Colorectal Cancer
Conditions
Keywords
colorectal cancer, advanced, metastatic, KRAS, biomarkers (BRAF, IGF1P/MMp7,PI3K-PTEN), cetuximab
Brief summary
Advanced colorectal cancer (ACRC) is a heterogeneous disease and classification of patients is nowadays inefficient. Roughly twenty per cent of patients present with favorable figures (less than 4 liver nodules and less than 5 cm) and are suitable for local treatments (surgery or local-ablative therapies). Additionally, 10-15% of patients have poor performance status (PS \>2) or are severe disabled due to geriatric syndromes or/and co-morbid diseases that preclude any treatment strategies than best supportive care alone. The rest of patients (fit patients not suitable for radical treatments) constitute the population of patients treated with palliative therapies. Despite of it not all these patients have the same prognosis. Patients with PS 0,1 and levels of LDH \<ULN (Intermediate-risk patients) have better PFS and OS irrespective of therapy in all randomized clinical trials (de Gramont et al, JCO 2000; Douillard et al, Lancet 2000; Koopman et al, 2007). CRYSTAL trial shows a benefit in PFS (1.5 months) in RASWT of FOLFIRI plus cetuximab compared with FOLFIRI alone. Nowadays the selection of patients for cetuximab treatment is based on mutational status of KRAS, which allow to select those patients who will not respond to therapy. Other surrogate markers of activity should be also evaluated. Our hypothesis is that the suggested biomarkers will allow the selection of the patients who will benefit the most from the biweekly cetuximab treatment.
Interventions
DRUGFOLFIRI (m)
FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: * Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. * l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1. * One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. * 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours.
DRUGFOLFOX-6 (m)
FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be: * Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle. * l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1. * One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1. * 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours.
DRUGCetuximab
\- 500 mg/m2 i.v. Every 2 weeks.
Sponsors
Grupo Espanol Multidisciplinario del Cancer Digestivo
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SCREENING
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, age ≥ 18 years * Able to sign an informed consent form * Advanced and/or metastatic colorectal cancer * Colorectal cancer with KRAS wild type genotype * At least one unidimensionally measurable lesion according to RECIST criteria (1.1 revised) (to be assessed ≤ 28 days prior to the study treatment) * All patients with the following features will be included: 1. Progression free survival \> 6 months after adjuvant treatment +/- radiotherapy 2. De novo diagnosis of the disease * Performance ECOG status of 0-2 * Life expectancy ≥ 3 months * Adequate bone marrow function: neutrophils ≥1,5 x 10\^9/L; platelets ≥ 100 x 10\^9/L; hemoglobin ≥9 g/dL. * Adequate liver, renal and hematological function as follows: 1. Adequate liver function: SGOT and SGPT 2.5 x ULN (5 x ULN in case of hepatic metastasis). Total bilirubin \< 1,5 x ULN. Alkaline phosphatase 2,5 x LSN (5 x ULN if hepatic metastasis or 10 x ULN if bone metastasis) 2. Creatinine clearance or creatinine clearance during 24 hours ≥ 50 mL/min 3. Magnesium ≥ LLN, calcium ≥ LLN
Exclusion criteria
* PS \> 2 or elderly patients with fragility criteria * Previous surgery for metastasis * Previous systemic treatment for the metastatic colorectal cancer * Previous treatment with antibodies anti-EGFR or treatment with small-molecule EGFR tyrosine kinase inhibitors or EGFR signal transduction inhibitors. Subjects who suspend their first dose due to a reaction to the infusion can participate * Central nervous system metastasis (except: treated subjects with asymptomatic CNS metastasis who have not received steroids within the 30 days prior to inclusion) * Prior malignant tumor in the last 5 years, except: basal cell carcinoma of the skin or pre-invasive cervical cancer * Unresolved toxicities from a prior systemic treatment which do not qualify the patient for inclusion * Presence of peripheral neuropathy (degree \> 1 in the ctc version 3.0) and serious nonhealing wound, ulcer, or bone fracture * Hormonal treatment, immunotherapy or experimental or approved antibodies/proteins ≤ 30 days before the inclusion * Uncontrolled serious cardiovascular disease or: congestive cardiac failure NYHA lll or lV, unstable angina pectoris, myocardial infarction precedents in the past 12 months, significant arrhythmias * Interstitial pneumonitis or pulmonary fibrosis precedents, or interstitial pneumonitis or pulmonary fibrosis signs on the thoracic CT-scan * Treatment for systemic infection within the 14 days prior to treatment * Acute/subacute intestinal occlusion and/or active inflammatory bowel disease or any other bowel disease producing chronic diarrhea * Precedent of Gilbert's syndrome or dihydropyrimidine dehydrogenase deficiency * Precedent of any disease which can increase the risks associated to the participation in the study or interfere in the study results * Known positive test for the following infections: HIV, Hepatitis C + abnormal liver enzymes values, active chronic Hepatitis B (except Hepatitis C seropositive with normal liver enzymes) * All concurrent diseases which can increase the toxicity risk * The individual presents a disorder of any kind which jeopardizes their ability to give their written consent form and/or fulfill the study procedures * Any investigational agent within 30 days before enrolment * Pregnant or breastfeeding woman, or planning to get pregnant within the 6 months after treatment * Surgery (excluding the diagnostic biopsy or placing of a central venous catheter) * Woman or man of childbearing potential not consenting to use adequate contraceptive precautions during the study and 6 months after de last administration for women, and 1 month for men * Unability to fulfill the study requirements by the patients * Psychological, family, sociological or geographical conditions that may interfere with the fulfillment of the study protocol and the follow-up calendar
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 4 years | Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan. Two groups will be defined based on the score built from the proposed clinical variables and biomarkers. Instead of a binomial distribution, a Log-rank method has been used to calculate the sample size in order to include all the incidents during the follow-up. Expecting a minimum 20% difference (60 vs. 40%) on PFS at 12 months between groups and with the following assumptions: Alpha error (bilateral): 5% Beta error: 20% Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | 4 years | Measured as time in months from start of study treatment to death or lost to follow up. Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm. |
| Response Duration | 4 years | Duration of the partial or total response to the treatment. Evaluation and classification according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors) |
| Frequency of Adverse Events | 4 years | Frequency and type of adverse events (AEs). AEs were coded according to NCI CTCAE V3.0 and classified by frequency, relatedness to study treatment (related/not related) and severity (Grade). Severity ranges from grade 1 (low intensity) to Grade 5 (max. intensity, death) |
| Secondary Biomarkers Analysis | 4 years | The secondary biomarkers in serum and tumoral tissue will be analysed in order to predict the acquired resistance. |
| Tumoral Response | 4 years | Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan. 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 Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm. |
Countries
Spain
Participant flow
Pre-assignment details
All patients were allocated in the same treatment arm. Some patient characteristics and results may be reported according to the mutational status of the patients despite all patients received the same treatment schedule
Participants by arm
| Arm | Count |
|---|---|
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab Patients with a determination of BRAF status and presence of Wild type (WT) BRAF gen.
FOLFOX/FOLFIRI + cetuximab 500mg/m2 bi-weekly for 6 months, then bi-weekly cetuximab as monotherapy.
FOLFIRI (m): FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be:
* Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle.
* l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1.
* One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1.
* 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours.
FOLFOX-6 (m): FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be:
* Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle.
* l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1.
* One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1.
* 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours.
Cetuximab: - 500 mg/m2 i.v. Every 2 weeks. | 161 |
| Mutant BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab Patients with a determination of BRAF status and presence of a mutation in the BRAF gen.
FOLFOX/FOLFIRI + cetuximab 500mg/m2 bi-weekly for 6 months, then bi-weekly cetuximab as monotherapy.
FOLFIRI (m): FOLFIRI (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be:
* Irinotecan 180 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle.
* l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2), in infusion i.v., 120 minutes, on day 1.
* One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1.
* 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours.
FOLFOX-6 (m): FOLFOX6 (m) chemotherapy will be administered on day 1 of each 14-days-cycle. The administered doses will be:
* Oxaliplatin 85 mg/m2 in infusion i.v., 120 minutes, on day 1 of each cycle.
* l-Leucovorin 200 mg/m2 (or d,l-leucovorin 400 mg/m2) in infusion i.v., 120 minutes, on day 1.
* One bolus i.v. (2-4 minutes) of 400 mg/m2 of 5-FU on day 1.
* 5-FU in continuous infusion (2400 mg/m2) administered through an ambulatory pump during 46-48 hours.
Cetuximab: - 500 mg/m2 i.v. Every 2 weeks. | 20 |
| Total | 181 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Screening failure | 40 |
Baseline characteristics
| Characteristic | Mutant BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Total | WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab |
|---|---|---|---|
| Age, Continuous | 67 Years STANDARD_DEVIATION 7.4 | 65 Years STANDARD_DEVIATION 9 | 62 Years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 20 Participants | 181 Participants | 161 Participants |
| Number of metastatic organs 1 | 7 Participants | 94 Participants | 87 Participants |
| Number of metastatic organs 2 | 11 Participants | 69 Participants | 58 Participants |
| Number of metastatic organs 3 | 2 Participants | 17 Participants | 15 Participants |
| Number of metastatic organs 4 or higher | 0 Participants | 1 Participants | 1 Participants |
| Performance Status (PS) ECOG 0 | 7 Participants | 119 Participants | 112 Participants |
| Performance Status (PS) ECOG 1 | 13 Participants | 62 Participants | 49 Participants |
| Primary location Ascending colon | 9 Participants | 32 Participants | 23 Participants |
| Primary location Descending colon | 4 Participants | 14 Participants | 10 Participants |
| Primary location Rectum | 2 Participants | 45 Participants | 43 Participants |
| Primary location Sigmoid colon | 3 Participants | 76 Participants | 73 Participants |
| Primary location Transverse colon | 2 Participants | 14 Participants | 12 Participants |
| Region of Enrollment Spain | 20 participants | 181 participants | 161 participants |
| Sex: Female, Male Female | 7 Participants | 53 Participants | 46 Participants |
| Sex: Female, Male Male | 13 Participants | 128 Participants | 115 Participants |
| Stage Stage I | 0 Participants | 1 Participants | 1 Participants |
| Stage Stage II | 0 Participants | 13 Participants | 13 Participants |
| Stage Stage III | 5 Participants | 35 Participants | 30 Participants |
| Stage Stage IV | 15 Participants | 132 Participants | 117 Participants |
| Surgery of the primary tumor | 10 Participants | 101 Participants | 91 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 136 / 218 |
| other Total, other adverse events | 198 / 218 |
| serious Total, serious adverse events | 173 / 218 |
Outcome results
Primary
Progression Free Survival
Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan. Two groups will be defined based on the score built from the proposed clinical variables and biomarkers. Instead of a binomial distribution, a Log-rank method has been used to calculate the sample size in order to include all the incidents during the follow-up. Expecting a minimum 20% difference (60 vs. 40%) on PFS at 12 months between groups and with the following assumptions: Alpha error (bilateral): 5% Beta error: 20% Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm.
Time frame: 4 years
Population: Evaluable population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Progression Free Survival | 11.4 Months |
| Mutant BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Progression Free Survival | 5.9 Months |
p-value: 0.00495% CI: [1.23, 3.29]Log Rank
Secondary
Frequency of Adverse Events
Frequency and type of adverse events (AEs). AEs were coded according to NCI CTCAE V3.0 and classified by frequency, relatedness to study treatment (related/not related) and severity (Grade). Severity ranges from grade 1 (low intensity) to Grade 5 (max. intensity, death)
Time frame: 4 years
Population: Safety population (all patients that received at least one infusion of study treatment)
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Frequency of Adverse Events | Any AEs | yes | 198 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Frequency of Adverse Events | Any AEs | no | 20 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Frequency of Adverse Events | Grade 3 or higher AEs | yes | 138 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Frequency of Adverse Events | Grade 3 or higher AEs | no | 80 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Frequency of Adverse Events | Grade 5 AEs | yes | 5 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Frequency of Adverse Events | Grade 5 AEs | no | 213 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Frequency of Adverse Events | Treatment related AEs of any grade | yes | 176 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Frequency of Adverse Events | Treatment related AEs of any grade | no | 42 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Frequency of Adverse Events | Treatment related AEs grade 3 or higher | yes | 101 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Frequency of Adverse Events | Treatment related AEs grade 3 or higher | no | 117 Participants |
Secondary
Overall Survival
Measured as time in months from start of study treatment to death or lost to follow up. Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm.
Time frame: 4 years
Population: Evaluable population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Overall Survival | 32.6 Months |
| Mutant BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Overall Survival | 9.3 Months |
p-value: <0.000195% CI: [1.33, 3.96]Log Rank
Secondary
Response Duration
Duration of the partial or total response to the treatment. Evaluation and classification according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors)
Time frame: 4 years
Population: Evaluable population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Response Duration | 8.66 Months |
Secondary
Secondary Biomarkers Analysis
The secondary biomarkers in serum and tumoral tissue will be analysed in order to predict the acquired resistance.
Time frame: 4 years
Population: Evaluable population
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Secondary Biomarkers Analysis | PI3K and PTEN | Mutant | 98 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Secondary Biomarkers Analysis | PI3K and PTEN | WT | 69 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Secondary Biomarkers Analysis | PI3K and PTEN | UK | 14 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Secondary Biomarkers Analysis | IGF-1RP/MMP7 | WT | 158 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Secondary Biomarkers Analysis | IGF-1RP/MMP7 | Mutant | 23 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Secondary Biomarkers Analysis | IGF-1RP/MMP7 | UK | 0 Participants |
Secondary
Tumoral Response
Measurements according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan. 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 Results are reported by subgroups to compare outcome measure according to BRAF mutation. All patients belong to same treatment/study arm.
Time frame: 4 years
Population: Evaluable population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Tumoral Response | Partial response (PR) | 106 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Tumoral Response | Progression disease (PD) | 8 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Tumoral Response | Stable disease (SD) | 25 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Tumoral Response | Not evaluable (NE) | 6 Participants |
| WT BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Tumoral Response | Complete response (CR) | 16 Participants |
| Mutant BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Tumoral Response | Not evaluable (NE) | 3 Participants |
| Mutant BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Tumoral Response | Complete response (CR) | 1 Participants |
| Mutant BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Tumoral Response | Partial response (PR) | 6 Participants |
| Mutant BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Tumoral Response | Stable disease (SD) | 6 Participants |
| Mutant BRAF - FOLFIRI (m) or FOLFOX-6 (m) + Cetuximab | Tumoral Response | Progression disease (PD) | 4 Participants |