PAVES: Pegfilgrastim Anti-vascular Endothelial Growth Factor (VEGF) Evaluation Study
Condition: Cancer; Colon Cancer; Colorectal Cancer; Fever; Locally Advanced; Metastatic Colorectal Cancer; Neutropenia; Rectal Cancer
MeSH terms: Colorectal Neoplasms; Neutropenia
Intervention: Pegfilgrastim; Placebo; Bevacizumab; Standard Chemotherapy
Intervention description: Administered as a single 6 mg subcutaneous injection using a pre-filled syringe. There will be no dosage adjustments for investigational product.; Administered as a single subcutaneous injection using a pre-filled syringe.; 5 mg/kg by intravenous (IV) infusion on day 1 of each 14-day cycle.; 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.
Intervention MeSH terms: Bevacizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Supportive Care
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 847.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: adenocarcinoma of the colon or rectum; febrile neutropenia; Bevacizumab; Avastin; 5-fluorouracil, Oxaliplatin, Leucovorin (FOLFOX); 5-fluorouracil, Irinotecan, Leucovorin (FOLFIRI)

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.
    

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