Rectal Cancer
Conditions
Keywords
Rectal Cancer, Chemoradiation, Aflibercept, Surgery
Brief summary
The purpose of this Phase II study will be to investigate the antiangiogenic agent, aflibercept, in combination with chemoradiation as preoperative treatment for patients with stage II/III rectal cancer, followed by 4 months of FOLFOX6 plus aflibercept adjuvantly.
Interventions
RADIATIONRadiation
DRUGAflibercept
PROCEDURESurgery
Abdominoperineal or low anterior resection with total mesorectal excision, per standard treatment guidelines
DRUGFOLFOX6
Sponsors
Sanofi
SCRI Development Innovations, LLC
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
1. Patients with histologically confirmed stage II or III rectal cancer (adenocarcinoma) 2. Patients must be candidates for preoperative chemoradiation 3. Male or female patients ≥18 years-of-age 4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 5. Adequate hematologic, liver and renal function 6. Male patients willing to use adequate contraceptive measures 7. Female patients who are not of child-bearing potential, and female patients of child-bearing potential who agree to use adequate contraceptive measures, who are not breastfeeding, and who have a negative serum or urine pregnancy test \<7 days prior to start of treatment 8. Life expectancy ≥12 weeks 9. Willingness and ability to comply with the trial and follow-up procedures 10. Ability to understand the nature of this trial and give written informed consent.
Exclusion criteria
1. Treatment with prior chemotherapy or radiation for rectal cancer. 2. Patients who have received any other investigational agents within the 28 days prior to Day 1 of the study. 3. Known to be human immunodeficiency virus positive or hepatitis B or C positive 4. Women who are pregnant or breastfeeding 5. History of acute myocardial infarction within the previous 6 months, uncontrolled hypertension (blood pressure \>150/100 mmHg and/or diastolic blood pressure \>100 mmHg), unstable angina, New York Heart Association Grade 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication (excluding atrial fibrillation), or ≥ Grade 2 peripheral vascular disease. 6. History of hypertensive crisis or hypertensive encephalopathy. 7. History of stroke or transient ischemic attack within the past 6 months. 8. Significant vascular disease (eg, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of therapy. 9. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months. 10. Patients with symptomatic sensory or peripheral neuropathy (Grade 2 or above). 11. Patients may not have received other agents, either investigational or marketed, that act by primary anti-angiogenic mechanisms. 12. Prior malignancy (except for adequately treated basal-cell or squamous-cell skin cancers, in situ carcinomas, or low grade \[Gleason score of 3+3 or less\] localized prostate cancer) in the past 5 years. 13. Patients with active concurrent infections or patients with serious underlying medical conditions. 14. Patients receiving full-dose oral or parenteral/SC anticoagulation must be on a stable dosing schedule prior to enrollment; a coumadin dose must be stable for 1 week. If this cannot be achieved, the patient will be ineligible for enrollment. 15. Major surgical procedure or significant traumatic injury within 28 days prior to study initiation, or anticipation of need for major surgical procedure during the course of the study. 16. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to initiation of therapy. 17. Patients with proteinuria, as demonstrated by a urine protein of 2+ or greater at screening. If 2+ or greater proteinuria, a 24-hour urine can be obtained, and if the result is \<1 gm/24 hours, the patient is eligible. 18. Any non-healing wound, ulcer, or bone fracture. 19. Any clinical evidence or history of a bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation). 20. History of hemoptysis (≥½ teaspoon of bright red blood per episode) within 1 month prior to initiation of therapy. 21. History of any other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Complete Response Rate | Between days 57 and 98 after preoperative chemotherapy | The Pathologic Complete Response (pCR) Rate is defined as the number of pathologic complete responders among all patients evaluable for response, including evaluable patients who did not proceed to surgery. A pCR is defined as the absence of any residual abnormality detected in a pathological specimen. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival Probability at 6 and 12 Months | up to 1 year | The probability of overall survival at 6 months and 12 months from date of first protocol treatment until date of death. |
| Sphincter Preservation Rate | Between days 57 and 98 after preoperative chemotherapy. | The percentage of patients who had Low Anterior Resection during surgery.. |
| Overall Survival | Every 3 months (±1 month) following documented progression, up to 5 years or death, whichever comes first. | Measured from date of first protocol treatment until date of death. |
| Disease Free Survival Probability at 6 and 12 Months | Up to 1 year | The probability of disease free survival at 6 and 12 months after initiating protocol treatment. |
| The Number of Participants Who Experienced Serious or Non-Serious Adverse Events as a Measure of Safety. | weekly for 6 weeks pre-op then every 2 weeks post-op, approximately 36 weeks | Adverse events and serious adverse events (AEs and SAEs) were graded according to National Cancer Institute Common Technology Criteria for Adverse Events (NCI CTCAE) v4.0. Specific AE and SAE terms are provided in the Adverse Event module. |
| Disease-Free Survival | Patients without evidence of progression will be followed every 3 months (±1 month) from date of last dose of study drug during Years 1-2, every 6 months during Years 3-4, and annually thereafter or until disease progression, estimated 5 years. | — |
Countries
United States
Participant flow
Recruitment details
Between January 2013 and July 2014, 39 patients with stage II or stage III rectal cancer were enrolled in the trial from multiple sites in the U.S.
Participants by arm
| Arm | Count |
|---|---|
| FOLFOX6/Aflibercept/Radation/Surgery Preoperative Chemoradiation (6 weeks) Surgery (6 weeks from last dose of aflibercept) Postoperative Chemotherapy and aflibercept (four 28-day cycles) | 39 |
| Total | 39 |
Baseline characteristics
| Characteristic | FOLFOX6/Aflibercept/Radation/Surgery |
|---|---|
| Age, Continuous | 60 years |
| Baseline ECOG Performance Status ECOG Performance Status = 0 | 32 participants |
| Baseline ECOG Performance Status ECOG Performance Status = 1 | 7 participants |
| Carcinoma Stage at Initial Diagnosis Stage II | 12 participants |
| Carcinoma Stage at Initial Diagnosis Stage III | 27 participants |
| Gender Female | 14 Participants |
| Gender Male | 25 Participants |
| Histologic Grade at Baseline Could not be assessed | 5 participants |
| Histologic Grade at Baseline Moderately differentiated | 28 participants |
| Histologic Grade at Baseline Poorly differentiated | 2 participants |
| Histologic Grade at Baseline Well differentiated | 4 participants |
| Race/Ethnicity, Customized Black/African American | 1 participants |
| Race/Ethnicity, Customized White/Caucasian | 38 participants |
| Region of Enrollment United States | 39 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / 39 |
| serious Total, serious adverse events | 9 / 39 |
Outcome results
Primary
Pathologic Complete Response Rate
The Pathologic Complete Response (pCR) Rate is defined as the number of pathologic complete responders among all patients evaluable for response, including evaluable patients who did not proceed to surgery. A pCR is defined as the absence of any residual abnormality detected in a pathological specimen.
Time frame: Between days 57 and 98 after preoperative chemotherapy
Population: All patients enrolled in the trial who were evaluable for pathologic response. Four patients were not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFOX6/Aflibercept/Radiation/Surgery | Pathologic Complete Response Rate | 7 participants |
Secondary
Disease-Free Survival
Time frame: Patients without evidence of progression will be followed every 3 months (±1 month) from date of last dose of study drug during Years 1-2, every 6 months during Years 3-4, and annually thereafter or until disease progression, estimated 5 years.
Population: All evaluable patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX6/Aflibercept/Radiation/Surgery | Disease-Free Survival | NA percentage of participants |
Secondary
Disease Free Survival Probability at 6 and 12 Months
The probability of disease free survival at 6 and 12 months after initiating protocol treatment.
Time frame: Up to 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFOX6/Aflibercept/Radiation/Surgery | Disease Free Survival Probability at 6 and 12 Months | 6-month DFS probability | 0.95 probability |
| FOLFOX6/Aflibercept/Radiation/Surgery | Disease Free Survival Probability at 6 and 12 Months | 12-month DFS probability | 0.87 probability |
Secondary
Overall Survival
Measured from date of first protocol treatment until date of death.
Time frame: Every 3 months (±1 month) following documented progression, up to 5 years or death, whichever comes first.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFOX6/Aflibercept/Radiation/Surgery | Overall Survival | NA participants |
Secondary
Overall Survival Probability at 6 and 12 Months
The probability of overall survival at 6 months and 12 months from date of first protocol treatment until date of death.
Time frame: up to 1 year
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFOX6/Aflibercept/Radiation/Surgery | Overall Survival Probability at 6 and 12 Months | 6-month OS probability | 0.97 probability |
| FOLFOX6/Aflibercept/Radiation/Surgery | Overall Survival Probability at 6 and 12 Months | 12 month OS probability | 0.94 probability |
Secondary
Sphincter Preservation Rate
The percentage of patients who had Low Anterior Resection during surgery..
Time frame: Between days 57 and 98 after preoperative chemotherapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFOX6/Aflibercept/Radiation/Surgery | Sphincter Preservation Rate | 62 percentage of patients |
Secondary
The Number of Participants Who Experienced Serious or Non-Serious Adverse Events as a Measure of Safety.
Adverse events and serious adverse events (AEs and SAEs) were graded according to National Cancer Institute Common Technology Criteria for Adverse Events (NCI CTCAE) v4.0. Specific AE and SAE terms are provided in the Adverse Event module.
Time frame: weekly for 6 weeks pre-op then every 2 weeks post-op, approximately 36 weeks
Population: All patients who received at least one dose of protocol treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FOLFOX6/Aflibercept/Radiation/Surgery | The Number of Participants Who Experienced Serious or Non-Serious Adverse Events as a Measure of Safety. | AEs | 38 participants |
| FOLFOX6/Aflibercept/Radiation/Surgery | The Number of Participants Who Experienced Serious or Non-Serious Adverse Events as a Measure of Safety. | SAEs | 9 participants |