Colorectal Cancer Metastatic
Conditions
Keywords
Metastatic Colorectal Cancer, K-RAS mutation, BRAF mutation, Regorafenib, BAY 73-4506, FOLFIRI, Irinotecan, 5-FU, Leucovorin, Placebo, Phase II, Multi-Center, Randomized, Lineberger, North Carolina Cancer Hospital, UNC
Brief summary
This randomized (2:1), multi-center, placebo-controlled, phase II efficacy study is designed to compare PFS between regorafenib + FOLFIRI chemotherapy (ARM A) versus placebo + FOLFIRI (ARM B) in patients with mCRC previously treated with a FOLFOX regimen.
Detailed description
This randomized (2:1 ratio), multi-center, placebo-controlled, phase II efficacy study is designed to compare progression-free survival (PFS) between regorafenib + FOLFIRI (5-fluorouracil + leucovorin + irinotecan \[ARM A\] versus placebo + FOLFIRI \[ARM B\]) in patients with metastatic colorectal carcinoma (mCRC) previously treated with a FOLFOX (5-fluorouracil + leucovorin + oxaliplatin) regimen. Secondary objectives include objective response (OR) rates, disease control (DC) rates, and overall survival (OS). A pharmacokinetic (PK) evaluation of irinotecan will be conducted in a subset of patients at selected sites. This trial also incorporates a number of exploratory analyses designed to evaluate potential correlations between blood and tissue biomarkers and clinical benefit.
Interventions
Regorafenib, 160 mg, PO, Days 4-10 and Days 18-24 of 28 day cycle
DRUGFOLFIRI
FOLFIRI (Irinotecan,180 mg/m2 IV over 90 minutes; 5-Fluorouracil l400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours; Leucovorin 200-400c mg/m2 IV over 2 hours) Day 1 and Day 15 of each 28 day cycle.
DRUGPlacebo
Placebo, 160 mg, PO, Days 4-10 and Days 18-24 of 28 day cycle
Sponsors
Bayer
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subject must meet all of the inclusion criteria to participate in this study: 1. Age ≥18 years of age (no upper age limit) 2. Histological or cytological documentation of adenocarcinoma of the colon or rectum 3. Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies required 4. Metastatic disease not amenable to surgical resection with curative intent 5. Progression during or within 6 months following administration of a standard regimen\[2\] for treatment of metastatic disease that included oxaliplatin with any of the following agents with or without bevacizumab: * 5-fluorouracil (F-FU) with or without leucovorin or levoleucovorin * Capecitabine Note: In patients receiving FOLFOX, oxaliplatin is sometimes discontinued due to toxicity or as part of maintenance therapy strategy. If such patients progress while on 5-FU alone, they are eligible for this trial. As an example, a patient who is begun on FOLFOX or CapeOx (capecitabine with oxaliplatin, with or without bevacizumab), whose oxaliplatin is held for neurotoxicity and who is switched to capecitabine monotherapy or capecitabine with bevacizumab, would be considered to have had one prior therapy. OR Patients who develop metastatic disease within 9 months of adjuvant FOLFOX for stage II or III colon cancer 6. Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST 1.1. 7. Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (see Appendix C) 8. Life expectancy of at least 3 months 9. Adequate bone marrow, renal, and hepatic function, as evidenced by the following: * absolute neutrophil count (ANC) ≥1,500/mm3 * platelets ≥100,000/mm3 * hemoglobin ≥9.0 g/dL * serum creatinine ≤1.5 x upper limit of normal (ULN) * Glomerular filtration rate (GFR) ≥30 ml/min/1.73m2 (see Appendix A) * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3x ULN ( ≤5.0 × ULN for patients with liver involvement of their cancer * Bilirubin ≤1.5 X ULN * Alkaline phosphatase ≤3 x ULN (≤5 x ULN with liver involvement of their cancer) * Amylase and lipase ≤1.5 x ULN * Spot urine must not show 1+ or more protein in urine or the patient will require a repeat urine analysis.If repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion \<1000 mg/24 hours * International normalized ratio (INR)/Partial thromboplastin time (PTT) ≤1.5 x ULN Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care. 10. Women of childbearing potential and male subjects must agree to use adequate contraception for the duration of study participation and up to 3 months following completion of therapy. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care. 11. The subject is capable of understanding and complying with parameters as outlined in the protocol 12. Signed, Institutional Review Board (IRB)-approved written informed consent
Exclusion criteria
Any subject meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 5.5 years | To compare PFS between regorafenib + FOLFIRI chemotherapy (ARM A) versus placebo + FOLFIRI (ARM B) in patients failing one prior oxaliplatin-containing regimen for metastatic colorectal cancer. PFS is defined as the time from randomization until metastatic colorectal cancer (mCRC) progression or death as a result of any cause. Radiographic response will be measured by RECIST, Response Evaluation Criteria In Solid Tumors Criteria, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response(OR)Rate | 3 years | To compare overall response (OR) rates (OR= CR + PR) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Disease Control (DC) Rate | 3 years | To compare Disease Control (DC) Rate (DC= CR + PR + SD) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions and Stable Disease (SD) ), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Overall Survival (OS) | 5.5 years | To compare overall survival (OS) between ARM A and ARM B. OS is defined as the time from randomization until death as a result of any cause. |
| Drug Metabolism | 28 days | To compare the pharmacokinetic (PK) profile of FOLFIRI between a subset of patients receiving regorafenib (ARM A) and patients receiving placebo (Arm B). The Area Under the Curve (AUC) levels of the irinotecan metabolite SN-38 were compared. |
| Percentage of Patients With Severe Adverse Events | 3 years | Toxicity Assessments were made according to NCI CTCAE v. 4.0 . Severe events (grades 3-4) that occurred in a higher percentage of regorafenib treated participants as compared to placebo are reported below. |
Countries
Ireland, United States
Participant flow
Recruitment details
224 participants were consented to the study from 39 institutions from 4/7/11 - 8/10/15.
Pre-assignment details
30 participants were ineligible, 7 withdrew prior to beginning protocol therapy, 3 could not participate due to study closure, 2 were unable to participate for financial reasons, 1 did not provide a reason for non-participation; 181 patients were enrolled and went on treatment.
Participants by arm
| Arm | Count |
|---|---|
| Arm A regorafenib 160 mg + FOLFIRI
Regorafenib (BAY 73-4506): Regorafenib, 160 mg, PO, daily, per 7 day cycle
FOLFIRI: FOLFIRI (Irinotecan,180 mg/m2 IV over 90 minutes; 5-Fluorouracil l400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours; Leucovorin 200-400c mg/m2 IV over 2 hours) Day 1 and Day 15 of each 28 day cycle. | 120 |
| Arm B Placebo + FOLFIRI
Placebo: Placebo, oral administration, Days 4-10 and Days 18-24 of 28 day cycle +
FOLFIRI: FOLFIRI (Irinotecan,180 mg/m2 IV over 90 minutes; 5-Fluorouracil l400 mg/m2 IV bolus followed by 2400 mg/m2 IV over 46 hours; Leucovorin 200-400c mg/m2 IV over 2 hours) Day 1 and Day 15 of each 28 day cycle. | 61 |
| Total | 181 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 20 | 2 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Disease progression, relapse during acti | 64 | 40 |
| Overall Study | Ineligibility | 0 | 1 |
| Overall Study | Other complicating disease | 2 | 1 |
| Overall Study | Physician Decision | 4 | 2 |
| Overall Study | Surgery | 2 | 1 |
| Overall Study | Symptomatic progression/deterioration | 3 | 2 |
| Overall Study | Treatment delay > 4 weeks | 4 | 5 |
| Overall Study | Withdrawal by Subject | 21 | 6 |
Baseline characteristics
| Characteristic | Arm B | Total | Arm A |
|---|---|---|---|
| Age, Continuous | 62 years | 62 years | 62 years |
| ECOG Performance Status 0 | 23 Participants | 75 Participants | 52 Participants |
| ECOG Performance Status 1 | 38 Participants | 106 Participants | 68 Participants |
| Locally Reported BRAF Mutated | 2 Participants | 12 Participants | 10 Participants |
| Locally Reported BRAF Unknown | 47 Participants | 135 Participants | 88 Participants |
| Locally Reported BRAF Wildtype | 12 Participants | 34 Participants | 22 Participants |
| Locally Reported RAS Mutated | 37 Participants | 91 Participants | 54 Participants |
| Locally Reported RAS Unknown | 6 Participants | 23 Participants | 17 Participants |
| Locally Reported RAS Wildtype | 18 Participants | 67 Participants | 49 Participants |
| Prior Biologic Agent Bevacizumab | 41 Participants | 117 Participants | 76 Participants |
| Prior Biologic Agent EGFR inhibitor | 4 Participants | 15 Participants | 11 Participants |
| Prior Biologic Agent None | 16 Participants | 49 Participants | 33 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 31 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 48 Participants | 147 Participants | 99 Participants |
| Region of Enrollment Ireland | 18 count of participants | 54 count of participants | 36 count of participants |
| Region of Enrollment United States | 43 count of participants | 127 count of participants | 84 count of participants |
| Sex: Female, Male Female | 29 Participants | 81 Participants | 52 Participants |
| Sex: Female, Male Male | 32 Participants | 100 Participants | 68 Participants |
| Stage at diagnosis I | 0 Participants | 3 Participants | 3 Participants |
| Stage at diagnosis II | 4 Participants | 8 Participants | 4 Participants |
| Stage at diagnosis III | 11 Participants | 35 Participants | 24 Participants |
| Stage at diagnosis IV | 46 Participants | 132 Participants | 86 Participants |
| Stage at diagnosis Unknown | 0 Participants | 3 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 112 / 120 | 59 / 61 |
| other Total, other adverse events | 118 / 120 | 61 / 61 |
| serious Total, serious adverse events | 60 / 120 | 20 / 61 |
Outcome results
Primary
Progression Free Survival (PFS)
To compare PFS between regorafenib + FOLFIRI chemotherapy (ARM A) versus placebo + FOLFIRI (ARM B) in patients failing one prior oxaliplatin-containing regimen for metastatic colorectal cancer. PFS is defined as the time from randomization until metastatic colorectal cancer (mCRC) progression or death as a result of any cause. Radiographic response will be measured by RECIST, Response Evaluation Criteria In Solid Tumors Criteria, indicating if subject experienced a Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: 5.5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Progression Free Survival (PFS) | 6.1 Months |
| Arm B | Progression Free Survival (PFS) | 5.3 Months |
Secondary
Disease Control (DC) Rate
To compare Disease Control (DC) Rate (DC= CR + PR + SD) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions and Stable Disease (SD) ), no response or less response than Partial or Progressive; or Progressive Disease (PD), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: 3 years
Population: Only evaluable participants (those who had RECIST measurements after baseline) were included in this analysis
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Disease Control (DC) Rate | Disease Control Total (CR+PR+SD) | 84 Participants |
| Arm A | Disease Control (DC) Rate | Progression | 18 Participants |
| Arm B | Disease Control (DC) Rate | Disease Control Total (CR+PR+SD) | 43 Participants |
| Arm B | Disease Control (DC) Rate | Progression | 15 Participants |
Secondary
Drug Metabolism
To compare the pharmacokinetic (PK) profile of FOLFIRI between a subset of patients receiving regorafenib (ARM A) and patients receiving placebo (Arm B). The Area Under the Curve (AUC) levels of the irinotecan metabolite SN-38 were compared.
Time frame: 28 days
Population: This objective was designed to only look at a small subset of participants (11 on each arm)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Arm A | Drug Metabolism | Cycle 1 | 0.68 AUC/dose=(ng/mL*h)/(mg/m^2) |
| Arm A | Drug Metabolism | Cycle 2 | 0.59 AUC/dose=(ng/mL*h)/(mg/m^2) |
| Arm B | Drug Metabolism | Cycle 1 | 0.63 AUC/dose=(ng/mL*h)/(mg/m^2) |
| Arm B | Drug Metabolism | Cycle 2 | 0.72 AUC/dose=(ng/mL*h)/(mg/m^2) |
Secondary
Overall Response(OR)Rate
To compare overall response (OR) rates (OR= CR + PR) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: 3 years
Population: Only evaluable participants (those who had RECIST measurements after baseline) were included in this analysis
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Overall Response(OR)Rate | Complete Response (CR) | 0 Participants |
| Arm A | Overall Response(OR)Rate | Partial Response (PR) | 35 Participants |
| Arm A | Overall Response(OR)Rate | Other | 67 Participants |
| Arm B | Overall Response(OR)Rate | Complete Response (CR) | 0 Participants |
| Arm B | Overall Response(OR)Rate | Partial Response (PR) | 12 Participants |
| Arm B | Overall Response(OR)Rate | Other | 46 Participants |
Secondary
Overall Survival (OS)
To compare overall survival (OS) between ARM A and ARM B. OS is defined as the time from randomization until death as a result of any cause.
Time frame: 5.5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A | Overall Survival (OS) | 13.8 Months |
| Arm B | Overall Survival (OS) | 11.7 Months |
Secondary
Percentage of Patients With Severe Adverse Events
Toxicity Assessments were made according to NCI CTCAE v. 4.0 . Severe events (grades 3-4) that occurred in a higher percentage of regorafenib treated participants as compared to placebo are reported below.
Time frame: 3 years
Population: All patients who received treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A | Percentage of Patients With Severe Adverse Events | neutropenia | 41 percentage of participants |
| Arm A | Percentage of Patients With Severe Adverse Events | diarrhea | 15 percentage of participants |
| Arm A | Percentage of Patients With Severe Adverse Events | elevated lipase | 8 percentage of participants |
| Arm A | Percentage of Patients With Severe Adverse Events | hypophosphatemia | 14 percentage of participants |
| Arm A | Percentage of Patients With Severe Adverse Events | hypertension | 8 percentage of participants |
| Arm B | Percentage of Patients With Severe Adverse Events | elevated lipase | 3 percentage of participants |
| Arm B | Percentage of Patients With Severe Adverse Events | neutropenia | 30 percentage of participants |
| Arm B | Percentage of Patients With Severe Adverse Events | diarrhea | 5 percentage of participants |
| Arm B | Percentage of Patients With Severe Adverse Events | hypertension | 2 percentage of participants |
| Arm B | Percentage of Patients With Severe Adverse Events | hypophosphatemia | 0 percentage of participants |