Colorectal Cancer
Conditions
Keywords
colorectal cancer, K-Ras wildtype, first line metastatic, standard cetuximab + FOLFIRI, dose escalation cetuximab
Brief summary
The purposes of this study are to determine whether administering escalating doses of cetuximab in patients with no early skin toxicity could delay the progression of disease in a significant proportion of patients and to study the molecular signatures of response.
Detailed description
Colorectal carcinoma (CRC) is the third most common form of cancer worldwide and remains a leading malignancy both in incidence and mortality. In the light of existing knowledge, the investigators propose a phase II open label, two arm study in patients presenting with K-Ras wild-type metastatic colorectal tumours in the first line setting. The standard combination of irinotecan plus infusional 5-FU/LV (FOLFIRI) and cetuximab will be given to all patients entering the study. As the investigators hypothesize that increasing the dose of cetuximab might increase the intensity of skin reactions that directly correlates with outcome, in patients experiencing no skin toxicity, the dose of cetuximab will be escalated from 250 mg/m2 to 350 mg/m2 and then up to 500 mg/m2, in order to better define the effect of dose escalation in the first-line setting in a K-Ras wild type tumour population and in an attempt to increase efficacy. Pharmacokinetic studies will be performed to document PK parameters of cetuximab in patients from both arms in selected centers. Translational research studies are planned for all patients. Some more in depth molecular testing will be performed in a subset of patients from whom three serial tissue samples from accessible metastases by biopsy are available.
Interventions
DRUGDose escalation of cetuximab
Dose, frequency & treatment mode: 400 mg/m2 (loading at day 1) followed by 250 mg/m2 weekly (at day 8 and 15) Arm allocation at day 22: Patients with skin toxicity grade 0 will follow an increasing dose schedule: on days 22 and 29 they will receive 350 mg/m2 and from day 36 onwards, 500 mg/m2 weekly
DRUGStandard first line treatment with cetuximab + Folfiri
Dose, frequency & treatment mode: 400 mg/m2 (loading at day 1) followed by 250 mg/m2 weekly (at day 8 and 15) Arm allocation at day 22: Patients with skin toxicity grade 1-4 or other significant toxicity who are not eligible for dose escalation will continue on the standard dose of cetuximab: 250 mg/m2 weekly.
Sponsors
Merck KGaA, Darmstadt, Germany
Universitaire Ziekenhuizen KU Leuven
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent (+ optional for PK and TR) must be given according to ICH/GCP and national/local regulations. 2. Patient is at least 18 years of age. 3. Patient's body weight is ≤ 120 kg. 4. Histologically proven and measurable (RECIST criteria v.1.1) metastatic adenocarcinoma of the colon or rectum, not in a previously irradiated area. 5. K-Ras wild type tumour eligible for treatment with cetuximab. 6. Unresectable metastatic disease. 7. Life expectancy of at least 12 weeks. 8. WHO ECOG performance status: 0 or 1. 9. Effective contraception for both male and female patients if the risk of conception exists. 10. Adequate organ function. 11. Adequate bone marrow, hepatic and renal function (assessed within 14 days prior to study entry): * Hemoglobin \> 10.0 g/dL, absolute neutrophil count \> 1.5 x 109/L, platelet count \> 100 x 109/L * ALAT, ASAT \< 2.5 x ULN, up to \< 5 x ULN in case of liver metastases * Alkaline phosphatase \< 2.5 x ULN * Total bilirubin \< 1.5 x ULN * Creatinine clearance \> 50 mL/min (calculated according to Cockroft and Gault)
Exclusion criteria
1. Prior treatment for metastatic disease (adjuvant therapy with fluoropyrimidines +/-oxaliplatin based regimens allowed if stopped 6 months prior to registration on study). 2. Prior treatment with EGFR inhibitor or chemotherapy with irinotecan in adjuvant settings. 3. Surgery (excluding diagnostic biopsy) or irradiation within 4 weeks prior to study entry. 4. Administration of any investigational drug or agent/procedure, i.e. participation in another trial within 4 weeks before beginning treatment. 5. Concurrent chronic systemic immune therapy, chemotherapy, radiation therapy or hormone therapy not indicated in the study protocol. 6. Any active dermatological condition \> grade 1. 7. Brain metastasis (known or suspected). 8. Significant impairment of intestinal absorption (e.g. chronic diarrhea, inflammatory bowel disease). 9. Other uncontrolled concomitant illness, including serious uncontrolled intercurrent infection. 10. Uncontrolled coronary artery disease and/or unstable angina, a history of a myocardial infarction within the last 12 months or heart failure NYHA class III or IV. High risk of uncontrolled arrhythmia. 11. Known allergy or any other adverse reaction to any of the drugs or to any related compound. 12. Known dihydropyrimidine dehydrogenase (DPD) deficiency. 13. Gilbert disease. 14. Previous (within 5 years) or concurrent malignancies at other sites with the exception of surgically cured or adequately treated carcinoma in-situ of the cervix and basal cell carcinoma of the skin. 15. Organ allografts requiring immunosuppressive therapy. 16. Pregnancy (absence confirmed by serum/urine beta human choriongonadotrophin in pre-menopausal women) or breast-feeding. 17. Medical, social or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PFS Probability Rate at 9 Months in the Dose Escalation Arm | 9 months | A precise estimate (+/- 10%) of the probability of not having progression at 9 months. This measure is an estimation derived from the Kaplan-Meier algorithm and does not represent a dimple percentage of participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Median Time | Treatment + follow-up (3 years from database lock) | Progression free survival time was considered from start of treatment until the first observation of disease progression or death from any cause, whichever occurred first. All patients (ITT). |
| Progression Free Survival (PFS) Median Time for Resected Patients | Treatment + follow-up (3 years from database lock) | Progression free survival time was considered from start of treatment until the first observation of disease progression or death from any cause, whichever occurred first. This is the subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment or after progression on treatment were not considered as 'resected for metastatic lesions on study'. Patients were not censored at time of surgery. |
| Progression Free Survival (PFS) Time for Resected Versus Non-resected Patients (Hazard Ratio) | Treatment + follow-up (3 years from database lock) | Progression free survival time was considered from start of treatment until the first observation of disease progression or death from any cause, whichever occurred first. This is the subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment or after progression on treatment were not considered as 'resected for metastatic lesions on study'. Patients were not censored at time of surgery. |
| Death Rates by 3 Years Follow-up | Treatment + follow-up (3 years from database lock) | Deaths by 3 years follow-up after last cetuximab administration + 30 days. All patients (ITT). |
| Overall Survival (OS) Median Time | Treatment + follow-up (3 years from database lock) | Overall survival was considered from start of treatment to death. All patients (ITT). |
| Overall Survival (OS) Median Time for Resected Patients | Treatment + follow-up (3 years from database lock) | Overall survival was considered from start of treatment to death. Subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment (600-01-006 and 600-04-006) or after progression (100-02-002, End point description: Clinical trial results 2009-009992-36 version 1 EU-CTR publication date: Page 15 of 38 200-03-001, and 600-01-038) were not considered as 'resected for metastatic lesions on study. |
| Overall Response | Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months. | Overall response is defined as the best tumor response on treatment of either complete response (CR) or partial response (PR) (CR + PR). Tumor response is based on the CT/MRI assessments of target and non-target lesions as well as considering the occurrence of new lesions as per RECIST criteria. All patients (ITT). |
| Overall Response in Patients With Liver-limited Disease | Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months. | Overall response is defined as the best tumor response on treatment of either complete response (CR) or partial response (PR) (CR + PR). Tumor response is based on the imaging (CT/MRI) assessments of target and non-target lesions as well as considering the occurrence of new lesions as per RECIST criteria. Subset of patients with liver-limited disease. |
| Disease Control | Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months. | Disease control is defined as a best response on treatment (e.g. till end of treatment evaluation) of either complete response (CR), partial response (PR), or stable disease (SD) (CR + PR + SD). RECIST criteria (CT/MRI). All patients (ITT). |
| Disease Control in Patients With Liver-limited Disease | Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months. | Disease control is defined as a best response on treatment (e.g. till end of treatment evaluation) of either complete response (CR), partial response (PR), or stable disease (SD) (CR + PR + SD). RECIST criteria (CT/MRI). Subset of patients with liver-limited disease. |
| Duration of Response | Treatment + follow-up (3 years from database lock) | The duration of response in responding patients is defined as the time interval from the time measurement criteria are first met for CR/PR during treatment to either the first time disease progression is documented or death. Subset of responders. |
| Duration of Response in Liver-limited Disease Patients | Treatment + follow-up (3 years from database lock) | The duration of response in responding patients is defined as the time interval from the time measurement criteria are first met for CR/PR during treatment to either the first time disease progression is documented or death. Subset of responders among patients with liver-limited disease. |
| Resections for Metastatic Lesions | Treatment + follow-up (3 years from database lock) | All patients were deemed non-resectable at baseline but some became resectable during or posttreatment. All patients (ITT). Only those patients in whom resection of secondary lesions with curative intent was performed were considered as 'resected'. Patients resected after they started subsequent anti-cancer treatment (600-01-006 and 600-04-006) or after progression (100-02-002, 200-03-001, and 600-01-038) were not considered as 'resected for metastatic lesions on study'. |
| R0 Rate (Free of Tumor After Resection for Metastatic Lesions) | Treatment + follow-up (3 years from database lock) | Rate of patients free of tumor after surgery. Subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment (600-01-006 and 600-04-006) or after progression (100-02-002, 200-03-001, and 600-01- 038) were not considered as 'resected for metastatic lesions on study'. |
| Skin Toxicity (Safety) | From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months. | Treatment-emergent adverse events identified by the investigator as skin reaction or events with description skin infection or nail infection. Grading of severity was per NCI CTCAE version 4.0. All events are summarized based on the timing of occurrence per Arm in the first two rows, and worst grade per patient events are presented (following 3 rows). Grade 0 is the absence of any skin reaction and grade 3 is worst severity. All patients treated (Safety set). Note: There were 3 deviations from arm allocation rules based on the occurrence of skin toxicity. Detailed data is available upon request. |
| Laboratory Safety Assessments | From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months. | Severe laboratory abnormalities (hematology and biochemistry grade 3 and higher). Worst grade per patient. All patients treated (Safety set). |
| Deaths Till 30 Days From Last Cetuximab Administration | From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months. | Deaths of all causes occuring between the signature of consent and the date of last cetuximab administration + 30 days are listed per arm. None of these fatalities were deemed related to the investigational drug. |
Countries
Austria, Belgium, France, Hungary, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A - Dose Escalation of Cetuximab Patients with no cetuximab-related skin toxicity or other significant toxicity after first 3 weeks of treatment with cetuximab standard dosing in combination with FOLFIRI, in whom cetuximab doses were increased at day 22.
Dose escalation of cetuximab: Dose, frequency & treatment mode: 400 mg/m2 (loading at day 1) followed by 250 mg/m2 weekly (at day 8 and 15)
Arm allocation at day 22:
Patients with skin toxicity grade 0 will follow an increasing dose schedule: on days 22 and 29 they will receive 350 mg/m2 and from day 36 onwards, 500 mg/m2 weekly | 8 |
| Arm B - Standard Dose of Cetuximab Patients with any grade cetuximab-related skin toxicity or other significant toxicity after first 3 weeks of treatment with cetuximab standard dosing in combination with FOLFIRI, in whom cetuximab doses were maintained at standard levels at day 22.
Standard first line treatment with cetuximab + Folfiri: Dose, frequency & treatment mode: 400 mg/m2 (loading at day 1) followed by 250 mg/m2 weekly (at day 8 and 15)
Arm allocation at day 22:
Patients with skin toxicity grade 1-4 or other significant toxicity who are not eligible for dose escalation will continue on the standard dose of cetuximab: 250 mg/m2 weekly. | 93 |
| Not Allocated Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 7 |
| Total | 108 |
Baseline characteristics
| Characteristic | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 6 Participants | 24 Participants | 2 Participants | 32 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 69 Participants | 5 Participants | 76 Participants |
| Age, Continuous | 66 years | 60 years | 64 years | 60 years |
| Diastolic blood pressure | 68.9 mmHg | 78.8 mmHg | 78.7 mmHg | 78.1 mmHg |
| ECOG PS PS = 0 | 6 Participants | 48 Participants | 1 Participants | 55 Participants |
| ECOG PS PS = 1 | 2 Participants | 45 Participants | 6 Participants | 53 Participants |
| Heart rate | 76.7 Bpm | 77.7 Bpm | 84.5 Bpm | 78 Bpm |
| Index lesions 1 location | 4 Participants | 44 Participants | 4 Participants | 52 Participants |
| Index lesions 2 locations | 2 Participants | 28 Participants | 1 Participants | 31 Participants |
| Index lesions >= 3 locations | 2 Participants | 21 Participants | 2 Participants | 25 Participants |
| Metastases Liver only | 4 Participants | 39 Participants | 2 Participants | 45 Participants |
| Metastases Liver + other | 4 Participants | 45 Participants | 2 Participants | 51 Participants |
| Metastases Other (no liver) | 0 Participants | 9 Participants | 3 Participants | 12 Participants |
| Nodal stage N0 | 2 Participants | 7 Participants | 2 Participants | 11 Participants |
| Nodal stage N1 | 0 Participants | 24 Participants | 0 Participants | 24 Participants |
| Nodal stage N2 | 3 Participants | 34 Participants | 2 Participants | 39 Participants |
| Nodal stage Nx | 3 Participants | 28 Participants | 3 Participants | 34 Participants |
| Primary tumour Colon left | 2 Participants | 47 Participants | 5 Participants | 54 Participants |
| Primary tumour Colon right | 2 Participants | 16 Participants | 0 Participants | 18 Participants |
| Primary tumour Rectum | 4 Participants | 30 Participants | 2 Participants | 36 Participants |
| Prior cancer treatment Chemotherapy only | 0 Participants | 4 Participants | 1 Participants | 5 Participants |
| Prior cancer treatment No prior cancer treatment | 5 Participants | 73 Participants | 6 Participants | 84 Participants |
| Prior cancer treatment Other / Combinations | 2 Participants | 5 Participants | 0 Participants | 7 Participants |
| Prior cancer treatment Radiotherapy only | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Prior cancer treatment Surgery for primary tumor | 1 Participants | 10 Participants | 0 Participants | 11 Participants |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Region of Enrollment Austria | 0 participants | 4 participants | 0 participants | 4 participants |
| Region of Enrollment Belgium | 6 participants | 18 participants | 0 participants | 24 participants |
| Region of Enrollment France | 0 participants | 5 participants | 2 participants | 7 participants |
| Region of Enrollment Hungary | 0 participants | 20 participants | 2 participants | 22 participants |
| Region of Enrollment Spain | 2 participants | 46 participants | 3 participants | 51 participants |
| Sex: Female, Male Female | 5 Participants | 24 Participants | 1 Participants | 30 Participants |
| Sex: Female, Male Male | 3 Participants | 69 Participants | 6 Participants | 78 Participants |
| Systollic blood pressure | 120.9 mmHg | 129.7 mmHg | 126.6 mmHg | 128.9 mmHg |
| Tumour stage T1 | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Tumour stage T2 | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Tumour stage T3 | 2 Participants | 46 Participants | 2 Participants | 50 Participants |
| Tumour stage T4 | 4 Participants | 27 Participants | 4 Participants | 35 Participants |
| Tumour stage Tx | 2 Participants | 16 Participants | 1 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 8 | 6 / 93 | 2 / 7 |
| other Total, other adverse events | 6 / 8 | 66 / 93 | 3 / 7 |
| serious Total, serious adverse events | 6 / 8 | 39 / 93 | 6 / 7 |
Outcome results
Primary
PFS Probability Rate at 9 Months in the Dose Escalation Arm
A precise estimate (+/- 10%) of the probability of not having progression at 9 months. This measure is an estimation derived from the Kaplan-Meier algorithm and does not represent a dimple percentage of participants.
Time frame: 9 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Dose Escalation of Cetuximab | PFS Probability Rate at 9 Months in the Dose Escalation Arm | 45 percent probability |
| Arm B - Standard Dose of Cetuximab | PFS Probability Rate at 9 Months in the Dose Escalation Arm | 48 percent probability |
| Not Allocated | PFS Probability Rate at 9 Months in the Dose Escalation Arm | 0 percent probability |
| ITT / Safety Set | PFS Probability Rate at 9 Months in the Dose Escalation Arm | 55 percent probability |
Secondary
Death Rates by 3 Years Follow-up
Deaths by 3 years follow-up after last cetuximab administration + 30 days. All patients (ITT).
Time frame: Treatment + follow-up (3 years from database lock)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Death Rates by 3 Years Follow-up | Deceased | 6 Participants |
| Arm A - Dose Escalation of Cetuximab | Death Rates by 3 Years Follow-up | Lost to follow-up before 3 years followup | 0 Participants |
| Arm A - Dose Escalation of Cetuximab | Death Rates by 3 Years Follow-up | Alive after 3 years follow-up | 2 Participants |
| Arm B - Standard Dose of Cetuximab | Death Rates by 3 Years Follow-up | Deceased | 65 Participants |
| Arm B - Standard Dose of Cetuximab | Death Rates by 3 Years Follow-up | Lost to follow-up before 3 years followup | 12 Participants |
| Arm B - Standard Dose of Cetuximab | Death Rates by 3 Years Follow-up | Alive after 3 years follow-up | 16 Participants |
| Not Allocated | Death Rates by 3 Years Follow-up | Alive after 3 years follow-up | 0 Participants |
| Not Allocated | Death Rates by 3 Years Follow-up | Deceased | 7 Participants |
| Not Allocated | Death Rates by 3 Years Follow-up | Lost to follow-up before 3 years followup | 0 Participants |
| ITT / Safety Set | Death Rates by 3 Years Follow-up | Deceased | 78 Participants |
| ITT / Safety Set | Death Rates by 3 Years Follow-up | Lost to follow-up before 3 years followup | 12 Participants |
| ITT / Safety Set | Death Rates by 3 Years Follow-up | Alive after 3 years follow-up | 18 Participants |
Secondary
Deaths Till 30 Days From Last Cetuximab Administration
Deaths of all causes occuring between the signature of consent and the date of last cetuximab administration + 30 days are listed per arm. None of these fatalities were deemed related to the investigational drug.
Time frame: From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | All causes | 1 participants |
| Arm A - Dose Escalation of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Colonic perforation | 1 participants |
| Arm A - Dose Escalation of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Malaise | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Bronchial infection | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Lung infection | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Circulatory failure | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Cardiac arrest | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Colonic obstruction | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Peritoneal infection | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Ileus | 0 participants |
| Arm B - Standard Dose of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Malaise | 1 participants |
| Arm B - Standard Dose of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Peritoneal infection | 0 participants |
| Arm B - Standard Dose of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Bronchial infection | 1 participants |
| Arm B - Standard Dose of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Lung infection | 1 participants |
| Arm B - Standard Dose of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Circulatory failure | 1 participants |
| Arm B - Standard Dose of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Cardiac arrest | 1 participants |
| Arm B - Standard Dose of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Ileus | 0 participants |
| Arm B - Standard Dose of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Colonic obstruction | 1 participants |
| Arm B - Standard Dose of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | All causes | 6 participants |
| Arm B - Standard Dose of Cetuximab | Deaths Till 30 Days From Last Cetuximab Administration | Colonic perforation | 0 participants |
| Not Allocated | Deaths Till 30 Days From Last Cetuximab Administration | Colonic obstruction | 0 participants |
| Not Allocated | Deaths Till 30 Days From Last Cetuximab Administration | Cardiac arrest | 0 participants |
| Not Allocated | Deaths Till 30 Days From Last Cetuximab Administration | Ileus | 1 participants |
| Not Allocated | Deaths Till 30 Days From Last Cetuximab Administration | All causes | 2 participants |
| Not Allocated | Deaths Till 30 Days From Last Cetuximab Administration | Bronchial infection | 0 participants |
| Not Allocated | Deaths Till 30 Days From Last Cetuximab Administration | Circulatory failure | 0 participants |
| Not Allocated | Deaths Till 30 Days From Last Cetuximab Administration | Peritoneal infection | 1 participants |
| Not Allocated | Deaths Till 30 Days From Last Cetuximab Administration | Colonic perforation | 0 participants |
| Not Allocated | Deaths Till 30 Days From Last Cetuximab Administration | Lung infection | 0 participants |
| Not Allocated | Deaths Till 30 Days From Last Cetuximab Administration | Malaise | 0 participants |
| ITT / Safety Set | Deaths Till 30 Days From Last Cetuximab Administration | Lung infection | 1 participants |
| ITT / Safety Set | Deaths Till 30 Days From Last Cetuximab Administration | Colonic obstruction | 1 participants |
| ITT / Safety Set | Deaths Till 30 Days From Last Cetuximab Administration | Circulatory failure | 1 participants |
| ITT / Safety Set | Deaths Till 30 Days From Last Cetuximab Administration | Ileus | 1 participants |
| ITT / Safety Set | Deaths Till 30 Days From Last Cetuximab Administration | Cardiac arrest | 1 participants |
| ITT / Safety Set | Deaths Till 30 Days From Last Cetuximab Administration | Colonic perforation | 1 participants |
| ITT / Safety Set | Deaths Till 30 Days From Last Cetuximab Administration | Malaise | 1 participants |
| ITT / Safety Set | Deaths Till 30 Days From Last Cetuximab Administration | Bronchial infection | 1 participants |
| ITT / Safety Set | Deaths Till 30 Days From Last Cetuximab Administration | All causes | 9 participants |
| ITT / Safety Set | Deaths Till 30 Days From Last Cetuximab Administration | Peritoneal infection | 1 participants |
Secondary
Disease Control
Disease control is defined as a best response on treatment (e.g. till end of treatment evaluation) of either complete response (CR), partial response (PR), or stable disease (SD) (CR + PR + SD). RECIST criteria (CT/MRI). All patients (ITT).
Time frame: Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Disease Control | Other (PD, not evaluable, missing) | 0 Participants |
| Arm A - Dose Escalation of Cetuximab | Disease Control | CR, PR, or SD | 8 Participants |
| Arm B - Standard Dose of Cetuximab | Disease Control | Other (PD, not evaluable, missing) | 9 Participants |
| Arm B - Standard Dose of Cetuximab | Disease Control | CR, PR, or SD | 84 Participants |
| Not Allocated | Disease Control | CR, PR, or SD | 0 Participants |
| Not Allocated | Disease Control | Other (PD, not evaluable, missing) | 7 Participants |
| ITT / Safety Set | Disease Control | Other (PD, not evaluable, missing) | 16 Participants |
| ITT / Safety Set | Disease Control | CR, PR, or SD | 92 Participants |
Secondary
Disease Control in Patients With Liver-limited Disease
Disease control is defined as a best response on treatment (e.g. till end of treatment evaluation) of either complete response (CR), partial response (PR), or stable disease (SD) (CR + PR + SD). RECIST criteria (CT/MRI). Subset of patients with liver-limited disease.
Time frame: Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Disease Control in Patients With Liver-limited Disease | CR, PR, or SD | 4 Participants |
| Arm A - Dose Escalation of Cetuximab | Disease Control in Patients With Liver-limited Disease | Other (PD, missing) | 0 Participants |
| Arm B - Standard Dose of Cetuximab | Disease Control in Patients With Liver-limited Disease | Other (PD, missing) | 2 Participants |
| Arm B - Standard Dose of Cetuximab | Disease Control in Patients With Liver-limited Disease | CR, PR, or SD | 37 Participants |
| Not Allocated | Disease Control in Patients With Liver-limited Disease | CR, PR, or SD | 0 Participants |
| Not Allocated | Disease Control in Patients With Liver-limited Disease | Other (PD, missing) | 2 Participants |
| ITT / Safety Set | Disease Control in Patients With Liver-limited Disease | CR, PR, or SD | 41 Participants |
| ITT / Safety Set | Disease Control in Patients With Liver-limited Disease | Other (PD, missing) | 4 Participants |
Secondary
Duration of Response
The duration of response in responding patients is defined as the time interval from the time measurement criteria are first met for CR/PR during treatment to either the first time disease progression is documented or death. Subset of responders.
Time frame: Treatment + follow-up (3 years from database lock)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Duration of Response | 8.3 Months |
| Arm B - Standard Dose of Cetuximab | Duration of Response | 11.7 Months |
| Not Allocated | Duration of Response | 11.7 Months |
Secondary
Duration of Response in Liver-limited Disease Patients
The duration of response in responding patients is defined as the time interval from the time measurement criteria are first met for CR/PR during treatment to either the first time disease progression is documented or death. Subset of responders among patients with liver-limited disease.
Time frame: Treatment + follow-up (3 years from database lock)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Duration of Response in Liver-limited Disease Patients | 13.9 Months |
| Arm B - Standard Dose of Cetuximab | Duration of Response in Liver-limited Disease Patients | 11.1 Months |
| Not Allocated | Duration of Response in Liver-limited Disease Patients | 11.1 Months |
Secondary
Laboratory Safety Assessments
Severe laboratory abnormalities (hematology and biochemistry grade 3 and higher). Worst grade per patient. All patients treated (Safety set).
Time frame: From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | Potassium decreased | 2 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | Bilirubin increased | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | Neutrophils decreased | 3 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | Sodium decreased | 1 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | ALAT increased | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | White blood cell count decreased | 3 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | ALP increased | 2 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | ASAT increased | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | Magnesium decreased | 1 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | Lymphocytes decreased | 2 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | Serum calcium decreased | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | Hemoglobin decreased | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | Platelet count decreased | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Laboratory Safety Assessments | Magnesium increased | 0 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | Potassium decreased | 7 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | Hemoglobin decreased | 3 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | White blood cell count decreased | 8 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | Neutrophils decreased | 19 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | Lymphocytes decreased | 6 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | Platelet count decreased | 2 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | Bilirubin increased | 3 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | ALAT increased | 2 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | ASAT increased | 1 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | ALP increased | 4 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | Sodium decreased | 3 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | Magnesium decreased | 2 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | Magnesium increased | 1 participants |
| Arm B - Standard Dose of Cetuximab | Laboratory Safety Assessments | Serum calcium decreased | 2 participants |
| Not Allocated | Laboratory Safety Assessments | Magnesium increased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | Sodium decreased | 1 participants |
| Not Allocated | Laboratory Safety Assessments | Platelet count decreased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | Lymphocytes decreased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | Potassium decreased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | Neutrophils decreased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | Hemoglobin decreased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | Magnesium decreased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | White blood cell count decreased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | ASAT increased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | ALAT increased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | Serum calcium decreased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | ALP increased | 0 participants |
| Not Allocated | Laboratory Safety Assessments | Bilirubin increased | 0 participants |
Secondary
Overall Response
Overall response is defined as the best tumor response on treatment of either complete response (CR) or partial response (PR) (CR + PR). Tumor response is based on the CT/MRI assessments of target and non-target lesions as well as considering the occurrence of new lesions as per RECIST criteria. All patients (ITT).
Time frame: Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Overall Response | CR or PR | 6 Participants |
| Arm A - Dose Escalation of Cetuximab | Overall Response | Other (SD, PD, not evaluable, missing) | 2 Participants |
| Arm B - Standard Dose of Cetuximab | Overall Response | Other (SD, PD, not evaluable, missing) | 29 Participants |
| Arm B - Standard Dose of Cetuximab | Overall Response | CR or PR | 64 Participants |
| Not Allocated | Overall Response | CR or PR | 0 Participants |
| Not Allocated | Overall Response | Other (SD, PD, not evaluable, missing) | 7 Participants |
| ITT / Safety Set | Overall Response | CR or PR | 70 Participants |
| ITT / Safety Set | Overall Response | Other (SD, PD, not evaluable, missing) | 38 Participants |
Secondary
Overall Response in Patients With Liver-limited Disease
Overall response is defined as the best tumor response on treatment of either complete response (CR) or partial response (PR) (CR + PR). Tumor response is based on the imaging (CT/MRI) assessments of target and non-target lesions as well as considering the occurrence of new lesions as per RECIST criteria. Subset of patients with liver-limited disease.
Time frame: Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Overall Response in Patients With Liver-limited Disease | CR or PR | 2 Participants |
| Arm A - Dose Escalation of Cetuximab | Overall Response in Patients With Liver-limited Disease | Other (SD, PD, missing) | 2 Participants |
| Arm B - Standard Dose of Cetuximab | Overall Response in Patients With Liver-limited Disease | Other (SD, PD, missing) | 9 Participants |
| Arm B - Standard Dose of Cetuximab | Overall Response in Patients With Liver-limited Disease | CR or PR | 30 Participants |
| Not Allocated | Overall Response in Patients With Liver-limited Disease | CR or PR | 0 Participants |
| Not Allocated | Overall Response in Patients With Liver-limited Disease | Other (SD, PD, missing) | 2 Participants |
| ITT / Safety Set | Overall Response in Patients With Liver-limited Disease | CR or PR | 32 Participants |
| ITT / Safety Set | Overall Response in Patients With Liver-limited Disease | Other (SD, PD, missing) | 13 Participants |
Secondary
Overall Survival (OS) Median Time
Overall survival was considered from start of treatment to death. All patients (ITT).
Time frame: Treatment + follow-up (3 years from database lock)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Overall Survival (OS) Median Time | 28.4 months |
| Arm B - Standard Dose of Cetuximab | Overall Survival (OS) Median Time | 31.4 months |
| Not Allocated | Overall Survival (OS) Median Time | 4.9 months |
| ITT / Safety Set | Overall Survival (OS) Median Time | 29.8 months |
Secondary
Overall Survival (OS) Median Time for Resected Patients
Overall survival was considered from start of treatment to death. Subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment (600-01-006 and 600-04-006) or after progression (100-02-002, End point description: Clinical trial results 2009-009992-36 version 1 EU-CTR publication date: Page 15 of 38 200-03-001, and 600-01-038) were not considered as 'resected for metastatic lesions on study.
Time frame: Treatment + follow-up (3 years from database lock)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Overall Survival (OS) Median Time for Resected Patients | NA Months |
| Arm B - Standard Dose of Cetuximab | Overall Survival (OS) Median Time for Resected Patients | NA Months |
| Not Allocated | Overall Survival (OS) Median Time for Resected Patients | NA Months |
Secondary
Progression Free Survival (PFS) Median Time
Progression free survival time was considered from start of treatment until the first observation of disease progression or death from any cause, whichever occurred first. All patients (ITT).
Time frame: Treatment + follow-up (3 years from database lock)
Population: All patients for whom there was evidence they were administered any dose of cetuximab or FOLFIRI on study. For this study, the safety set includes all patients and is identical to the intention-to-treat (ITT) set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Progression Free Survival (PFS) Median Time | 8.8 Months |
| Arm B - Standard Dose of Cetuximab | Progression Free Survival (PFS) Median Time | 11.5 Months |
| Not Allocated | Progression Free Survival (PFS) Median Time | 1.3 Months |
| ITT / Safety Set | Progression Free Survival (PFS) Median Time | 10.7 Months |
Secondary
Progression Free Survival (PFS) Median Time for Resected Patients
Progression free survival time was considered from start of treatment until the first observation of disease progression or death from any cause, whichever occurred first. This is the subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment or after progression on treatment were not considered as 'resected for metastatic lesions on study'. Patients were not censored at time of surgery.
Time frame: Treatment + follow-up (3 years from database lock)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Progression Free Survival (PFS) Median Time for Resected Patients | 11.3 Months |
| Arm B - Standard Dose of Cetuximab | Progression Free Survival (PFS) Median Time for Resected Patients | 14.5 Months |
| Not Allocated | Progression Free Survival (PFS) Median Time for Resected Patients | 14.2 Months |
Secondary
Progression Free Survival (PFS) Time for Resected Versus Non-resected Patients (Hazard Ratio)
Progression free survival time was considered from start of treatment until the first observation of disease progression or death from any cause, whichever occurred first. This is the subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment or after progression on treatment were not considered as 'resected for metastatic lesions on study'. Patients were not censored at time of surgery.
Time frame: Treatment + follow-up (3 years from database lock)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Progression Free Survival (PFS) Time for Resected Versus Non-resected Patients (Hazard Ratio) | 1.17 Hazard ratio |
| Arm B - Standard Dose of Cetuximab | Progression Free Survival (PFS) Time for Resected Versus Non-resected Patients (Hazard Ratio) | 0.82 Hazard ratio |
| Not Allocated | Progression Free Survival (PFS) Time for Resected Versus Non-resected Patients (Hazard Ratio) | NA Hazard ratio |
| ITT / Safety Set | Progression Free Survival (PFS) Time for Resected Versus Non-resected Patients (Hazard Ratio) | 0.79 Hazard ratio |
Secondary
R0 Rate (Free of Tumor After Resection for Metastatic Lesions)
Rate of patients free of tumor after surgery. Subset of resected patients (resection of secondary lesions with curative intent was performed). Patients resected after they started subsequent anti-cancer treatment (600-01-006 and 600-04-006) or after progression (100-02-002, 200-03-001, and 600-01- 038) were not considered as 'resected for metastatic lesions on study'.
Time frame: Treatment + follow-up (3 years from database lock)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A - Dose Escalation of Cetuximab | R0 Rate (Free of Tumor After Resection for Metastatic Lesions) | Free of tumor | 1 Participants |
| Arm A - Dose Escalation of Cetuximab | R0 Rate (Free of Tumor After Resection for Metastatic Lesions) | Not free of tumor | 0 Participants |
| Arm B - Standard Dose of Cetuximab | R0 Rate (Free of Tumor After Resection for Metastatic Lesions) | Free of tumor | 12 Participants |
| Arm B - Standard Dose of Cetuximab | R0 Rate (Free of Tumor After Resection for Metastatic Lesions) | Not free of tumor | 4 Participants |
| Not Allocated | R0 Rate (Free of Tumor After Resection for Metastatic Lesions) | Free of tumor | 13 Participants |
| Not Allocated | R0 Rate (Free of Tumor After Resection for Metastatic Lesions) | Not free of tumor | 4 Participants |
Secondary
Resections for Metastatic Lesions
All patients were deemed non-resectable at baseline but some became resectable during or posttreatment. All patients (ITT). Only those patients in whom resection of secondary lesions with curative intent was performed were considered as 'resected'. Patients resected after they started subsequent anti-cancer treatment (600-01-006 and 600-04-006) or after progression (100-02-002, 200-03-001, and 600-01-038) were not considered as 'resected for metastatic lesions on study'.
Time frame: Treatment + follow-up (3 years from database lock)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Resections for Metastatic Lesions | Resected (surgery with curative intent performed) | 1 Participants |
| Arm A - Dose Escalation of Cetuximab | Resections for Metastatic Lesions | Non-resected | 7 Participants |
| Arm B - Standard Dose of Cetuximab | Resections for Metastatic Lesions | Non-resected | 77 Participants |
| Arm B - Standard Dose of Cetuximab | Resections for Metastatic Lesions | Resected (surgery with curative intent performed) | 16 Participants |
| Not Allocated | Resections for Metastatic Lesions | Resected (surgery with curative intent performed) | 0 Participants |
| Not Allocated | Resections for Metastatic Lesions | Non-resected | 7 Participants |
| ITT / Safety Set | Resections for Metastatic Lesions | Resected (surgery with curative intent performed) | 17 Participants |
| ITT / Safety Set | Resections for Metastatic Lesions | Non-resected | 91 Participants |
Secondary
Skin Toxicity (Safety)
Treatment-emergent adverse events identified by the investigator as skin reaction or events with description skin infection or nail infection. Grading of severity was per NCI CTCAE version 4.0. All events are summarized based on the timing of occurrence per Arm in the first two rows, and worst grade per patient events are presented (following 3 rows). Grade 0 is the absence of any skin reaction and grade 3 is worst severity. All patients treated (Safety set). Note: There were 3 deviations from arm allocation rules based on the occurrence of skin toxicity. Detailed data is available upon request.
Time frame: From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A - Dose Escalation of Cetuximab | Skin Toxicity (Safety) | Grade 3 | 2 participants |
| Arm A - Dose Escalation of Cetuximab | Skin Toxicity (Safety) | Any (onset prior to arm allocation) | 2 participants |
| Arm A - Dose Escalation of Cetuximab | Skin Toxicity (Safety) | Any (all times) | 7 participants |
| Arm A - Dose Escalation of Cetuximab | Skin Toxicity (Safety) | Grade 1 | 0 participants |
| Arm A - Dose Escalation of Cetuximab | Skin Toxicity (Safety) | Grade 2 | 5 participants |
| Arm B - Standard Dose of Cetuximab | Skin Toxicity (Safety) | Grade 1 | 19 participants |
| Arm B - Standard Dose of Cetuximab | Skin Toxicity (Safety) | Grade 2 | 44 participants |
| Arm B - Standard Dose of Cetuximab | Skin Toxicity (Safety) | Any (onset prior to arm allocation) | 92 participants |
| Arm B - Standard Dose of Cetuximab | Skin Toxicity (Safety) | Grade 3 | 30 participants |
| Arm B - Standard Dose of Cetuximab | Skin Toxicity (Safety) | Any (all times) | 93 participants |
| Not Allocated | Skin Toxicity (Safety) | Grade 2 | 1 participants |
| Not Allocated | Skin Toxicity (Safety) | Any (all times) | 3 participants |
| Not Allocated | Skin Toxicity (Safety) | Grade 1 | 2 participants |
| Not Allocated | Skin Toxicity (Safety) | Grade 3 | 0 participants |
| Not Allocated | Skin Toxicity (Safety) | Any (onset prior to arm allocation) | 3 participants |