Colon Cancer, Colorectal Cancer, Rectal Cancer
Conditions
Keywords
Neulasta®, pegfilgrastim, Advanced, Chemotherapy
Brief summary
The purpose of this research study is to evaluate the safety and effectiveness of pegfilgrastim in reducing grade 3/4 neutropenia when given after one of three chemotherapy regimens (FOIL, FOLFOX or FOLFIRI) in patients with locally advanced or metastatic colorectal cancer. This study is considered to be investigational because the time between receiving pegfilgrastim and the next cycle of chemotherapy is only 11 days.
Interventions
DRUGPlacebo
Subjects randomized to placebo will receive a 6 mg subcutaneous injection once per cycle at least 24 hours after completion of 5-FU chemotherapy infusion. Subjects will continue to receive one injection per cycle until completion of 4 cycles, or until early termination from the study treatment period, whichever occurs first.
DRUGPegfilgrastim
Subjects randomized to pegfilgrastim will receive a 6 mg subcutaneous injection once per cycle at least 24 hours after completion of 5-FU chemotherapy infusion. Subjects will continue to receive one injection per cycle until completion of 4 cycles, or until early termination from the study treatment period, whichever occurs first.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Locally advanced or metastatic colorectal adenocarcinoma not curable by surgery or amenable to radiation therapy with curative intent. * Histologically or cytologically documented locally advanced or metastatic colorectal cancer. The site of the primary lesion must be or has been confirmed endoscopically, radiologically, or surgically to be or has been in the large bowel. * Measurable or evaluable disease. * ECOG performance status 0, 1 or 2 * Life expectancy ≥ 12 weeks * All of the following: (1) ≥ 4 weeks must have elapsed from the time of major surgery and subjects must have recovered from the effects (e.g., laparotomy); (2) ≥ 2 weeks must have elapsed from the time of minor surgery and subjects must have recovered from the operation (insertion of a vascular access device is not considered major or minor surgery); (3) ≥ 4 weeks must have elapsed from the time of major radiotherapy (e.g., chest or bone palliative radiation therapy). * Subjects may have received prior adjuvant therapy and one prior chemotherapy regimen for metastatic disease providing 30 days has elapsed from last chemotherapy dose. * Subject must have recovered from prior chemotherapy complications and in the opinion of the investigator, the subjects current status does not place the subject at risk for entry into the trial. * Subjects with prior exposure to both oxaliplatin and irinotecan will not be eligible to participate in this study. However, if subject received prior therapy with oxaliplatin, they will be eligible to receive the FOLFIRI regimen. If subject received prior therapy with irinotecan, they will be eligible to receive the FOLFOX regimen. * Age ≥ 18 years * Absolute neutrophil count ≥ 1.5 x 109/L * Platelet count ≥100 x 109/L * Hemoglobin ≥ 9.0 g/dL (subjects may be receive a red blood cell transfusion to achieve this requirement) * Creatinine ≤ 1.5 x UNL * Total bilirubin ≤ 1.5 mg/dL (≤ 25.65 μmol/L), regardless of whether subjects have liver involvement secondary to tumor * Aspartate aminotransferase ≤ 5 x UNL * Alkaline phosphatase ≤ 5 x UNL * Informed consent to participate on the study.
Exclusion criteria
* Standard chemoradiation as adjuvant treatment for colorectal cancer will be allowed, but prior radiotherapy to \>15% of bone marrow or outside of standard adjuvant colorectal cancer chemoradiation is not allowed. * Known central nervous system metastases or carcinomatous meningitis. * Predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated by baseline pattern of \>3 loose stools daily in subjects without a colostomy or ileostomy. Subjects with a colostomy or ileostomy may be entered at the Investigator's discretion. * Pleural effusion or ascites, which cause respiratory compromise (≥Grade 2 dyspnea). * Concurrent use of other investigational agents. * No active infection requiring the start of systemic (intravenous or oral) anti-infective (antibiotic, antifungal, antiviral) within 72 hours of the administration of the first cycle of study chemotherapy. * Symptomatic sensory peripheral neuropathy. * The following conditions: Uncontrolled high blood pressure; unstable angina; symptomatic congestive heart failure; myocardial infarction ≤ 6 months prior to randomization; serious uncontrolled cardiac arrhythmia; New York Heart Association classification III or IV. * Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas, or other cancer from which the patient has been disease-free for at least five years. * Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung. * Medical or psychiatric conditions which, in the opinion of the Investigator, make participation in an investigational trial of this nature a poor risk. * Known sensitivity to E. coli derived products (e.g., Filgrastim, HUMULIN® insulin, L-asparaginase, HUMATROPE® Growth Hormone, INTRON® A) or known sensitivity to any of the products to be administered during dosing. * Subject is currently enrolled or has not yet completed at least 30 days since ending other investigational device or drug trial(s) or is receiving other investigational agent(s). * Subject of child-bearing potential is evidently pregnant (e.g., positive HCG test) or is breast feeding. * Subject is not using adequate contraceptive precautions. * Subject will not be available for follow-up assessment. * Concerns for subject's compliance with the protocol procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Grade 3 or 4 Neutropenia | First 4 cycles of treatment (8 weeks) | Grade 3 or 4 neutropenia, defined as an absolute neutrophil count (ANC) \< 1 x 10\^9/L, in any of the first four cycles of treatment |
| Grade 4 Neutropenia | First 4 cycles of treatment (8 weeks) | Grade 4 neutropenia, defined as an absolute neutrophil count (ANC) \<0.5 x 10\^9/L, in any of the first four cycles of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Febrile Neutropenia | First 4 cycles of treatment (8 weeks) | Febrile neutropenia, Defined as a temperature ≥ 38.2 °C on a given day, with an ANC \< 1.0 x 10\^9/L recorded on the same day or the next day, during any of the first 4 cycles of treatment. |
| Hospitalization Due to a Neutropenia-Related Event | First 4 cycles of neutropenia (8 weeks) | Hospitalization because of a neutropenia-related event during the first 4 cycles of treatment |
| Progression-Free Survival | Up to 24 months after first four cycles of treatment | Kaplan-Meier estimate of the median time to disease progression or death |
| Dose Delay or Reduction Due to Neutropenia | First 4 cycles of treatment (8 weeks) | Dose delay or reduction in chemotherapy doses due to neutropenia |
| Survival | Up to 24 months after first four cycles of treatment | Death from any cause through the end of the follow-up period |
| Antibiotic Use Due to Febrile Neutropenia | First 4 cycles of treatment (8 weeks) | Antibiotic use during any of the first 4 cycles of treatment due to febrile neutropenia. |
| Objective Tumor Response | First 4 cycles of treatment (8 weeks) | Objective tumor response (complete or partial) at the end of treatment, defined as a reduction of at least 50% in the area of all measurable lesions (partial response) or disappearance of all measurable or evaluable disease without the development of new lesions (complete response) on computed tomographic (CT) or other scanning. |
| Dose Delay or Reduction for Any Reason | First 4 cycles of treatment (8 weeks) | Dose delay or reduction in chemotherapy dose during the first 4 cycles for any reason |
Participant flow
Recruitment details
Participants were enrolled from 12 February 2003 through 13 January 2006
Participants by arm
| Arm | Count |
|---|---|
| Pegfilgrastim (Neulasta) Pegfilgrastim 6 mg by subcutaneous injection once every 2 weeks at least 24 hours after 5-fluorouracil infusion | 123 |
| Placebo Placebo administered by subcutaneous injection once every 2 weeks at least 24 hours after 5-fluorouracil infusion | 118 |
| Total | 241 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
| Overall Study | Death | 19 | 25 |
| Overall Study | Disease progression | 3 | 3 |
| Overall Study | Informed consent signed after treatment | 1 | 0 |
| Overall Study | Lost to Follow-up | 6 | 6 |
| Overall Study | Noncompliance | 1 | 0 |
| Overall Study | Other | 2 | 4 |
| Overall Study | Physician Decision | 3 | 5 |
| Overall Study | Protocol deviation | 2 | 2 |
| Overall Study | Protocol-specified criteria | 1 | 1 |
| Overall Study | Study drug not received | 2 | 8 |
| Overall Study | Withdrawal by Subject | 8 | 9 |
Baseline characteristics
| Characteristic | Placebo | Total | Pegfilgrastim (Neulasta) |
|---|---|---|---|
| Age, Continuous | 62.9 Years STANDARD_DEVIATION 13.21 | 62.7 Years STANDARD_DEVIATION 12.71 | 62.4 Years STANDARD_DEVIATION 12.26 |
| Chemotherapy Regimen FOIL | 30 Participants | 60 Participants | 30 Participants |
| Chemotherapy Regimen FOLFIRI | 30 Participants | 62 Participants | 32 Participants |
| Chemotherapy Regimen FOLFOX | 58 Participants | 119 Participants | 61 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 6 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 12 Participants | 24 Participants | 12 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 16 Participants | 19 Participants | 3 Participants |
| Race/Ethnicity, Customized Japanese | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White or Caucasian | 84 Participants | 187 Participants | 103 Participants |
| Sex: Female, Male Female | 34 Participants | 79 Participants | 45 Participants |
| Sex: Female, Male Male | 84 Participants | 162 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 108 / 117 | 112 / 124 |
| serious Total, serious adverse events | 36 / 117 | 44 / 124 |
Outcome results
Primary
Grade 3 or 4 Neutropenia
Grade 3 or 4 neutropenia, defined as an absolute neutrophil count (ANC) \< 1 x 10\^9/L, in any of the first four cycles of treatment
Time frame: First 4 cycles of treatment (8 weeks)
Population: Primary Analysis Set, composed of all participants who received study drug and who signed an informed consent before any invasive procedures
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegfilgrastim (Neulasta) | Grade 3 or 4 Neutropenia | 16 Participants |
| Placebo | Grade 3 or 4 Neutropenia | 51 Participants |
p-value: <0.000195% CI: [0.1, 0.37]Mantel Haenszel
Primary
Grade 4 Neutropenia
Grade 4 neutropenia, defined as an absolute neutrophil count (ANC) \<0.5 x 10\^9/L, in any of the first four cycles of treatment
Time frame: First 4 cycles of treatment (8 weeks)
Population: Primary Analysis Set, composed of all participants who received study drug and who signed an informed consent before any invasive procedures
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegfilgrastim (Neulasta) | Grade 4 Neutropenia | 13 Participants |
| Placebo | Grade 4 Neutropenia | 17 Participants |
p-value: 0.379295% CI: [0.32, 1.53]Mantel Haenszel
Secondary
Antibiotic Use Due to Febrile Neutropenia
Antibiotic use during any of the first 4 cycles of treatment due to febrile neutropenia.
Time frame: First 4 cycles of treatment (8 weeks)
Population: Primary Analysis Set, composed of all participants who received study drug and who signed an informed consent before any invasive procedures
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegfilgrastim (Neulasta) | Antibiotic Use Due to Febrile Neutropenia | 2 Participants |
| Placebo | Antibiotic Use Due to Febrile Neutropenia | 8 Participants |
p-value: 0.045795% CI: [0.05, 1.09]Mantel Haenszel
Secondary
Dose Delay or Reduction Due to Neutropenia
Dose delay or reduction in chemotherapy doses due to neutropenia
Time frame: First 4 cycles of treatment (8 weeks)
Population: Primary Analysis Set, composed of all participants who received study drug and who signed an informed consent before any invasive procedures
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegfilgrastim (Neulasta) | Dose Delay or Reduction Due to Neutropenia | 5 Participants |
| Placebo | Dose Delay or Reduction Due to Neutropenia | 26 Participants |
p-value: <0.000195% CI: [-26.2, -9.8]Mantel Haenszel
Secondary
Dose Delay or Reduction for Any Reason
Dose delay or reduction in chemotherapy dose during the first 4 cycles for any reason
Time frame: First 4 cycles of treatment (8 weeks)
Population: Primary Analysis Set, composed of all participants who received study drug and who signed an informed consent before any invasive procedures
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegfilgrastim (Neulasta) | Dose Delay or Reduction for Any Reason | 41 Participants |
| Placebo | Dose Delay or Reduction for Any Reason | 53 Participants |
p-value: 0.064695% CI: [-23.7, 0.5]Mantel Haenszel
Secondary
Febrile Neutropenia
Febrile neutropenia, Defined as a temperature ≥ 38.2 °C on a given day, with an ANC \< 1.0 x 10\^9/L recorded on the same day or the next day, during any of the first 4 cycles of treatment.
Time frame: First 4 cycles of treatment (8 weeks)
Population: Primary Analysis Set, composed of all participants who received study drug and who signed an informed consent before any invasive procedures
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegfilgrastim (Neulasta) | Febrile Neutropenia | 3 Participants |
| Placebo | Febrile Neutropenia | 10 Participants |
p-value: 0.038495% CI: [0.07, 1]Mantel Haenszel
Secondary
Hospitalization Due to a Neutropenia-Related Event
Hospitalization because of a neutropenia-related event during the first 4 cycles of treatment
Time frame: First 4 cycles of neutropenia (8 weeks)
Population: Primary Analysis Set, composed of all participants who received study drug and who signed an informed consent before any invasive procedures
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegfilgrastim (Neulasta) | Hospitalization Due to a Neutropenia-Related Event | 7 Participants |
| Placebo | Hospitalization Due to a Neutropenia-Related Event | 9 Participants |
p-value: 0.551495% CI: [0.26, 2.04]Mantel Haenszel
Secondary
Objective Tumor Response
Objective tumor response (complete or partial) at the end of treatment, defined as a reduction of at least 50% in the area of all measurable lesions (partial response) or disappearance of all measurable or evaluable disease without the development of new lesions (complete response) on computed tomographic (CT) or other scanning.
Time frame: First 4 cycles of treatment (8 weeks)
Population: Primary Analysis Set, composed of all participants who received study drug and who signed an informed consent before any invasive procedures
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegfilgrastim (Neulasta) | Objective Tumor Response | 34 Participants |
| Placebo | Objective Tumor Response | 37 Participants |
p-value: 0.543495% CI: [-14.8, 7.8]Mantel Haenszel
Secondary
Progression-Free Survival
Kaplan-Meier estimate of the median time to disease progression or death
Time frame: Up to 24 months after first four cycles of treatment
Population: Primary Analysis Set, composed of all participants who received study drug and who signed an informed consent before any invasive procedures
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegfilgrastim (Neulasta) | Progression-Free Survival | 318 Days |
| Placebo | Progression-Free Survival | 322 Days |
Secondary
Survival
Death from any cause through the end of the follow-up period
Time frame: Up to 24 months after first four cycles of treatment
Population: Primary Analysis Set, composed of all participants who received study drug and who signed an informed consent before any invasive procedures.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegfilgrastim (Neulasta) | Survival | 47 Participants |
| Placebo | Survival | 49 Participants |
95% CI: [-28.1, 4]