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

Cancer Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00911170
• Other study ID #: 20080259
• Status: Completed
• Phase: Phase 3
• First received: May 21, 2009
• Last updated: December 5, 2017
• Start date: November 3, 2009
• Est. completion date: January 2, 2015

Study information

• Verified date: December 2017
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 847
• Est. completion date: January 2, 2015
• Est. primary completion date: September 17, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Cancer
• Colon Cancer
• Colorectal Cancer
• Colorectal Neoplasms
• Fever
• Locally Advanced
• Metastatic Colorectal Cancer
• Neutropenia
• Rectal Cancer

Intervention

Drug:
• Pegfilgrastim
Administered as a single 6 mg subcutaneous injection using a pre-filled syringe. There will be no dosage adjustments for investigational product.
• Placebo
Administered as a single subcutaneous injection using a pre-filled syringe.

Biological:
• Bevacizumab
5 mg/kg by intravenous (IV) infusion on day 1 of each 14-day cycle.

Drug:
• Standard Chemotherapy
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.

Locations

Country	Name	City	State
Australia	Research Site	Ballarat	Victoria
Australia	Research Site	Coburg	Victoria
Australia	Research Site	Footscray	Victoria
Australia	Research Site	Frankston	Victoria
Australia	Research Site	Hobart	Tasmania
Belgium	Research Site	Aalst
Belgium	Research Site	Roeselare
Belgium	Research Site	Verviers
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Sofia
Bulgaria	Research Site	Varna
Canada	Research Site	Brampton	Ontario
Canada	Research Site	Laval	Quebec
Canada	Research Site	Levis	Quebec
Canada	Research Site	London	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Sault Ste. Marie	Ontario
Canada	Research Site	Sudbury	Ontario
Canada	Research Site	Toronto	Ontario
Czechia	Research Site	Horovice
Czechia	Research Site	Nova Ves pod Plesi
Czechia	Research Site	Olomouc
Czechia	Research Site	Znojmo
France	Research Site	Amiens
France	Research Site	Bordeaux Cedex
France	Research Site	Cahors Cedex
France	Research Site	Lille cedex 01
France	Research Site	Rouen
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Gyor
Hungary	Research Site	Gyula
Hungary	Research Site	Kaposvar
Hungary	Research Site	Kecskemet
Hungary	Research Site	Szeged
Hungary	Research Site	Szolnok
Ireland	Research Site	Cork
Ireland	Research Site	Dublin
Ireland	Research Site	Dublin
Ireland	Research Site	Dublin
Ireland	Research Site	Dublin
Ireland	Research Site	Galway
Ireland	Research Site	Waterford
Italy	Research Site	Benevento
Italy	Research Site	Palermo
Italy	Research Site	Roma (RM)
Italy	Research Site	Rozzano (MI)
Italy	Research Site	Taormina (ME)
Latvia	Research Site	Daugavpils
Latvia	Research Site	Riga
Latvia	Research Site	Riga
Mexico	Research Site	Colima
Mexico	Research Site	San Luis Potosi	San Luis P
Mexico	Research Site	Toluca
Poland	Research Site	Gdansk
Poland	Research Site	Lodz
Poland	Research Site	Olsztyn
Poland	Research Site	Suwalki
Poland	Research Site	Warszawa
Romania	Research Site	Bucharest
Romania	Research Site	Bucharest
Romania	Research Site	Cluj Napoca
Romania	Research Site	Sibiu
Russian Federation	Research Site	Chelyabinsk
Russian Federation	Research Site	Kazan
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Saint Petersburg
Russian Federation	Research Site	Samara
Russian Federation	Research Site	Yaroslavl
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Kosice
Slovakia	Research Site	Rimavska Sobota
Slovakia	Research Site	Trnava
Ukraine	Research Site	Dnipropetrovsk
Ukraine	Research Site	Donetsk
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Lviv
Ukraine	Research Site	Uzhgorod
United States	Research Site	Abingdon	Virginia
United States	Research Site	Albuquerque	New Mexico
United States	Research Site	Anaheim	California
United States	Research Site	Asheville	North Carolina
United States	Research Site	Bethesda	Maryland
United States	Research Site	Beverly Hills	California
United States	Research Site	Billings	Montana
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boston	Massachusetts
United States	Research Site	Bryan	Texas
United States	Research Site	Canton	Ohio
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Corpus Christi	Texas
United States	Research Site	Corpus Christi	Texas
United States	Research Site	Council Bluffs	Iowa
United States	Research Site	Cumberland	Maryland
United States	Research Site	Dover	Delaware
United States	Research Site	Gainesville	Florida
United States	Research Site	Grand Island	Nebraska
United States	Research Site	Greenwich	Connecticut
United States	Research Site	Gurnee	Illinois
United States	Research Site	Hazard	Kentucky
United States	Research Site	Hickory	North Carolina
United States	Research Site	High Point	North Carolina
United States	Research Site	Hilton Head Island	South Carolina
United States	Research Site	Honolulu	Hawaii
United States	Research Site	Hutchinson	Kansas
United States	Research Site	Jefferson City	Missouri
United States	Research Site	Jonesboro	Arkansas
United States	Research Site	Kansas City	Missouri
United States	Research Site	Kearney	Nebraska
United States	Research Site	Kennewick	Washington
United States	Research Site	Lake Success	New York
United States	Research Site	Lancaster	Pennsylvania
United States	Research Site	Langhorne	Pennsylvania
United States	Research Site	Lexington	Kentucky
United States	Research Site	Little Silver	New Jersey
United States	Research Site	Loxahatchee Groves	Florida
United States	Research Site	Lynchburg	Virginia
United States	Research Site	Massillon	Ohio
United States	Research Site	Maywood	Illinois
United States	Research Site	Middletown	Ohio
United States	Research Site	Modesto	California
United States	Research Site	Muscle Shoals	Alabama
United States	Research Site	Myrtle Beach	South Carolina
United States	Research Site	Nashville	Tennessee
United States	Research Site	New Albany	Indiana
United States	Research Site	Nyack	New York
United States	Research Site	Omaha	Nebraska
United States	Research Site	Paducah	Kentucky
United States	Research Site	Port Saint Lucie	Florida
United States	Research Site	Portsmouth	New Hampshire
United States	Research Site	Quincy	Illinois
United States	Research Site	Randallstown	Maryland
United States	Research Site	Reading	Pennsylvania
United States	Research Site	Rockford	Illinois
United States	Research Site	Saint Louis	Missouri
United States	Research Site	San Diego	California
United States	Research Site	Shreveport	Louisiana
United States	Research Site	Sioux City	Iowa
United States	Research Site	Somerville	New Jersey
United States	Research Site	South Bend	Indiana
United States	Research Site	Spokane	Washington
United States	Research Site	Springfield	Missouri
United States	Research Site	Tamarac	Florida
United States	Research Site	Towson	Maryland
United States	Research Site	Upland	Pennsylvania
United States	Research Site	Waterloo	Iowa
United States	Research Site	Waterloo	Iowa
United States	Research Site	West Reading	Pennsylvania
United States	Research Site	Willow Grove	Pennsylvania
United States	Research Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Bulgaria,  Canada,  Czechia,  France,  Hungary,  Ireland,  Italy,  Latvia,  Mexico,  Poland,  Romania,  Russian Federation,  Slovakia,  Ukraine, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)

External Links

•   AmgenTrials clinical trials website