Metastatic Colorectal Cancer
Conditions
Keywords
Metastatic, Colorectal, Colorectal Cancer, Resected or Ablated Metastatic Colorectal Cancer
Brief summary
The main purpose of this study is to evaluate if aflibercept can reduce the chance that metastatic (spread of) colorectal cancer can grow back after finishing standard treatment. The study will also look at the side effects of aflibercept and the effect on quality of life.
Detailed description
There are over 1.2 million new cases of colorectal cancer and 600,000 deaths worldwide. The liver is the dominant site of metastases. Approximately 20-25% of patients with advanced colorectal cancer will be candidates for resection/ablation of all sites of metastatic disease.1 Unfortunately, despite resection/ablation of all metastatic sites only about 20% of these patients are ultimately cured.1 An effective adjuvant agent would prevent tumor recurrence. Aflibercept and bevacizumab are effective when combined with FOLFIRI for metastatic colon cancer. Neither has been tested in a randomized study in the adjuvant setting for patients with resected metastatic disease. Since aflibercept more effectively inhibits all forms of VEGF including VEGF-A, VEGF-B and PIGF, in striking contrast to bevacizumab which inhibits only VEGF-A, aflibercept likely will be more effective than bevacizumab as a single agent in the adjuvant metastatic setting. Therefore, we propose a randomized study of adjuvant aflibercept for patients metastatic colorectal cancer who have received 10-12 cycles of perioperative FOLFOX and have had had a complete response to all sites of metastases after chemotherapy and local modalities such as surgical resection or ablation. SBRT may also be used to produce a complete response in a metastatic site not easily amenable to surgery or ablation. Only patients with very high risk of recurrence, defined as 3 or more metastatic sites, will be included in this study.
Interventions
DRUGAflibercept
Aflibercept: 4mg/kg IV q2weeks until progression for a maximum of 2 years
Sponsors
Rhode Island Hospital
The Miriam Hospital
Lifespan
University of California, San Diego
Montefiore Medical Center
University of Florida
Sanofi
Brown University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
3.1.1 First-line treatment of metastatic colorectal cancer with 3 or more metastases 3.1.2At least 10 cycles of combination therapy with an oxaliplatin or irinotecan based regimen per institutional preference (patients may receive 6 cycles, go to surgery, then complete 4 cycles, they may complete all 10 (or more) prior to surgery, or receive any combination as long as they receive at least 10 cycles. ) 3.1.3 Resection or ablation of all metastatic sites that have not achieved complete response with perioperative therapy (regimen). The sequencing of resection, ablation, and 10-12 cycles of combination therapy (regimen) with an oxaliplatin or irinotecan based regimen may be performed according to standard institutional procedure. 3.1.4 Patients achieving a complete response in a metastatic site by stereotactic body radiation are eligible if the site was not easily accessible by surgery or ablation and a complete response was achieved. 3.1.5 No severe, uncontrolled concurrent illness that would interfere with protocol therapy. 3.1.6 No known CNS disease 3.1.7 ECOG Performance Status 0-2 3.1.8 No chemotherapy or radiation therapy within last 3 weeks 3.1.9 For patients who had 3 months of perioperative therapy (regimen), then surgery, then 3 months of therapy (regimen), patients must be off therapy for no more than 8 weeks prior to randomization. For patients who had all their therapy and then surgery, they must be no more than 8 weeks from surgery prior to randomization. 3.1.10 No concurrent anticancer therapy. 3.1.11 Absolute neutrophil count ≥ 1,500/uL, Hgb \> 9.0 g/dl, platelet ≥ 100,000/uL. 3.1.12 Total bilirubin ≤ 1.5x upper limit of normal (ULN) and AST or ALT ≤ 5x ULN; 3.1.13 Creatinine \< 1.5 x ULN 3.1.14 Life expectancy of at least 12 weeks. 3.1.15 Age ≥ 18 years 3.1.16 Women of childbearing potential must have a negative pregnancy test. 3.1.17 Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter. 3.1.18 Voluntary written informed consent.
Exclusion criteria
3.2.1 Residual metastatic disease after resection/ablation 3.2.2 Clinically significant cardiac disease (e.g., uncontrolled hypertension \[blood pressure of \>160/90 mmHg on medication\], history of myocardial infarction within 6 months,), New York Heart Association (NYHA) Class II or greater congestive heart failure within 6 months, unstable arrhythmia. Patients with an atrial arrhythmia must have this condition well controlled on stable medication. Patients with current or recent (within 6 months) unstable angina are also not eligible. Documentation of cardiac medical history to be provided. 3.2.3 Significant bleeding diathesis or coagulopathy 3.2.4 History of cerebral aneurysms or cerebral arteriovenous malformations. 3.2.5 Patients with recent (within 12 months) arterial thromboembolic events, including transient ischemic attack (TIA), cerebrovascular accident (CVA), or clinically significant peripheral artery disease should also be excluded. 3.2.6 Patients with a history of a gastrointestinal fistula or perforation. 3.2.7 Women who are breast-feeding. 3.2.8 Patients who have undergone major surgery, chemotherapy, or radiotherapy within the last 3 weeks. 3.2.9 Patients on concurrent anticancer therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Who Progressed | Every 3 months until disease progression (for up to 2 years). | Disease free survival in patients with advanced colorectal cancer who have undergone resection/ablation of all metastatic sites. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced a Toxicity Profile of Adjuvant Ziv-aflibercept, up to 2-years of Duration, for Patients Who Previously Received Systemic Perioperative Therapy (Regimen) and Surgical Resection/Ablation. | Throughout study treatment until 30 days post off study, approximately 2 years | Toxicity defined by CTCAE Version 4.0 toxicities |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aflibercept Patients will be randomized 2:1, to receive Aflibercept,4mg/kg IV q2weeks until progression for a maximum of 2 years
Aflibercept: Aflibercept: 4mg/kg IV q2weeks until progression for a maximum of 2 years | 7 |
| Observation Patients will be randomized 2:1 to receive Aflibercept. Patients who are randomized to observation will be followed per the study table, but will receive no intervention. | 3 |
| Total | 10 |
Baseline characteristics
| Characteristic | Observation | Aflibercept | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 7 Participants | 9 Participants |
| Age, Continuous | 57 years | 53.5 years | 54.6 years |
| Region of Enrollment United States | 3 participants | 7 participants | 10 participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 7 | 2 / 3 |
| serious Total, serious adverse events | 0 / 7 | 0 / 3 |
Outcome results
Primary
Number of Patients Who Progressed
Disease free survival in patients with advanced colorectal cancer who have undergone resection/ablation of all metastatic sites.
Time frame: Every 3 months until disease progression (for up to 2 years).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept | Number of Patients Who Progressed | 2 participants |
| Observation | Number of Patients Who Progressed | 0 participants |
Secondary
Number of Participants Who Experienced a Toxicity Profile of Adjuvant Ziv-aflibercept, up to 2-years of Duration, for Patients Who Previously Received Systemic Perioperative Therapy (Regimen) and Surgical Resection/Ablation.
Toxicity defined by CTCAE Version 4.0 toxicities
Time frame: Throughout study treatment until 30 days post off study, approximately 2 years
Population: Data table reflects total number of patients who experienced a toxicity on study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aflibercept | Number of Participants Who Experienced a Toxicity Profile of Adjuvant Ziv-aflibercept, up to 2-years of Duration, for Patients Who Previously Received Systemic Perioperative Therapy (Regimen) and Surgical Resection/Ablation. | 6 Participants |
| Observation | Number of Participants Who Experienced a Toxicity Profile of Adjuvant Ziv-aflibercept, up to 2-years of Duration, for Patients Who Previously Received Systemic Perioperative Therapy (Regimen) and Surgical Resection/Ablation. | 2 Participants |