Rectal Cancer, Adenocarcinoma of the Rectum
Conditions
Keywords
Fluorouracil, bevacizumab, erlotinib, external beam radiation therapy, EBRT
Brief summary
The purpose of this study is determine the safety of 5-fluorouracil, bevacizumab and erlotinib when administered in combination with external beam radiation therapy(Phase I portion) as well as to begin to collect information about whether this combination treatment is effective in treating(Phase II portion) patients with locally advanced rectal cancer.
Detailed description
* All participants will receive the following drugs: 5-fluorouracil (5-FU) given as a continuous 24-hour infusion; Bevacizumab given intravenously; erlotinib given orally at home. In the Phase I portion, we are looking for the highest dose of erlotinib that can be given safely in combination with the 5-FU, bevacizumab and radiation therapy. Therefore the dose of erlotinib may not be the same for each participant. The dose will increase until we find the highest dose without causing serious or unmanageable side effects. * Study treatment is given as an outpatient and consists of 14 day cycles with a total of 3 cycles. Patients will be given all three study drugs and radiation therapy on a monday (unless a monday falls on on a holiday). This will be day 1 of the first treatment cycle. 5-FU is given continuously days 1-14. Bevacizumab is given on day 1. Erlotinib will be given on days 1-14. Radiation therapy will be performed on Days 1-5 and 8-12. * The following tests and procedures will be performed weekly while participants are receiving study treatment: physical examination, measurement of vital signs, height and weight; performance status; blood work, urine sample. * At the end of treatment the following tests will be performed: physical examination and measurement of vital signs; performance status; blood work; CT scans of chest, abdomen and pelvis. Patients will also be evaluated for surgery at this time. Patients will be followed every three months for the first three years after surgery, then every 6 months for the next two years.
Interventions
DRUG5-fluorouracil
Given as a 24-hour infusion on days 1-14 of each 14-day cycle for a total of 3 cycles.
DRUGbevacizumab
Given intravenously on day 1 of each 14-day cycle for a total of 3 cycles.
DRUGerlotinib
Taken orally on days 1-14 of each 14-day cycle for a total of 3 cycles.
Given on days 1-5 and 8-12
Sponsors
Beth Israel Deaconess Medical Center
Dana-Farber Cancer Institute
Genentech, Inc.
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed primary adenocarcinoma of the rectum that begins within 15cm of the anal verge as determined by sigmoidoscopy or colonoscopy * Clinical T3 or T4 tumors as determined by endoscopic ultrasound and/or rectal MRI * ECOG performance status of 0-2 * 18 years of age or older * Creatinine of \< 2.0 * Adequate hepatic function * Adequate hematopoietic function * Use of effective means of contraception in subjects of child-bearing potential
Exclusion criteria
* Evidence of metastatic disease as determined by chest/abdominal/pelvic CT or physical exam * Prior chemotherapy or radiation therapy for treatment of colorectal cancer * Prior treatment with 5-FU * Prior treatment with a tyrosine kinase inhibitor, EGFR inhibitor, or VEGF inhibitor * Patients must not be receiving any other investigational agent * Prior malignancy within the last 5 years except for completely excised skin cancer, in situ cervical cancer * Warfarin anticoagulation * Co-existent malignant disease * Current or recent participation in a clinical trial (within 4 weeks from the first day of treatment) * Pregnancy * Blood pressure of \>150/100 mmHg * Unstable angina * NYHA Grade II or greater congestive heart failure * History of myocardial infarction within 6 months * History of stroke within 6 months * Clinically significant peripheral vascular disease * Evidence of bleeding diathesis or coagulopathy * Presence of central nervous system or brain metastases * Major surgical procedure, open biopsy, or significant trauma injury within 28 days prior to day 0, anticipation of need for major surgical procedure during the course of the study * Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to day 0 * Pregnant or lactating * Urine protein:creatinine ratio \> or equal to one at screening * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 0\] * Serious, non-healing wound, ulcer, or bone fracture
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Erlotinib When Administered in Combination With 5-fluorouracil (5-FU), Bevacizumab, and External Beam Radiation Therapy | 3 years | MTD of Erlotinib was determined using a traditional 3 + 3 dose escalation scheme of three dose levels (50,100,150mg). Successive cohorts of 3-6 patients were enrolled into dose escalation cohorts for 14 day cycles. MTD reflects the highest dose of Erlotinib that had ≤1 out of 6 patients with Dose-Limiting Toxicity (DLT) at the highest dose level below the maximally administered dose. The maximally administered dose is the first dose that causes DLT in \>33% of patients. DLT was defined as: Any grade 4 neutropenia, Any grade 3 thrombocytopenia, or Any ≥ grade 3 non-hematologic toxicity that results in greater than 7 days interruption in therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Grade 3 or Greater Toxicity | 3 years | Summary of grade 3 or greater toxicity by grade and type. All adverse events were evaluated using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3: Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated. |
| Percentage of Participants With Disease-free Survival | 1, 2, 3 years | Summary of disease free survival at 1, 2, and 3 years. Disease free survival is the length of time after primary treatment for cancer ends that the participant survives without any clinical signs or symptoms of that cancer. The data is shown of the percentage of participants still in disease free survival at one, two, and three years. |
| Post-operative Complications After Resection of Rectal Cancers Following Preoperative 5-FU, Bevacizumab, Erlotinib, and External Beam Radiation Therapy. | 3 years | Surgical morbidity following R0 resection with one of the following procedures: abdominal perineal resection, low anterior resection, and low anterior resection with coloanal anastomosis. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Complete Response | 3 years | The number of subjects who achieved a pathologic complete response as determine by pathologist, following completion of the study therapy. Pathologic complete response represents the absence of residual invasive disease in the rectum and in the regional lymph nodes. |
Countries
United States
Participant flow
Recruitment details
This is a single center (institutions comprising Dana Farber Partners/Harvard Cancer Center) trial. Subjects were selected upon referral to the respective clinics of the investigators' institution. Patients Patients were enrolled on to the study between May 2006 and December 2009.
Participants by arm
| Arm | Count |
|---|---|
| 5-fluorocuracil, Bevacizumab, Erlotinib and Radiation All patients receive chemoradiation with continuous infusion 5-fluorouracil, bevacizumab and erlotinib. | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | 5-fluorocuracil, Bevacizumab, Erlotinib and Radiation |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants |
| Age, Continuous | 53.5 years |
| Clinical staging T3N0 | 6 Participants |
| Clinical staging T3N1 | 15 Participants |
| Clinical staging T3N2M0 | 4 Participants |
| Clinical staging T3Nx | 4 Participants |
| Clinical staging T4N0 | 2 Participants |
| Clinical staging T4N1 | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Race/Ethnicity, Customized White | 29 Participants |
| Region of Enrollment United States | 32 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 24 Participants |
| Stage Grouping II | 11 Participants |
| Stage Grouping III | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 32 |
| other Total, other adverse events | 32 / 32 |
| serious Total, serious adverse events | 8 / 32 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Erlotinib When Administered in Combination With 5-fluorouracil (5-FU), Bevacizumab, and External Beam Radiation Therapy
MTD of Erlotinib was determined using a traditional 3 + 3 dose escalation scheme of three dose levels (50,100,150mg). Successive cohorts of 3-6 patients were enrolled into dose escalation cohorts for 14 day cycles. MTD reflects the highest dose of Erlotinib that had ≤1 out of 6 patients with Dose-Limiting Toxicity (DLT) at the highest dose level below the maximally administered dose. The maximally administered dose is the first dose that causes DLT in \>33% of patients. DLT was defined as: Any grade 4 neutropenia, Any grade 3 thrombocytopenia, or Any ≥ grade 3 non-hematologic toxicity that results in greater than 7 days interruption in therapy.
Time frame: 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 5-FU, Bevacizumab, Erlotinib and Radiation | Maximum Tolerated Dose (MTD) of Erlotinib When Administered in Combination With 5-fluorouracil (5-FU), Bevacizumab, and External Beam Radiation Therapy | 100 mg |
Secondary
Percentage of Participants With Disease-free Survival
Summary of disease free survival at 1, 2, and 3 years. Disease free survival is the length of time after primary treatment for cancer ends that the participant survives without any clinical signs or symptoms of that cancer. The data is shown of the percentage of participants still in disease free survival at one, two, and three years.
Time frame: 1, 2, 3 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 5-FU, Bevacizumab, Erlotinib and Radiation | Percentage of Participants With Disease-free Survival | 2 Years | 83.4 percentage of participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Percentage of Participants With Disease-free Survival | 3 Years | 75.5 percentage of participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Percentage of Participants With Disease-free Survival | 1 Year | 93.4 percentage of participants |
Secondary
Post-operative Complications After Resection of Rectal Cancers Following Preoperative 5-FU, Bevacizumab, Erlotinib, and External Beam Radiation Therapy.
Surgical morbidity following R0 resection with one of the following procedures: abdominal perineal resection, low anterior resection, and low anterior resection with coloanal anastomosis.
Time frame: 3 years
Population: Total study population excluding one patient who refused surgery.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 5-FU, Bevacizumab, Erlotinib and Radiation | Post-operative Complications After Resection of Rectal Cancers Following Preoperative 5-FU, Bevacizumab, Erlotinib, and External Beam Radiation Therapy. | anastomotic leaks | 4 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Post-operative Complications After Resection of Rectal Cancers Following Preoperative 5-FU, Bevacizumab, Erlotinib, and External Beam Radiation Therapy. | intra-abdominal infection | 2 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Post-operative Complications After Resection of Rectal Cancers Following Preoperative 5-FU, Bevacizumab, Erlotinib, and External Beam Radiation Therapy. | wound infections | 2 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Post-operative Complications After Resection of Rectal Cancers Following Preoperative 5-FU, Bevacizumab, Erlotinib, and External Beam Radiation Therapy. | pulmonary embolus | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Post-operative Complications After Resection of Rectal Cancers Following Preoperative 5-FU, Bevacizumab, Erlotinib, and External Beam Radiation Therapy. | small bowel obstruction | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Post-operative Complications After Resection of Rectal Cancers Following Preoperative 5-FU, Bevacizumab, Erlotinib, and External Beam Radiation Therapy. | urinary obstruction/retention | 5 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Post-operative Complications After Resection of Rectal Cancers Following Preoperative 5-FU, Bevacizumab, Erlotinib, and External Beam Radiation Therapy. | fever | 1 participants |
Secondary
Summary of Grade 3 or Greater Toxicity
Summary of grade 3 or greater toxicity by grade and type. All adverse events were evaluated using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3: Severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. Grade 4 Life-threatening consequences; urgent intervention indicated.
Time frame: 3 years
Population: Toxicity was grouped together for all phase I dose cohorts and the phase II cohort in order to summarize all the grade 3 or greater toxicities associated with the combined study therapy, instead of focusing on the dose limiting toxicities from the phase 1 dose escalation of Erlotinib. Grade 3 or higher AE data is not available by dose cohort.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Fatigue | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Cardiac-ischemia | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Febrile neutropenia | 0 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Rash: acne/acneiform | 2 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Lymphopenia | 16 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Hyperuricemia | 0 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | ALT-SGPT | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Hypokalemia | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Hypertension | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Hyponatremia | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | AST-SGOT | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Muco/stomatitis (symptom) oral cavity | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Diarrhea w/o prior colostomy | 6 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Muco/stomatitis by exam-oral cavity | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Colitis | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Radiation dermatitis | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Proteinuria | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Rash/desquamation | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Dehydration | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Rectum-pain | 1 participants |
| 5-FU, Bevacizumab, Erlotinib and Radiation | Summary of Grade 3 or Greater Toxicity | Hypophosphatemia | 3 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Rectum-pain | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Proteinuria | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Lymphopenia | 5 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Diarrhea w/o prior colostomy | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Hypophosphatemia | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Rash: acne/acneiform | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | ALT-SGPT | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Cardiac-ischemia | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Colitis | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Dehydration | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Fatigue | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Febrile neutropenia | 1 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Hypertension | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Hyperuricemia | 1 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Hypokalemia | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Hyponatremia | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Muco/stomatitis (symptom) oral cavity | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Muco/stomatitis by exam-oral cavity | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Radiation dermatitis | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | Rash/desquamation | 0 participants |
| Grade 4 | Summary of Grade 3 or Greater Toxicity | AST-SGOT | 0 participants |
Other Pre-specified
Pathologic Complete Response
The number of subjects who achieved a pathologic complete response as determine by pathologist, following completion of the study therapy. Pathologic complete response represents the absence of residual invasive disease in the rectum and in the regional lymph nodes.
Time frame: 3 years
Population: Patients who completed study therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 5-FU, Bevacizumab, Erlotinib and Radiation | Pathologic Complete Response | 9 Participants |
| Grade 4 | Pathologic Complete Response | 10 Participants |
| Treated at MTD | Pathologic Complete Response | 7 Participants |