PAVES: Pegfilgrastim Anti-vascular Endothelial Growth Factor (VEGF) Evaluation Study

Study Overview
=================
Brief Summary
-----------------
This is a phase 3, randomized, double-blind, placebo-controlled multi-center study evaluating the efficacy of pegfilgrastim to reduce the incidence of febrile neutropenia (FN) in patients with newly diagnosed, locally-advanced or metastatic colorectal cancer receiving first-line treatment with bevacizumab and either 5-fluorouracil, Oxaliplatin, Leucovorin (FOLFOX) or 5-fluorouracil, Irinotecan, Leucovorin (FOLFIRI). This study will also investigate the effect of adding pegfilgrastim to bevacizumab and either FOLFOX or FOLFIRI by evaluating overall survival, progression-free survival, and overall response rate in each arm at regular intervals over a maximum of 60 months follow-up.

Official Title
-----------------
A Phase 3, Randomized, Double-blind, Placebo-controlled Study of Pegfilgrastim Admininstered to Subjects With Newly Diagnosed, Locally-advanced or Metastatic Colorectal Cancer Treated With Bevacizumab & Either 5-fluorouracil, Oxaliplatin, Leucovorin (FOLFOX) or 5-fluorouracil, Irinotecan, Leucovorin (FOLFIRI)

Conditions
-----------------
Cancer, Colon Cancer, Colorectal Cancer, Fever, Locally Advanced, Metastatic Colorectal Cancer, Neutropenia, Rectal Cancer

Intervention / Treatment
-----------------
* Drug: Pegfilgrastim
* Drug: Placebo
* Biological: Bevacizumab
* Drug: Standard Chemotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Disease-related: Histologically or cytologically-confirmed adenocarcinoma of the colon or rectum Locally-advanced or metastatic disease by radiographic evaluation Measurable disease Has not previously received chemotherapy for locally-advanced or metastatic colorectal cancer. Patient may have received adjuvant therapy for primary colorectal cancer provided that at least 6 months have elapsed from the time the adjuvant therapy was concluded and recurrent/metastatic disease was documented. Eastern Cooperative Oncology Group (ECOG) Performance status 0-2 Demographic: - Age of 18 years or over Laboratory: Adequate organ and marrow function as defined below: Absolute neutrophil count at least 1.5 x 10^9/L Platelet count at least 100 x 10^9/L Bilirubin ≤ 1.5 times upper limit of normal Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x upper limit of normal or Aspartate aminotransferase and alanine aminotransferase ≤ 5.0 x upper limit of normal if attributable to liver metastasis An in-range international normalized ratio (INR) (in-range is usually defined as between 2 and 3) for patients on a stable dose of oral anticoagulant or stable dose of low molecular weight heparin Has no active bleeding or pathological condition that carries high risk of bleeding (eg, tumor involving major vessels or known varices). If a suspicion of bleeding diathesis exists, a bleeding time should be performed Creatinine ≤ 1.5 times upper limit of normal General: Written informed consent obtained Afebrile on day 1 of cycle 1 Must be able and willing to comply with study and/or follow-up procedures Exclusion Criteria: Disease-Related: Known brain metastases History of another primary malignancy less than/equal to 5 years prior to randomization, with the exception of non-melanoma skin cancer, carcinoma in situ of uterine cervix, and prostatic intraepithelial neoplasia without evidence of prostate cancer Prior major surgical procedure less than 28 days prior to day 1 of cycle 1 chemotherapy dosing; anticipated need for major surgical procedure during the 4 cycle treatment period of the study Fine needle aspirations or core biopsies within 7 days prior to day 1 of cycle 1 chemotherapy dosing Serious nonhealing wound, ulcer, or bone fracture, or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 1 of cycle 1 Uncontrolled high blood pressure, history of labile hypertension, uncontrolled congestive heart failure, unstable angina within the past 3 months, myocardial infarction or history of stroke within the past 12 months, unstable symptomatic arrhythmia requiring medication, or clinically significant peripheral vascular disease History of clinically significant bleeding within 6 months prior to randomization History of arterial or venous thromboembolism within 6 months prior to randomization History of other disease including uncontrolled diabetes, serious active or uncontrolled infection, metabolic dysfunction; physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of the prescribed therapy or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications Laboratory: - Proteinuria > 1+, or total quantitative protein > 500 mg protein/day as determined by 24-hr urine collection Medications: Prior radiotherapy unless treatment was limited to the target lesion and only 1 measurable lesion was treated. Progression of the irradiated lesion must be demonstrated. Patients may not have received prior radiotherapy to greater than 25% of bone marrow. Radiation must have concluded ≥ 4 weeks prior to enrollment. Prior radio-sensitizing chemoradiation will be allowed as long as it was concluded ≥ 4 weeks prior to enrollment. Radiotherapy to non-target lesions for pain control will be allowed Prior bevacizumab use or other agents targeting VEGF Concurrent use of other biological agents Use of systemic anti-infectives for active infection, during the 3 calendar days before starting study chemotherapy and bevacizumab or planned during the study treatment period General: Current, recent (within 4 weeks of the first infusion of this study), or planned participation (during the study treatment period) in an experimental therapeutics study other than this protocol Female participants who are pregnant or lactating or men and women of reproductive potential not willing to employ an effective method of birth control during treatment and for 20 weeks for women, and 30 weeks for men after discontinuing study treatment History of allergic reactions attributed to compounds of similar chemical or biologic composition to bevacizumab, irinotecan, 5-fluorouracil (5-FU), oxaliplatin, or leucovorin, including known sensitivity to E. Coli derived products (eg, Filgrastim, HUMULIN insulin, L-asparaginase) Known dihydropyrimidine dehydrogenase deficiency

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2, and bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus placebo subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). | Drug: Placebo<br>* Administered as a single subcutaneous injection using a pre-filled syringe.<br>Biological: Bevacizumab<br>* 5 mg/kg by intravenous (IV) infusion on day 1 of each 14-day cycle.<br>* Other names: Avastin®;Drug: Standard Chemotherapy<br>* Each participant received one of the following chemotherapy regimens at the discretion of treating physician: FOLFOX: Oxaliplatin, leucovorin, and 5-fluorouracil; FOLFIRI: Irinotecan, leucovorin and 5-flurouracil.<br>|
| Placebo Comparator: Pegfilgrastim<br>Participants received standard chemotherapy (FOLFOX or FOLFIRI) on Days 1-2 and bevacizumab 5 mg/kg intravenous (IV) infusion on Day 1 of each 14-day cycle plus pegfilgrastim 6 mg administered as a single subcutaneous injection once per cycle, for a maximum of 4 cycles, 24 hours after chemotherapy (Day 4). | Drug: Pegfilgrastim<br>* Administered as a single 6 mg subcutaneous injection using a pre-filled syringe. There will be no dosage adjustments for investigational product.<br>* Other names: Neulasta®;Biological: Bevacizumab<br>* 5 mg/kg by intravenous (IV) infusion on day 1 of each 14-day cycle.<br>* Other names: Avastin®;Drug: Standard Chemotherapy<br>* Each participant received one of the following chemotherapy regimens at the discretion of treating physician: FOLFOX: Oxaliplatin, leucovorin, and 5-fluorouracil; FOLFIRI: Irinotecan, leucovorin and 5-flurouracil.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Grade 3/4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy | Grade 3/4 febrile neutropenia (FN) is defined as: • A temperature ≥ 38.0°C (≥ 100.4°F) and absolute neutrophil count (ANC) < 1.0 × 10^9/L, where ANC was measured the same day or within ± 1 calendar day of a temperature ≥ 38.0°C (≥ 100.4°F), or • An ANC < 1.0 × 10^9/L in combination with: - documented sepsis or infection, OR - neutropenia-related hospitalization where ANC was measured the same day or within ± 1 calendar day. Participants monitored their oral temperatures and maintained diaries to record their temperature twice per day: once in the morning and once in the evening, as well as whenever they suspect they had fever throughout the first 4 cycles of chemotherapy treatment. | Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Median time from randomization to date of death caclulated using the Kaplan-Meier method. Participants were censored on the date of last contact (i.e., the date the participant was last known to be alive) if they were not known to have died. | From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months. | 
| Progression Free Survival | Time from randomization to date of radiological disease progression or death from any cause, whichever event occurs first, calculated using the Kaplan-Meier method. Participants without either event by the analysis data cutoff date were censored on the date of their last evaluable disease assessment. Disease progression based on the investigator's assessment of radiographic scans using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Clinical progression without radiological assessment was not be considered a disease progression in this analysis. Progression defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. | From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months. | 
| Time to Progression | Time from randomization to date of radiological disease progression calculated using the Kaplan-Meier method. Participants without progression were censored on the date of their last radiographic tumor assessment. Disease progression based on the investigator's assessment of scans using the RECIST v1.1. Clinical progression without radiological assessment was not considered a disease progression. Progression defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. | From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months. | 
| Percentage of Participants With an Objective Response | The percentage of participants with a complete response (CR) or partial response (PR) defined by the RECIST v1.1 criteria at any time during the study. Response was be determined by the investigator's assessment of radiographic scans. CR: Disappearance of all non-nodal target lesions and the disappearance of all non-nodal non-target lesions, and no new lesions. All nodal lesions must have reduction of short axis to < 10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters and no new lesions and/or unequivocal progression of existing non-target lesions, or, the disappearance of all non-nodal target lesions with persistence of one or more non-target lesion(s). | From randomization to the data cut-off date of 8 June 2012. Median time on study was 11.6 months and the maximum was 27.6 months. | 
| Percentage of Participants With Grade 4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy | Grade 4 febrile neutropenia (FN) is defined as: A temperature ≥ 38.0ºC (≥ 100.4ºF) and absolute neutrophil count (ANC) < 0.5 × 10^9/L, where ANC is measured the same day or within +/- 1 calendar day of a temperature ≥ 38.0ºC (≥ 100.4ºF), or An ANC <0.5 × 10^9/L in combination with: Documented sepsis or infection, OR Neutropenia-related hospitalization where ANC is measured the same day or within +/- 1 calendar day. | Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle) | 
| Percentage of Participants With Grade 3/4 Neutropenia Across the First 4 Cycles of Chemotherapy | Grade 3/4 severe neutropenia is defined as neutropenia with absolute neutrophil count (ANC) <1.0 x 10^9/L. | Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle) | 
| Percentage of Participants With Grade 4 Neutropenia Across the First 4 Cycles of Chemotherapy | Grade 4 severe neutropenia is defined as neutropenia with absolute neutrophil count (ANC) <0.5 x 10^9/L. | Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle) | 
| Number of Participants With Adverse Events (AEs) | A serious adverse event (SAE) is defined as an adverse event that - is fatal; - is life threatening (places the participant at immediate risk of death); - requires inpatient hospitalization or prolongation of existing hospitalization; - results in persistent or significant disability/incapacity; - is a congenital anomaly/birth defect; - other significant medical hazard. AEs were assessed for severity according to National Cancer Institute, Common Terminology Criteria for Adverse Events, Version 3.0, based on this general guideline: Grade 1 = Mild AE; Grade 2 = Moderate AE; Grade 3 = Severe AE; Grade 4 = Life-threatening or disabling AE; Grade 5 = Death related to AE. | Approximately 8 weeks (4 treatment cycles) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adenocarcinoma of the colon or rectum, febrile neutropenia, Bevacizumab, Avastin, 5-fluorouracil, Oxaliplatin, Leucovorin (FOLFOX), 5-fluorouracil, Irinotecan, Leucovorin (FOLFIRI)