Metastatic Colorectal Cancer
Conditions
Keywords
colorectal neoplasms
Brief summary
The purpose of the study is to evaluate the safety and efficacy of FOLFIRI (Irinotecan, Leucovorin and 5 Fluorouracil) chemotherapy when combined with sunitinib or FOLFIRI chemotherapy without adding sunitinib as the first line treatment of patients with metastatic colorectal cancer.
Detailed description
On June 25, 2009, the independent Data Monitoring Committee (DMC) reviewed the progress of Study A6181122. The DMC determined Study A6181122 had met pre-specified futility criteria and was unlikely to meet its primary endpoint to demonstrate a statistically significant improvement in progression-free survival (PFS) in patients treated with sunitinib plus FOLFIRI versus placebo plus FOLFIRI. No new safety findings were noted. Pfizer notified clinical trial investigators involved in the study and regulatory agencies of these findings. Patients receiving benefit on treatment as determined by the investigator may remain on study.
Interventions
DRUG5 fluorouracil
400mg/m2 bolus injection day 1 followed by 2400mg/m2 continuous infusion for 46 hours every 14 days
DRUGirinotecan
180mg/m2 iv day 1 every 14 days
DRUGlevo- leucovorin
200mg/m2 iv; day 1 every 14 days
DRUGsunitinib
37.5mg of blinded therapy every day for 28 days followed by 14 days of blinded therapy free period
DRUGplacebo
37.5mg of blinded placebo therapy every day for 28 days followed by 14 days of blinded therapy free period
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed (histologically or cytologically) colorectal adenocarcinoma with metastatic disease. * Not received previous therapy for metastatic colorectal disease but for whom FOLFIRI treatment is clinically indicated. * Adequate organ function defined by blood test.
Exclusion criteria
* History of another primary cancer in the last 3 years. * Previous full field radiotherapy within the last 4 weeks or limited field radiotherapy within 2 weeks of enrolling into the study. Or previous radiation treatment of more that 30% of the bone marrow. * History of presence of brain metastasis, spinal cord compression carcinomatous meningitis or leptomeningeal disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | First dose of study treatment up to 30 months | PFS defined as time from date of randomization to date of first documentation of objective tumour progression or death due to any cause, whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Confirmed Objective Response | Day 28 of Cycle 1 up to 30 months | Objective disease response: participants with a confirmed complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST). CR was defined as the disappearance of all target lesions. PR was defined as a greater than or equal to 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. |
| Duration of Response (DR) | Day 28 of Cycle 1 up to 30 months | DR was defined as the time from the first objective documentation of CR or PR that was subsequently confirmed to the first documentation of disease progression or to death due to any cause, whichever occurred first. |
| Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Day 1 of Cycles 1-3 and Day 1 of every odd-numbered cycle thereafter until end of treatment (EOT)/withdrawal | Symptom Intensity score is comprised of the sum of 13 MDASI core items (ie, pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, remembering things, lack of appetite, drowsiness, dry mouth, sadness, vomiting, numbness or tingling). Participant asked to rate severity of each symptom at their worst in past 24 hours; each item rated from 0 to 10, with 0=symptom not present and 10=as bad as you can imagine; lower scores indicated better outcome (range: 0 to 130). |
| Overall Survival (OS) | Baseline up to 30 months | OS was defined as the time from randomization to the date of death due to any cause. OS data were censored on the day following the date of the last contact at which the patient was known to be alive. |
| Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Day 1 of Cycles 1-3 and Day 1 of every odd-numbered cycle thereafter until EOT/withdrawal | EQ-5D: participant-rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problem); 3 indicates worst health state (eg, confined to bed). Scoring formula developed by EuroQol Group assigns a utility value for each domain. Score is transformed and results in total score range -1.11 to 1.000; higher score indicates better health state. |
| Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Day 1 of Cycles 1-3 and Day 1 of every odd-numbered cycle thereafter until EOT/withdrawal | EQ-5D: participant-rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. |
| Change From Baseline in MDASI-GI Symptom Interference Score | Day 1 of Cycles 1-3 and Day 1 of every odd-numbered cycle thereafter until EOT/withdrawal | Symptom Interference score is comprised of the sum 6 function items from MDASI core (general activity, walking, work, mood, relations with other people, and enjoyment of life). Participant asked to rate how much symptoms have interfered in past 24 hours; each item rated from 0 to 10, with 0=did not interfere and 10=interfered completely; lower scores indicated better outcome (range: 0 to 60). |
Countries
Argentina, Australia, Austria, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, Chile, Colombia, Cyprus, Czechia, Germany, Hong Kong, Hungary, India, Ireland, Mexico, Norway, Poland, Portugal, Romania, Russia, Serbia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Ukraine, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| FOLFIRI + Sunitinib Intravenous (IV) irinotecan (180 milligrams per square meter \[mg/m²\]), and levo-leucovorin (200 mg/m² or leucovorin at 400 mg/m²) immediately followed by 5-fluorouracil (5-FU) IV bolus (400 mg/m²) and 5-FU 46-hour continuous IV infusion (2400 mg/m²) every 2 weeks (FOLFIRI). Sunitinib 37.5 mg oral capsules once daily on Schedule 4/2 (4 weeks on, 2 weeks off). Three courses of FOLFIRI were administered during every 6 week sunitinib cycle. | 386 |
| FOLFIRI + Placebo IV irinotecan (180 mg/m²), and levo-leucovorin (200 mg/m² or leucovorin at 400 mg/m²) immediately followed by 5-FU IV bolus (400 mg/m²) and 5-FU 46-hour continuous IV infusion (2400 mg/m²) every 2 weeks (FOLFIRI). Placebo oral capsules once daily on Schedule 4/2 (4 weeks on, 2 weeks off). Three courses of FOLFIRI were administered during every 6 week placebo cycle. | 382 |
| Total | 768 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Death | 163 | 148 |
| Overall Study | Disease progression, study terminated | 180 | 196 |
| Overall Study | Lost to Follow-up | 23 | 14 |
| Overall Study | Protocol Violation | 1 | 3 |
| Overall Study | Study terminated by Sponsor | 1 | 1 |
| Overall Study | Subject refused (reason other than AE) | 14 | 19 |
Baseline characteristics
| Characteristic | FOLFIRI + Sunitinib | FOLFIRI + Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.6 years STANDARD_DEVIATION 10.36 | 57.6 years STANDARD_DEVIATION 10.77 | 58.1 years STANDARD_DEVIATION 10.57 |
| Sex: Female, Male Female | 164 Participants | 179 Participants | 343 Participants |
| Sex: Female, Male Male | 222 Participants | 203 Participants | 425 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 382 / 384 | 362 / 379 |
| serious Total, serious adverse events | 170 / 384 | 111 / 379 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS defined as time from date of randomization to date of first documentation of objective tumour progression or death due to any cause, whichever occurred first.
Time frame: First dose of study treatment up to 30 months
Population: Intent-to-treat (ITT) population included all participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFIRI + Sunitinib | Progression-free Survival (PFS) | 33.6 Weeks |
| FOLFIRI + Placebo | Progression-free Survival (PFS) | 36.6 Weeks |
p-value: 0.807295% CI: [0.892, 1.344]Log Rank
Secondary
Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire
EQ-5D: participant-rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression; 1 indicates better health state (no problem); 3 indicates worst health state (eg, confined to bed). Scoring formula developed by EuroQol Group assigns a utility value for each domain. Score is transformed and results in total score range -1.11 to 1.000; higher score indicates better health state.
Time frame: Day 1 of Cycles 1-3 and Day 1 of every odd-numbered cycle thereafter until EOT/withdrawal
Population: ITT population. The EQ-5D health state index results were assessed for only those cycles where at least 10 participants on either treatment arm had available data (Cycles 2, 3, 5, 7, 9, and 11).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| FOLFIRI + Sunitinib | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 5, Day 1 | 0.02 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 11, Day 1 | 0.01 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 9, Day 1 | 0.00 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 3, Day 1 | 0.02 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 7, Day 1 | 0.03 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 2, Day 1 | 0.02 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 7, Day 1 | 0.05 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 2, Day 1 | 0.04 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 3, Day 1 | 0.04 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 5, Day 1 | 0.03 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 9, Day 1 | 0.05 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in European Quality of Life (EuroQol) EQ-5D Self-Report Questionnaire | Cycle 11, Day 1 | 0.09 Scores on a scale |
Secondary
Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS)
EQ-5D: participant-rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state.
Time frame: Day 1 of Cycles 1-3 and Day 1 of every odd-numbered cycle thereafter until EOT/withdrawal
Population: ITT population. The change from baseline scores for EQ-VAS were assessed for only those cycles where at least 10 participants on either treatment arm had available data (Cycles 2, 3, 5, 7, 9, and 11).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| FOLFIRI + Sunitinib | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 2, Day 1 | 1.0 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 7, Day 1 | 3.8 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 3, Day 1 | 1.7 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 11, Day 1 | -1.6 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 5, Day 1 | 1.8 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 9, Day 1 | -0.9 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 7, Day 1 | 4.3 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 9, Day 1 | 4.0 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 11, Day 1 | 9.0 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 2, Day 1 | 3.3 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 3, Day 1 | 4.3 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in EuroQol (EQ) Visual Analog Scale (VAS) (EQ-VAS) | Cycle 5, Day 1 | 6.6 Scores on a scale |
Secondary
Change From Baseline in MDASI-GI Symptom Interference Score
Symptom Interference score is comprised of the sum 6 function items from MDASI core (general activity, walking, work, mood, relations with other people, and enjoyment of life). Participant asked to rate how much symptoms have interfered in past 24 hours; each item rated from 0 to 10, with 0=did not interfere and 10=interfered completely; lower scores indicated better outcome (range: 0 to 60).
Time frame: Day 1 of Cycles 1-3 and Day 1 of every odd-numbered cycle thereafter until EOT/withdrawal
Population: ITT population. The change from baseline MDASI-GI within each treatment arm was evaluated only for those cycles where at least 10 participants had available data (Cycles 2, 3, 5, 7, 9, 11).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| FOLFIRI + Sunitinib | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 3, Day 1 | -0.1 scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 7, Day 1 | -0.5 scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 9, Day 1 | 2.1 scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 5, Day 1 | 0.2 scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 11, Day 1 | 3.1 scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 2, Day 1 | 0.0 scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 11, Day 1 | -1.0 scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 2, Day 1 | -1.3 scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 3, Day 1 | -1.7 scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 5, Day 1 | -1.2 scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 7, Day 1 | -0.2 scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in MDASI-GI Symptom Interference Score | Cycle 9, Day 1 | -1.7 scores on a scale |
Secondary
Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score
Symptom Intensity score is comprised of the sum of 13 MDASI core items (ie, pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, remembering things, lack of appetite, drowsiness, dry mouth, sadness, vomiting, numbness or tingling). Participant asked to rate severity of each symptom at their worst in past 24 hours; each item rated from 0 to 10, with 0=symptom not present and 10=as bad as you can imagine; lower scores indicated better outcome (range: 0 to 130).
Time frame: Day 1 of Cycles 1-3 and Day 1 of every odd-numbered cycle thereafter until end of treatment (EOT)/withdrawal
Population: ITT population. The change from baseline MDASI-GI within each treatment arm was evaluated only for those cycles where at least 10 participants had available data (Cycles 2, 3, 5, 7, 9, and 11).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| FOLFIRI + Sunitinib | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 9, Day 1 | 0.8 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 3, Day 1 | 0.8 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 11, Day 1 | 5.0 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 2, Day 1 | 1.7 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 5, Day 1 | 1.0 Scores on a scale |
| FOLFIRI + Sunitinib | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 7, Day 1 | 0.7 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 2, Day 1 | 0.4 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 7, Day 1 | 2.7 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 9, Day 1 | 1.2 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 5, Day 1 | 1.8 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 11, Day 1 | -2.7 Scores on a scale |
| FOLFIRI + Placebo | Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Assessment Inventory of Gastrointestinal Symptoms (MDASI-GI) Symptom Intensity Score | Cycle 3, Day 1 | 0.9 Scores on a scale |
Secondary
Duration of Response (DR)
DR was defined as the time from the first objective documentation of CR or PR that was subsequently confirmed to the first documentation of disease progression or to death due to any cause, whichever occurred first.
Time frame: Day 28 of Cycle 1 up to 30 months
Population: ITT Population (participants with a confirmed objective tumor response).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFIRI + Sunitinib | Duration of Response (DR) | 30.1 Weeks |
| FOLFIRI + Placebo | Duration of Response (DR) | 39.0 Weeks |
Secondary
Number of Participants With Overall Confirmed Objective Response
Objective disease response: participants with a confirmed complete response (CR) or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST). CR was defined as the disappearance of all target lesions. PR was defined as a greater than or equal to 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions.
Time frame: Day 28 of Cycle 1 up to 30 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FOLFIRI + Sunitinib | Number of Participants With Overall Confirmed Objective Response | 124 Participants |
| FOLFIRI + Placebo | Number of Participants With Overall Confirmed Objective Response | 128 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from randomization to the date of death due to any cause. OS data were censored on the day following the date of the last contact at which the patient was known to be alive.
Time frame: Baseline up to 30 months
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| FOLFIRI + Sunitinib | Overall Survival (OS) | 87.9 Weeks |
| FOLFIRI + Placebo | Overall Survival (OS) | 85.9 Weeks |
p-value: 0.916395% CI: [0.936, 1.466]Log Rank