Clinical trial NCT00911170: PAVES: Pegfilgrastim Anti-vascular Endothelial Growth Factor (VEGF) Evaluation Study
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cancer
Colon Cancer
Colorectal Cancer
Fever
Locally Advanced
Metastatic Colorectal Cancer
Neutropenia
Rectal Cancer
Keywords: adenocarcinoma of the colon or rectum
febrile neutropenia
Bevacizumab
Avastin
5-fluorouracil, Oxaliplatin, Leucovorin (FOLFOX)
5-fluorouracil, Irinotecan, Leucovorin (FOLFIRI)
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2009-06-01
Enrollment: 847
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

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.


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

Primary outcomes:
measure: Percentage of Participants With Grade 3/4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy
timeFrame: Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)
Secondary outcomes:
measure: Overall Survival
timeFrame: 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.
measure: Progression Free Survival
timeFrame: 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.
measure: Time to Progression
timeFrame: 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.
measure: Percentage of Participants With an Objective Response
timeFrame: 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.
measure: Percentage of Participants With Grade 4 Febrile Neutropenia Across the First 4 Cycles of Chemotherapy
timeFrame: Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)
measure: Percentage of Participants With Grade 3/4 Neutropenia Across the First 4 Cycles of Chemotherapy
timeFrame: Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)
measure: Percentage of Participants With Grade 4 Neutropenia Across the First 4 Cycles of Chemotherapy
timeFrame: Approximately 2 months duration (Daily for 4 cycles of treatment; 2 weeks per cycle)
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Approximately 8 weeks (4 treatment cycles)
Other outcomes:
Locations:
city: Muscle Shoals
country: United States
facility: Research Site
state: Alabama
city: Jonesboro
country: United States
facility: Research Site
state: Arkansas
city: Anaheim
country: United States
facility: Research Site
state: California
city: Beverly Hills
country: United States
facility: Research Site
state: California
city: Modesto
country: United States
facility: Research Site
state: California
city: San Diego
country: United States
facility: Research Site
state: California
city: Greenwich
country: United States
facility: Research Site
state: Connecticut
city: Dover
country: United States
facility: Research Site
state: Delaware
city: Gainesville
country: United States
facility: Research Site
state: Florida
city: Loxahatchee Groves
country: United States
facility: Research Site
state: Florida
city: Port Saint Lucie
country: United States
facility: Research Site
state: Florida
city: Tamarac
country: United States
facility: Research Site
state: Florida
city: Honolulu
country: United States
facility: Research Site
state: Hawaii
city: Gurnee
country: United States
facility: Research Site
state: Illinois
city: Maywood
country: United States
facility: Research Site
state: Illinois
city: Quincy
country: United States
facility: Research Site
state: Illinois
city: Rockford
country: United States
facility: Research Site
state: Illinois
city: New Albany
country: United States
facility: Research Site
state: Indiana
city: South Bend
country: United States
facility: Research Site
state: Indiana
city: Council Bluffs
country: United States
facility: Research Site
state: Iowa
city: Sioux City
country: United States
facility: Research Site
state: Iowa
city: Waterloo
country: United States
facility: Research Site
state: Iowa
city: Waterloo
country: United States
facility: Research Site
state: Iowa
city: Hutchinson
country: United States
facility: Research Site
state: Kansas
city: Hazard
country: United States
facility: Research Site
state: Kentucky
city: Lexington
country: United States
facility: Research Site
state: Kentucky
city: Paducah
country: United States
facility: Research Site
state: Kentucky
city: Shreveport
country: United States
facility: Research Site
state: Louisiana
city: Bethesda
country: United States
facility: Research Site
state: Maryland
city: Cumberland
country: United States
facility: Research Site
state: Maryland
city: Randallstown
country: United States
facility: Research Site
state: Maryland
city: Towson
country: United States
facility: Research Site
state: Maryland
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Jefferson City
country: United States
facility: Research Site
state: Missouri
city: Kansas City
country: United States
facility: Research Site
state: Missouri
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Springfield
country: United States
facility: Research Site
state: Missouri
city: Billings
country: United States
facility: Research Site
state: Montana
city: Grand Island
country: United States
facility: Research Site
state: Nebraska
city: Kearney
country: United States
facility: Research Site
state: Nebraska
city: Omaha
country: United States
facility: Research Site
state: Nebraska
city: Portsmouth
country: United States
facility: Research Site
state: New Hampshire
city: Little Silver
country: United States
facility: Research Site
state: New Jersey
city: Somerville
country: United States
facility: Research Site
state: New Jersey
city: Albuquerque
country: United States
facility: Research Site
state: New Mexico
city: Lake Success
country: United States
facility: Research Site
state: New York
city: Nyack
country: United States
facility: Research Site
state: New York
city: Asheville
country: United States
facility: Research Site
state: North Carolina
city: Hickory
country: United States
facility: Research Site
state: North Carolina
city: High Point
country: United States
facility: Research Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Research Site
state: North Carolina
city: Canton
country: United States
facility: Research Site
state: Ohio
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Massillon
country: United States
facility: Research Site
state: Ohio
city: Middletown
country: United States
facility: Research Site
state: Ohio
city: Lancaster
country: United States
facility: Research Site
state: Pennsylvania
city: Langhorne
country: United States
facility: Research Site
state: Pennsylvania
city: Reading
country: United States
facility: Research Site
state: Pennsylvania
city: Upland
country: United States
facility: Research Site
state: Pennsylvania
city: West Reading
country: United States
facility: Research Site
state: Pennsylvania
city: Willow Grove
country: United States
facility: Research Site
state: Pennsylvania
city: Hilton Head Island
country: United States
facility: Research Site
state: South Carolina
city: Myrtle Beach
country: United States
facility: Research Site
state: South Carolina
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Bryan
country: United States
facility: Research Site
state: Texas
city: Corpus Christi
country: United States
facility: Research Site
state: Texas
city: Corpus Christi
country: United States
facility: Research Site
state: Texas
city: Abingdon
country: United States
facility: Research Site
state: Virginia
city: Lynchburg
country: United States
facility: Research Site
state: Virginia
city: Kennewick
country: United States
facility: Research Site
state: Washington
city: Spokane
country: United States
facility: Research Site
state: Washington
city: Hobart
country: Australia
facility: Research Site
state: Tasmania
city: Ballarat
country: Australia
facility: Research Site
state: Victoria
city: Coburg
country: Australia
facility: Research Site
state: Victoria
city: Footscray
country: Australia
facility: Research Site
state: Victoria
city: Frankston
country: Australia
facility: Research Site
state: Victoria
city: Aalst
country: Belgium
facility: Research Site
city: Roeselare
country: Belgium
facility: Research Site
city: Verviers
country: Belgium
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Varna
country: Bulgaria
facility: Research Site
city: Brampton
country: Canada
facility: Research Site
state: Ontario
city: London
country: Canada
facility: Research Site
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Research Site
state: Ontario
city: Sudbury
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Laval
country: Canada
facility: Research Site
state: Quebec
city: Levis
country: Canada
facility: Research Site
state: Quebec
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Horovice
country: Czechia
facility: Research Site
city: Nova Ves pod Plesi
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Znojmo
country: Czechia
facility: Research Site
city: Amiens
country: France
facility: Research Site
city: Bordeaux Cedex
country: France
facility: Research Site
city: Cahors Cedex
country: France
facility: Research Site
city: Lille cedex 01
country: France
facility: Research Site
city: Rouen
country: France
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Debrecen
country: Hungary
facility: Research Site
city: Gyor
country: Hungary
facility: Research Site
city: Gyula
country: Hungary
facility: Research Site
city: Kaposvar
country: Hungary
facility: Research Site
city: Kecskemet
country: Hungary
facility: Research Site
city: Szeged
country: Hungary
facility: Research Site
city: Szolnok
country: Hungary
facility: Research Site
city: Cork
country: Ireland
facility: Research Site
city: Dublin
country: Ireland
facility: Research Site
city: Dublin
country: Ireland
facility: Research Site
city: Dublin
country: Ireland
facility: Research Site
city: Dublin
country: Ireland
facility: Research Site
city: Galway
country: Ireland
facility: Research Site
city: Waterford
country: Ireland
facility: Research Site
city: Benevento
country: Italy
facility: Research Site
city: Palermo
country: Italy
facility: Research Site
city: Roma (RM)
country: Italy
facility: Research Site
city: Rozzano (MI)
country: Italy
facility: Research Site
city: Taormina (ME)
country: Italy
facility: Research Site
city: Daugavpils
country: Latvia
facility: Research Site
city: Riga
country: Latvia
facility: Research Site
city: Riga
country: Latvia
facility: Research Site
city: San Luis Potosi
country: Mexico
facility: Research Site
state: San Luis P
city: Colima
country: Mexico
facility: Research Site
city: Toluca
country: Mexico
facility: Research Site
city: Gdansk
country: Poland
facility: Research Site
city: Lodz
country: Poland
facility: Research Site
city: Olsztyn
country: Poland
facility: Research Site
city: Suwalki
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Bucharest
country: Romania
facility: Research Site
city: Cluj Napoca
country: Romania
facility: Research Site
city: Sibiu
country: Romania
facility: Research Site
city: Chelyabinsk
country: Russian Federation
facility: Research Site
city: Kazan
country: Russian Federation
facility: Research Site
city: Moscow
country: Russian Federation
facility: Research Site
city: Saint Petersburg
country: Russian Federation
facility: Research Site
city: Samara
country: Russian Federation
facility: Research Site
city: Yaroslavl
country: Russian Federation
facility: Research Site
city: Bratislava
country: Slovakia
facility: Research Site
city: Kosice
country: Slovakia
facility: Research Site
city: Rimavska Sobota
country: Slovakia
facility: Research Site
city: Trnava
country: Slovakia
facility: Research Site
city: Dnipropetrovsk
country: Ukraine
facility: Research Site
city: Donetsk
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Lviv
country: Ukraine
facility: Research Site
city: Uzhgorod
country: Ukraine
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Pinter T, Klippel Z, Cesas A, Croitoru A, Decaestecker J, Gibbs P, Hotko Y, Jassem J, Kurteva G, Novotny J, O'Reilly S, Salek T, Reiner M, Morrow PK, Choi MR, Whittaker S, Blanke C. A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pegfilgrastim in Patients Receiving First-Line FOLFOX/Bevacizumab or FOLFIRI/Bevacizumab for Locally Advanced or Metastatic Colorectal Cancer: Final Results of the Pegfilgrastim and Anti-VEGF Evaluation Study (PAVES). Clin Colorectal Cancer. 2017 Jun;16(2):103-114.e3. doi: 10.1016/j.clcc.2016.08.008. Epub 2016 Sep 7.