Colorectal Cancer, Neoplasm Metastasis
Conditions
Keywords
Previously untreated metastatic colorectal cancer, Metastatic Colorectal Cancer, combined therapy, biologics therapy, antibody, chemotherapy, EGFR, epidermal growth factor receptor
Brief summary
This is a Phase II, open label, non-randomized study in subjects with histologically confirmed diagnosis of advanced KRAS wild type adenocarcinoma of the colon or rectum, who have not received prior chemotherapy for metastatic disease.
Detailed description
The current treatment options for metastatic colon cancer are in need of further improvement. The three-drug combination of oxaliplatin with 5-FU/LV (fluorouracil/leucovorin) in the second-line treatment of metastatic colorectal cancer have shown a significant increase in response rate compared to 5-FU/LV alone. Oxaliplatin has recently been FDA-approved for this indication and is now a standard first-line agent in combination with a fluoropyrimidine. Cetuximab, a chimeric monoclonal antibody against the growth factor receptor, has shown activity with and without irinotecan in subjects with colorectal cancer refractory to irinotecan alone. Cetuximab has also been shown to be safe and effective when administered with infusional 5-FU/folinic acid plus irinotecan. These results suggest that the addition of cetuximab to fluoropyrimidine/oxaliplatin-based regimen in the 1st line setting should be explored. The use of the oral fluoropyrimidine, capecitabine, to replace infusional 5FU has been widely used for improved convenience and possible safety. We have chosen a modified biweekly CapeOx (capecitabine plus oxaliplatin) regimen due to its improved tolerance and response rate with a fixed dose of capecitabine given its widespread practice and ease of use.
Interventions
DRUGCetuximab
500 mg/m2, IV every two weeks
DRUGOxaliplatin
85 mg/m2, IV, q 2 weeks
DRUGCapecitabine
2500 mg, po bid x 7 days every two weeks
Sponsors
Eli Lilly and Company
Bristol-Myers Squibb
NYU Langone Health
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must have signed an approved informed consent. * Histologically confirmed diagnosis of advanced adenocarcinoma of the colon or rectum, with KRAS wild type on mutational analysis. * No prior chemotherapy for metastatic disease (chemotherapy naive). Prior adjuvant therapy with 5FU/LV or IFL (irinotecan, fluorouracilis, and leucovorin (folinic acid)) permitted if completed at least six months prior to entering this study. * Measurable disease by RECIST criteria as defined in Section 3.3.1. * Subjects for whom tumor tissue is available for IHC ( Immunohistochemistry) testing for EGFR expression. * ECOG (Eastern Cooperative Oncology Group) Performance Status 0-1. * Recovery in full from any previous surgical procedure. * Expected survival greater than 12 weeks. * Subjects at least 18 years of age. * Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the study in such a manner that the risk of pregnancy is minimized. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication. * Adequate hematologic function defined by an absolute neutrophil count (ANC) \> 1,500/mm3, a platelet count \> 100,000/mm3 . * Adequate hepatic function defined by a total bilirubin level no greater than 2.0 times the upper limit of normal (ULN) and AST (Aspartate Aminotransferase) and ALT (alanine transaminase) levels noo greater than 2.5 times the ULN (AST and ALT levels no greater than 5 times the ULN in the presence of liver metastases). * Adequate renal function defined by a serum creatinine level no greater than 1.5 times the ULN.
Exclusion criteria
* WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 4 weeks after the study. * Women who are pregnant or breastfeeding. * Women with a positive pregnancy test on enrollment or prior to study drug administration. * Sexually active fertile men not using effective birth control if their partners are women of child-bearing potential. * Subjects with \> Grade 1 neuropathy. * Any active or uncontrolled infection. * History of myocardial infarction within the previous six months or current clinical evidence of congestive heart failure. * History of any other cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix) unless in complete remission and off all therapy for that cancer for at least 5 years. * Central nervous system metastases. * Pregnant or lactating women. Men and women of reproductive potential must agree to use an effective contraceptive method. * Medical or psychiatric disorders that would interfere with informed consent or make them a poor risk for participation in this trial. * Prior allergic reaction to chimerized or murine monoclonal antibody therapy or documented presence of human anti-mouse antibodies (HAMA). * Subjects receiving a prior investigational agent within 30 days. * Prior therapy with oxaliplatin, cetuximab, or prior therapy that targets the EGF ( epidermal growth factor) pathway. * Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study. * Mutation in the KRAS gene
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate for the Combination Treatment | 6 months since the start of treatment | The tumor response rate (RR) will be defined as the total number of subjects whose best response is partial response (PR) or complete response (CR) during the first six months of treatment, divided by the number of subjects. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity Rates | 1 year since the first treatment and every year after for up to 10 years | \# of subjects who experienced \>= grade 1 adverse event that is positively related to treatment. |
| Time to Progression | 6 months since the start of treatment and every 3 months after treatment for up to 10 years | Time to Treatment Failure (progression or death) will be defined as the time from the first day of treatment until the date Progressive Disease (PD) or death is first reported. Subjects who die without a reported prior progression will be considered to have progressed on the day of their death. Subjects who did not progress will be censored at the day of their last tumor assessment. |
| Survival | 6 months since the start of treatment and every 3 months after treatment for up to 10 years | Survival will be defined as the number of days from the first day of therapy to the date of death. If the subject is lost to follow-up, survival will be censored on the last date the subject was known to be alive. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cetuximab, Capecitabine and Oxaliplatin Cetuximab: 500 mg/m2, IV every two weeks
Oxaliplatin: 85 mg/m2, IV, q 2 weeks
Capecitabine: 2500 mg, po bid x 7 days every two weeks | 36 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 3 |
| Overall Study | Disease Progression | 12 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Toxicity | 11 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Cetuximab, Capecitabine and Oxaliplatin |
|---|---|
| Age, Continuous | 62 years |
| Race/Ethnicity, Customized Asian | 7 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants |
| Race/Ethnicity, Customized Unknown | 5 Participants |
| Race/Ethnicity, Customized White | 21 Participants |
| Region of Enrollment United States | 36 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 36 |
| other Total, other adverse events | 26 / 36 |
| serious Total, serious adverse events | 14 / 36 |
Outcome results
Primary
Response Rate for the Combination Treatment
The tumor response rate (RR) will be defined as the total number of subjects whose best response is partial response (PR) or complete response (CR) during the first six months of treatment, divided by the number of subjects.
Time frame: 6 months since the start of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cetuximab, Capecitabine and Oxaliplatin | Response Rate for the Combination Treatment | 21 Participants |
Secondary
Survival
Survival will be defined as the number of days from the first day of therapy to the date of death. If the subject is lost to follow-up, survival will be censored on the last date the subject was known to be alive.
Time frame: 6 months since the start of treatment and every 3 months after treatment for up to 10 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab, Capecitabine and Oxaliplatin | Survival | 417 Days |
Secondary
Time to Progression
Time to Treatment Failure (progression or death) will be defined as the time from the first day of treatment until the date Progressive Disease (PD) or death is first reported. Subjects who die without a reported prior progression will be considered to have progressed on the day of their death. Subjects who did not progress will be censored at the day of their last tumor assessment.
Time frame: 6 months since the start of treatment and every 3 months after treatment for up to 10 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab, Capecitabine and Oxaliplatin | Time to Progression | 275 Days |
Secondary
Toxicity Rates
\# of subjects who experienced \>= grade 1 adverse event that is positively related to treatment.
Time frame: 1 year since the first treatment and every year after for up to 10 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cetuximab, Capecitabine and Oxaliplatin | Toxicity Rates | 36 Participants |