MD and Associates
state: Illinois
city: Skokie
country: United States
facility: Hematology Oncology Associates of Illinois - Skokie
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Michigan City
country: United States
facility: Franciscan Saint Anthony Health-Michigan City
state: Indiana
city: Bettendorf
country: United States
facility: Constantinou, Costas L MD (UIA Investigator)
state: Iowa
city: Sioux City
country: United States
facility: Siouxland Regional Cancer Center
state: Iowa
city: Sioux City
country: United States
facility: Mercy Medical Center-Sioux City
state: Iowa
city: Sioux City
country: United States
facility: Saint Luke's Regional Medical Center
state: Iowa
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Kalamazoo
country: United States
facility: Borgess Medical Center
state: Michigan
city: Burnsville
country: United States
facility: Fairview Ridges Hospital
state: Minnesota
city: Coon Rapids
country: United States
facility: Mercy Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview-Southdale Hospital
state: Minnesota
city: Fridley
country: United States
facility: Unity Hospital
state: Minnesota
city: Hutchinson
country: United States
facility: Hutchinson Area Health Care
state: Minnesota
city: Litchfield
country: United States
facility: Meeker County Memorial Hospital
state: Minnesota
city: Maplewood
country: United States
facility: Minnesota Oncology Hematology PA-Maplewood
state: Minnesota
city: Maplewood
country: United States
facility: Saint John's Hospital - Healtheast
state: Minnesota
city: Minneapolis
country: United States
facility: Abbott-Northwestern Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Virginia Piper Cancer Institute
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Robbinsdale
country: United States
facility: North Memorial Medical Health Center
state: Minnesota
city: Saint Louis Park
country: United States
facility: Metro Minnesota Community Oncology Research Consortium
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Clinic - Saint Louis Park
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Saint Paul
country: United States
facility: Saint Joseph's Hospital - Healtheast
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Shakopee
country: United States
facility: Saint Francis Regional Medical Center
state: Minnesota
city: Waconia
country: United States
facility: Ridgeview Medical Center
state: Minnesota
city: Woodbury
country: United States
facility: Minnesota Oncology Hematology PA-Woodbury
state: Minnesota
city: Woodbury
country: United States
facility: Woodwinds Health Campus
state: Minnesota
city: Lincoln
country: United States
facility: Nebraska Cancer Research Center
state: Nebraska
city: Omaha
country: United States
facility: Missouri Valley Cancer Consortium
state: Nebraska
city: Omaha
country: United States
facility: Alegent Health Immanuel Medical Center
state: Nebraska
city: Omaha
country: United States
facility: Alegent Health Bergan Mercy Medical Center
state: Nebraska
city: Omaha
country: United States
facility: Creighton University Medical Center
state: Nebraska
city: Mount Holly
country: United States
facility: Virtua Memorial
state: New Jersey
city: Sparta
country: United States
facility: Sparta Cancer Treatment Center
state: New Jersey
city: Voorhees
country: United States
facility: Virtua Voorhees
state: New Jersey
city: Woodbury
country: United States
facility: Inspira Medical Center Woodbury
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center-Wakefield Campus
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: Akron
country: United States
facility: Summa Akron City Hospital/Cooper Cancer Center
state: Ohio
city: Barberton
country: United States
facility: Summa Barberton Hospital
state: Ohio
city: Bellefontaine
country: United States
facility: Mary Rutan Hospital
state: Ohio
city: Chillicothe
country: United States
facility: Adena Regional Medical Center
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist Hospital
state: Ohio
city: Columbus
country: United States
facility: Grant Medical Center
state: Ohio
city: Columbus
country: United States
facility: Mount Carmel Health Center West
state: Ohio
city: Columbus
country: United States
facility: Doctors Hospital
state: Ohio
city: Delaware
country: United States
facility: Grady Memorial Hospital
state: Ohio
city: Lancaster
country: United States
facility: Fairfield Medical Center
state: Ohio
city: Lima
country: United States
facility: Saint Rita's Medical Center
state: Ohio
city: Marietta
country: United States
facility: Marietta Memorial Hospital
state: Ohio
city: Newark
country: United States
facility: Licking Memorial Hospital
state: Ohio
city: Springfield
country: United States
facility: Springfield Regional Medical Center
state: Ohio
city: Westerville
country: United States
facility: Saint Ann's Hospital
state: Ohio
city: Zanesville
country: United States
facility: Genesis Healthcare System Cancer Care Center
state: Ohio
city: Tulsa
country: United States
facility: Natalie Warren Bryant Cancer Center at Saint Francis
state: Oklahoma
city: Allentown
country: United States
facility: Lehigh Valley Hospital-Cedar Crest
state: Pennsylvania
city: Darby
country: United States
facility: Mercy Fitzgerald Hospital
state: Pennsylvania
city: East Stroudsburg
country: United States
facility: Pocono Medical Center
state: Pennsylvania
city: Ephrata
country: United States
facility: Ephrata Cancer Center
state: Pennsylvania
city: Media
country: United States
facility: Riddle Memorial Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Aria Health-Torresdale Campus
state: Pennsylvania
city: Philadelphia
country: United States
facility: Einstein Medical Center Philadelphia
state: Pennsylvania
city: Scranton
country: United States
facility: Hematology and Oncology Associates of North East Pennsylvania
state: Pennsylvania
city: Upland
country: United States
facility: Associates In Hematology Oncology PC-Upland
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Sanford Cancer Center Oncology Clinic
state: South Dakota
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Sioux Falls
country: United States
facility: Avera McKennan Hospital and University Health Center
state: South Dakota
city: Sioux Falls
country: United States
facility: Medical X-Ray Center
state: South Dakota
city: Sioux Falls
country: United States
facility: Sanford USD Medical Center - Sioux Falls
state: South Dakota
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: La Crosse
country: United States
facility: Gundersen Lutheran Medical Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert and the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: ECOG-ACRIN Cancer Research Group
name: Jerome C Landry
role: PRINCIPAL_INVESTIGATOR
References:
citation: Landry JC, Feng Y, Prabhu RS, Cohen SJ, Staley CA, Whittington R, Sigurdson ER, Nimeiri H, Verma U, Benson AB. Phase II Trial of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin, and Bevacizumab Followed by Surgery and Postoperative 5-Fluorouracil, Leucovorin, Oxaliplatin (FOLFOX), and Bevacizumab in Patients With Locally Advanced Rectal Cancer: 5-Year Clinical Outcomes ECOG-ACRIN Cancer Research Group E3204. Oncologist. 2015 Jun;20(6):615-6. doi: 10.1634/theoncologist.2015-0106. Epub 2015 Apr 29.