Everest2: Cetuximab Standard or Dose Escalation in First Line Colorectal Cancer
Sponsor
Universitaire Ziekenhuizen Leuven (Other)
Overall Status
Completed
CT.gov ID
NCT01251536
Collaborator
Merck KGaA, Darmstadt, Germany (Industry)
108
30
2
103
3.6
0
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Study Type:
Interventional
Actual Enrollment
:
108 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Two Arm Phase II Study of FOLFIRI in Combination With Standard or Escalating Dose of Cetuximab as First Line Treatment of K-Ras Wild Type Metastatic Colorectal Cancer: Everest 2
Actual Study Start Date
:
Dec 1, 2010
Actual Primary Completion Date
:
Jun 1, 2016
Actual Study Completion Date
:
Jul 1, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Arm B - standard dose of cetuximab 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. No comparison between arms was planned. |
Drug: 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.
Other Names:
|
| Experimental: Arm A - dose escalation of cetuximab 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. |
Drug: 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
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Written informed consent (+ optional for PK and TR) must be given according to ICH/GCP and national/local regulations.
-
Patient is at least 18 years of age.
-
Patient's body weight is ≤ 120 kg.
-
Histologically proven and measurable (RECIST criteria v.1.1) metastatic adenocarcinoma of the colon or rectum, not in a previously irradiated area.
-
K-Ras wild type tumour eligible for treatment with cetuximab.
-
Unresectable metastatic disease.
-
Life expectancy of at least 12 weeks.
-
WHO ECOG performance status: 0 or 1.
-
Effective contraception for both male and female patients if the risk of conception exists.
-
Adequate organ function.
-
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:
-
Prior treatment for metastatic disease (adjuvant therapy with fluoropyrimidines +/-oxaliplatin based regimens allowed if stopped 6 months prior to registration on study).
-
Prior treatment with EGFR inhibitor or chemotherapy with irinotecan in adjuvant settings.
-
Surgery (excluding diagnostic biopsy) or irradiation within 4 weeks prior to study entry.
-
Administration of any investigational drug or agent/procedure, i.e. participation in another trial within 4 weeks before beginning treatment.
-
Concurrent chronic systemic immune therapy, chemotherapy, radiation therapy or hormone therapy not indicated in the study protocol.
-
Any active dermatological condition > grade 1.
-
Brain metastasis (known or suspected).
-
Significant impairment of intestinal absorption (e.g. chronic diarrhea, inflammatory bowel disease).
-
Other uncontrolled concomitant illness, including serious uncontrolled intercurrent infection.
-
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.
-
Known allergy or any other adverse reaction to any of the drugs or to any related compound.
-
Known dihydropyrimidine dehydrogenase (DPD) deficiency.
-
Gilbert disease.
-
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.
-
Organ allografts requiring immunosuppressive therapy.
-
Pregnancy (absence confirmed by serum/urine beta human choriongonadotrophin in pre-menopausal women) or breast-feeding.
-
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Universitätsklinik für Innere medizin, Klinishe abteilung für hämatologie und Onkologie | Innsbruck | Austria | ||
| 2 | LKH Leoben, abteilung f. innere Medizin | Leoben | Austria | ||
| 3 | AKH Linz, Innere Medizin 3, Zentrum für Hämatologie und medizinishe Onkologie | Linz | Austria | ||
| 4 | Landeskrankenhaus Salzburg, Univ. Klinik für innere Medizin III, Universitätsklinikum der PMU | Salzburg | Austria | ||
| 5 | Krankenanstalt Rudolfstiftung, 1 medizinishe Abteilung | Wien | Austria | ||
| 6 | St Vincent Krankenhaus Betriebs GmbH | Zams | Austria | ||
| 7 | Imelda Ziekenhuis | Bonheiden | Belgium | ||
| 8 | Erasme Hospital | Brussels | Belgium | 1070 | |
| 9 | Cliniques Universitaires St Luc | Brussels | Belgium | 1200 | |
| 10 | AZ Middelares Gent | Gent | Belgium | ||
| 11 | UZ Gent | Gent | Belgium | ||
| 12 | Centre Hospitalier de Jolimont-Lobbes, Oncology Médicale | Haine Saint Paul | Belgium | ||
| 13 | AZ Groeninge | Kortrijk | Belgium | 8500 | |
| 14 | UZ Gasthuisberg | Leuven | Belgium | 3000 | |
| 15 | CHC Saint Joseph | Liege | Belgium | ||
| 16 | AZ Sint Maarten Mechelen/Duffel | Mechelen | Belgium | ||
| 17 | H. Hartziekenhuis | Roeselare | Belgium | 8800 | |
| 18 | AZ Turnhout (Campus St Elisabeth) | Turnhout | Belgium | ||
| 19 | Hôpital Avicennes | Bobigny | France | ||
| 20 | Hôpital Saint-André | Bordeaux | France | 33000 | |
| 21 | Hopital Européen Georges Pompidou | Paris | France | 75015 | |
| 22 | Centre Eugène Marquis | Rennes Cedex | France | 35042 | |
| 23 | CHU Charles Nicolle | Rouen | France | 76031 | |
| 24 | State Health Center | Budapest | Hungary | 1062 | |
| 25 | Medical Center of the University of Pecs , National Institute Oncology | Budapest | Hungary | 1122 | |
| 26 | Hospital Universitari Vall d'Hebron | Barcelona | Spain | 8035 | |
| 27 | Institut Català d'Oncologia | Barcelona | Spain | ||
| 28 | Hospital Universitario Marqués de Valdecilla | Santander | Spain | ||
| 29 | Hospital Universitario Virgen del Rocío | Sevilla | Spain | ||
| 30 | Hospital Clinico Universitario De Valencia | Valencia | Spain |
Sponsors and Collaborators
- Universitaire Ziekenhuizen Leuven
- Merck KGaA, Darmstadt, Germany
Investigators
- Principal Investigator: Eric Van Cutsem, MD, UZ Leuven
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier:
NCT01251536
Other Study ID Numbers:
- S51532
- 2009-009992-36
First Posted:
Dec 2, 2010
Last Update Posted:
Oct 11, 2019
Last Verified:
Oct 1, 2019
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Keywords provided by Universitaire Ziekenhuizen Leuven
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated |
|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. |
| Period Title: Overall Study | |||
| STARTED | 8 | 93 | 7 |
| COMPLETED | 8 | 93 | 7 |
| NOT COMPLETED | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | Total |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | Total of all reporting groups |
| Overall Participants | 8 | 93 | 7 | 108 |
| Age (Count of Participants) | ||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
2
25%
|
69
74.2%
|
5
71.4%
|
76
70.4%
|
| >=65 years |
6
75%
|
24
25.8%
|
2
28.6%
|
32
29.6%
|
| Age (years) [Median (Full Range) ] | ||||
| Median (Full Range) [years] |
66
|
60
|
64
|
60
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
5
62.5%
|
24
25.8%
|
1
14.3%
|
30
27.8%
|
| Male |
3
37.5%
|
69
74.2%
|
6
85.7%
|
78
72.2%
|
| Race and Ethnicity Not Collected (Count of Participants) | ||||
| Count of Participants [Participants] |
0
0%
|
|||
| Region of Enrollment (participants) [Number] | ||||
| Austria |
0
0%
|
4
4.3%
|
0
0%
|
4
3.7%
|
| Belgium |
6
75%
|
18
19.4%
|
0
0%
|
24
22.2%
|
| Hungary |
0
0%
|
20
21.5%
|
2
28.6%
|
22
20.4%
|
| France |
0
0%
|
5
5.4%
|
2
28.6%
|
7
6.5%
|
| Spain |
2
25%
|
46
49.5%
|
3
42.9%
|
51
47.2%
|
| Primary tumour (Count of Participants) | ||||
| Colon right |
2
25%
|
16
17.2%
|
0
0%
|
18
16.7%
|
| Colon left |
2
25%
|
47
50.5%
|
5
71.4%
|
54
50%
|
| Rectum |
4
50%
|
30
32.3%
|
2
28.6%
|
36
33.3%
|
| Tumour stage (Count of Participants) | ||||
| T1 |
0
0%
|
2
2.2%
|
0
0%
|
2
1.9%
|
| T2 |
0
0%
|
2
2.2%
|
0
0%
|
2
1.9%
|
| T3 |
2
25%
|
46
49.5%
|
2
28.6%
|
50
46.3%
|
| T4 |
4
50%
|
27
29%
|
4
57.1%
|
35
32.4%
|
| Tx |
2
25%
|
16
17.2%
|
1
14.3%
|
19
17.6%
|
| Nodal stage (Count of Participants) | ||||
| N0 |
2
25%
|
7
7.5%
|
2
28.6%
|
11
10.2%
|
| N1 |
0
0%
|
24
25.8%
|
0
0%
|
24
22.2%
|
| N2 |
3
37.5%
|
34
36.6%
|
2
28.6%
|
39
36.1%
|
| Nx |
3
37.5%
|
28
30.1%
|
3
42.9%
|
34
31.5%
|
| ECOG PS (Count of Participants) | ||||
| PS = 0 |
6
75%
|
48
51.6%
|
1
14.3%
|
55
50.9%
|
| PS = 1 |
2
25%
|
45
48.4%
|
6
85.7%
|
53
49.1%
|
| Metastases (Count of Participants) | ||||
| Liver only |
4
50%
|
39
41.9%
|
2
28.6%
|
45
41.7%
|
| Liver + other |
4
50%
|
45
48.4%
|
2
28.6%
|
51
47.2%
|
| Other (no liver) |
0
0%
|
9
9.7%
|
3
42.9%
|
12
11.1%
|
| Index lesions (Count of Participants) | ||||
| 1 location |
4
50%
|
44
47.3%
|
4
57.1%
|
52
48.1%
|
| 2 locations |
2
25%
|
28
30.1%
|
1
14.3%
|
31
28.7%
|
| >= 3 locations |
2
25%
|
21
22.6%
|
2
28.6%
|
25
23.1%
|
| Prior cancer treatment (Count of Participants) | ||||
| Chemotherapy only |
0
0%
|
4
4.3%
|
1
14.3%
|
5
4.6%
|
| Radiotherapy only |
0
0%
|
1
1.1%
|
0
0%
|
1
0.9%
|
| Surgery for primary tumor |
1
12.5%
|
10
10.8%
|
0
0%
|
11
10.2%
|
| Other / Combinations |
2
25%
|
5
5.4%
|
0
0%
|
7
6.5%
|
| No prior cancer treatment |
5
62.5%
|
73
78.5%
|
6
85.7%
|
84
77.8%
|
| Heart rate (Bpm) [Mean (Full Range) ] | ||||
| Mean (Full Range) [Bpm] |
76.7
|
77.7
|
84.5
|
78
|
| Systollic blood pressure (mmHg) [Mean (Full Range) ] | ||||
| Mean (Full Range) [mmHg] |
120.9
|
129.7
|
126.6
|
128.9
|
| Diastolic blood pressure (mmHg) [Mean (Full Range) ] | ||||
| Mean (Full Range) [mmHg] |
68.9
|
78.8
|
78.7
|
78.1
|
Outcome Measures
| Title | PFS Probability Rate at 9 Months in the Dose Escalation Arm |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ITT / Safety Set |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 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. |
| Measure Participants | 8 | 93 | 7 | 108 |
| Number [percent probability] |
45
|
48
|
0
|
55
|
| Title | Progression Free Survival (PFS) Median Time |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ITT / Safety Set |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 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. |
| Measure Participants | 8 | 93 | 7 | 108 |
| Median (95% Confidence Interval) [Months] |
8.8
|
11.5
|
1.3
|
10.7
|
| Title | Progression Free Survival (PFS) Median Time for Resected Patients |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | ITT / Safety Set |
|---|---|---|---|
| Arm/Group Description | 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 | 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. | 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. |
| Measure Participants | 1 | 16 | 17 |
| Median (95% Confidence Interval) [Months] |
11.3
|
14.5
|
14.2
|
| Title | Progression Free Survival (PFS) Time for Resected Versus Non-resected Patients (Hazard Ratio) |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ITT / Safety Set |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 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. |
| Measure Participants | 8 | 93 | 7 | 108 |
| Number (95% Confidence Interval) [Hazard ratio] |
1.17
|
0.82
|
NA
|
0.79
|
| Title | Death Rates by 3 Years Follow-up |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ITT / Safety Set |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 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. |
| Measure Participants | 8 | 93 | 7 | 108 |
| Deceased |
6
75%
|
65
69.9%
|
7
100%
|
78
72.2%
|
| Alive after 3 years follow-up |
2
25%
|
16
17.2%
|
0
0%
|
18
16.7%
|
| Lost to follow-up before 3 years followup |
0
0%
|
12
12.9%
|
0
0%
|
12
11.1%
|
| Title | Overall Survival (OS) Median Time |
|---|---|
| Description | Overall survival was considered from start of treatment to death. All patients (ITT). |
| Time Frame | Treatment + follow-up (3 years from database lock) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ITT / Safety Set |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 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. |
| Measure Participants | 8 | 93 | 7 | 108 |
| Median (95% Confidence Interval) [months] |
28.4
|
31.4
|
4.9
|
29.8
|
| Title | Overall Survival (OS) Median Time for Resected Patients |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | ITT / Safety Set |
|---|---|---|---|
| Arm/Group Description | 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 | 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. | 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. |
| Measure Participants | 1 | 16 | 17 |
| Median (95% Confidence Interval) [Months] |
NA
|
NA
|
NA
|
| Title | Overall Response |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ITT / Safety Set |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 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. |
| Measure Participants | 8 | 93 | 7 | 108 |
| CR or PR |
6
75%
|
64
68.8%
|
0
0%
|
70
64.8%
|
| Other (SD, PD, not evaluable, missing) |
2
25%
|
29
31.2%
|
7
100%
|
38
35.2%
|
| Title | Overall Response in Patients With Liver-limited Disease |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ITT / Safety Set |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 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. |
| Measure Participants | 4 | 39 | 2 | 45 |
| CR or PR |
2
25%
|
30
32.3%
|
0
0%
|
32
29.6%
|
| Other (SD, PD, missing) |
2
25%
|
9
9.7%
|
2
28.6%
|
13
12%
|
| Title | Disease Control |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ITT / Safety Set |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 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. |
| Measure Participants | 8 | 93 | 7 | 108 |
| CR, PR, or SD |
8
100%
|
84
90.3%
|
0
0%
|
92
85.2%
|
| Other (PD, not evaluable, missing) |
0
0%
|
9
9.7%
|
7
100%
|
16
14.8%
|
| Title | Disease Control in Patients With Liver-limited Disease |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ITT / Safety Set |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 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. |
| Measure Participants | 4 | 39 | 2 | 45 |
| CR, PR, or SD |
4
50%
|
37
39.8%
|
0
0%
|
41
38%
|
| Other (PD, missing) |
0
0%
|
2
2.2%
|
2
28.6%
|
4
3.7%
|
| Title | Duration of Response |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | ITT / Safety Set |
|---|---|---|---|
| Arm/Group Description | 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 | 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. | 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. |
| Measure Participants | 6 | 64 | 70 |
| Median (95% Confidence Interval) [Months] |
8.3
|
11.7
|
11.7
|
| Title | Duration of Response in Liver-limited Disease Patients |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | ITT / Safety Set |
|---|---|---|---|
| Arm/Group Description | 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 | 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. | 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. |
| Measure Participants | 2 | 30 | 32 |
| Median (95% Confidence Interval) [Months] |
13.9
|
11.1
|
11.1
|
| Title | Resections for Metastatic Lesions |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ITT / Safety Set |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 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. |
| Measure Participants | 8 | 93 | 7 | 108 |
| Resected (surgery with curative intent performed) |
1
12.5%
|
16
17.2%
|
0
0%
|
17
15.7%
|
| Non-resected |
7
87.5%
|
77
82.8%
|
7
100%
|
91
84.3%
|
| Title | R0 Rate (Free of Tumor After Resection for Metastatic Lesions) |
|---|---|
| Description | 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) |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | ITT / Safety Set |
|---|---|---|---|
| Arm/Group Description | 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 | 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. | 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. |
| Measure Participants | 1 | 16 | 17 |
| Free of tumor |
1
12.5%
|
12
12.9%
|
13
185.7%
|
| Not free of tumor |
0
0%
|
4
4.3%
|
4
57.1%
|
| Title | Skin Toxicity (Safety) |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated |
|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. |
| Measure Participants | 8 | 93 | 7 |
| Any (onset prior to arm allocation) |
2
25%
|
92
98.9%
|
3
42.9%
|
| Any (all times) |
7
87.5%
|
93
100%
|
3
42.9%
|
| Grade 1 |
0
0%
|
19
20.4%
|
2
28.6%
|
| Grade 2 |
5
62.5%
|
44
47.3%
|
1
14.3%
|
| Grade 3 |
2
25%
|
30
32.3%
|
0
0%
|
| Title | Laboratory Safety Assessments |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated |
|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. |
| Measure Participants | 8 | 93 | 7 |
| Hemoglobin decreased |
0
0%
|
3
3.2%
|
0
0%
|
| White blood cell count decreased |
3
37.5%
|
8
8.6%
|
0
0%
|
| Neutrophils decreased |
3
37.5%
|
19
20.4%
|
0
0%
|
| Lymphocytes decreased |
2
25%
|
6
6.5%
|
0
0%
|
| Platelet count decreased |
0
0%
|
2
2.2%
|
0
0%
|
| Bilirubin increased |
0
0%
|
3
3.2%
|
0
0%
|
| ALAT increased |
0
0%
|
2
2.2%
|
0
0%
|
| ASAT increased |
0
0%
|
1
1.1%
|
0
0%
|
| ALP increased |
2
25%
|
4
4.3%
|
0
0%
|
| Sodium decreased |
1
12.5%
|
3
3.2%
|
1
14.3%
|
| Potassium decreased |
2
25%
|
7
7.5%
|
0
0%
|
| Magnesium decreased |
1
12.5%
|
2
2.2%
|
0
0%
|
| Magnesium increased |
0
0%
|
1
1.1%
|
0
0%
|
| Serum calcium decreased |
0
0%
|
2
2.2%
|
0
0%
|
| Title | Deaths Till 30 Days From Last Cetuximab Administration |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ITT / Safety Set |
|---|---|---|---|---|
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | 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. |
| Measure Participants | 8 | 93 | 7 | 108 |
| All causes |
1
12.5%
|
6
6.5%
|
2
28.6%
|
9
8.3%
|
| Colonic perforation |
1
12.5%
|
0
0%
|
0
0%
|
1
0.9%
|
| Malaise |
0
0%
|
1
1.1%
|
0
0%
|
1
0.9%
|
| Bronchial infection |
0
0%
|
1
1.1%
|
0
0%
|
1
0.9%
|
| Lung infection |
0
0%
|
1
1.1%
|
0
0%
|
1
0.9%
|
| Circulatory failure |
0
0%
|
1
1.1%
|
0
0%
|
1
0.9%
|
| Cardiac arrest |
0
0%
|
1
1.1%
|
0
0%
|
1
0.9%
|
| Colonic obstruction |
0
0%
|
1
1.1%
|
0
0%
|
1
0.9%
|
| Peritoneal infection |
0
0%
|
0
0%
|
1
14.3%
|
1
0.9%
|
| Ileus |
0
0%
|
0
0%
|
1
14.3%
|
1
0.9%
|
Adverse Events
| 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. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | SAEs occurring between the signature of the informed consent and last drug administration plus 30 days are listed. Fatalities are entered if occurred within 30 days from last drug administration. All severe AEs (grade 3-5) including SAEs, are listed in the non-serious AE table. Skin toxicity and severe lab abnormalities are further detailed in section End points. | |||||
| Arm/Group Title | Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | |||
| Arm/Group Description | 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 | 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. | Patients unable to continue treatment with cetuximab and FOLFIRI at standard or reduced doses, requiring discontinuation before arm allocation at day 22. | |||
All Cause Mortality |
||||||
| Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/8 (12.5%) | 6/93 (6.5%) | 2/7 (28.6%) | |||
Serious Adverse Events |
||||||
| Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/8 (75%) | 39/93 (41.9%) | 6/7 (85.7%) | |||
| Cardiac disorders | ||||||
| Cardiac arrest | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Ventricular fibrillation | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Abdominal pain | 0/8 (0%) | 0 | 3/93 (3.2%) | 3 | 0/7 (0%) | 0 |
| Colonic hemorrhage | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Colonic obstruction | 0/8 (0%) | 0 | 3/93 (3.2%) | 4 | 0/7 (0%) | 0 |
| Colonic perforation | 1/8 (12.5%) | 1 | 1/93 (1.1%) | 1 | 1/7 (14.3%) | 1 |
| Diarrhea | 2/8 (25%) | 2 | 2/93 (2.2%) | 3 | 1/7 (14.3%) | 1 |
| Enterocolitis | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Ileus | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 1/7 (14.3%) | 1 |
| Jejunal obstruction | 1/8 (12.5%) | 1 | 0/93 (0%) | 0 | 0/7 (0%) | 0 |
| Rectal hemorrhage | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Small intestinal obstruction | 0/8 (0%) | 0 | 3/93 (3.2%) | 5 | 1/7 (14.3%) | 1 |
| General disorders | ||||||
| Fatigue | 1/8 (12.5%) | 1 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Fever | 1/8 (12.5%) | 1 | 0/93 (0%) | 0 | 1/7 (14.3%) | 1 |
| Malaise | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Hepatobiliary disorders | ||||||
| Galbladder obstruction | 0/8 (0%) | 0 | 2/93 (2.2%) | 2 | 0/7 (0%) | 0 |
| Hepatic hematoma | 1/8 (12.5%) | 1 | 0/93 (0%) | 0 | 0/7 (0%) | 0 |
| Portal vein thrombosis | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Immune system disorders | ||||||
| Anaphylaxis | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Infections and infestations | ||||||
| Bronchial infection | 0/8 (0%) | 0 | 2/93 (2.2%) | 2 | 0/7 (0%) | 0 |
| Catheder related infection | 0/8 (0%) | 0 | 1/93 (1.1%) | 2 | 0/7 (0%) | 0 |
| Enterocolitis infectious | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Erysipelas | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Kidney infection | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Lung infection | 0/8 (0%) | 0 | 3/93 (3.2%) | 3 | 0/7 (0%) | 0 |
| Pelvic infection | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Peritoneal infection | 0/8 (0%) | 0 | 0/93 (0%) | 0 | 1/7 (14.3%) | 1 |
| Sepsis | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Yersinia enterocolitica gastroenteritis | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Urinary tract infection | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Investigations | ||||||
| Neutrophil count decreased | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| White blood cell decreased | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| Diabetes angiopathy | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Severe undernutrition | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Nervous system disorders | ||||||
| Ischemia cerebrovascular | 0/8 (0%) | 0 | 0/93 (0%) | 0 | 1/7 (14.3%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Respiratory insufficience | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Vascular disorders | ||||||
| Circulatory failure | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Thromboembolic event | 0/8 (0%) | 0 | 8/93 (8.6%) | 8 | 1/7 (14.3%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||
| Arm A - Dose Escalation of Cetuximab | Arm B - Standard Dose of Cetuximab | Not Allocated | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 6/8 (75%) | 66/93 (71%) | 3/7 (42.9%) | |||
| Blood and lymphatic system disorders | ||||||
| Anemia | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Leukocytosis | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Febrile neutropenia | 0/8 (0%) | 0 | 2/93 (2.2%) | 2 | 0/7 (0%) | 0 |
| Cardiac disorders | ||||||
| Ventricullar fibrillation | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Cardiac arrest | 0/8 (0%) | 0 | 3/93 (3.2%) | 5 | 0/7 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Abdominal pain | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 1/7 (14.3%) | 1 |
| Colonic haemorrhage | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Hemorrhoids | 1/8 (12.5%) | 1 | 0/93 (0%) | 0 | 0/7 (0%) | 0 |
| Colonic obstruction | 0/8 (0%) | 0 | 3/93 (3.2%) | 4 | 0/7 (0%) | 0 |
| Diarrhea | 2/8 (25%) | 2 | 14/93 (15.1%) | 20 | 0/7 (0%) | 0 |
| Ileus | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Colonic perforation | 1/8 (12.5%) | 1 | 1/93 (1.1%) | 1 | 1/7 (14.3%) | 1 |
| Jejunal obstruction | 1/8 (12.5%) | 1 | 0/93 (0%) | 0 | 0/7 (0%) | 0 |
| Small intestinal obstruction | 0/8 (0%) | 0 | 2/93 (2.2%) | 2 | 1/7 (14.3%) | 1 |
| Mucositis oral | 0/8 (0%) | 0 | 3/93 (3.2%) | 3 | 0/7 (0%) | 0 |
| Vomiting | 0/8 (0%) | 0 | 0/93 (0%) | 0 | 0/7 (0%) | 0 |
| General disorders | ||||||
| General deterioration | 0/8 (0%) | 0 | 3/93 (3.2%) | 5 | 0/7 (0%) | 0 |
| Fatigue | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Hepatobiliary disorders | ||||||
| Hepatic hematoma | 1/8 (12.5%) | 1 | 0/93 (0%) | 0 | 0/7 (0%) | 0 |
| Gallbladder obstruction | 0/8 (0%) | 0 | 2/93 (2.2%) | 2 | 0/7 (0%) | 0 |
| Hepatic pain | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Portal vein thrombosis | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Immune system disorders | ||||||
| Anaphylaxis | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Infections and infestations | ||||||
| Bronchial infection | 0/8 (0%) | 0 | 2/93 (2.2%) | 2 | 0/7 (0%) | 0 |
| Enterocolitis infectious | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Acute cytolysis due to viral infection | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Erysipelas | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Lung infection | 0/8 (0%) | 0 | 3/93 (3.2%) | 3 | 0/7 (0%) | 0 |
| Paronychia | 2/8 (25%) | 2 | 1/93 (1.1%) | 3 | 0/7 (0%) | 0 |
| Catheter related infection | 0/8 (0%) | 0 | 1/93 (1.1%) | 2 | 0/7 (0%) | 0 |
| Kidney infection | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Papulopustular rash | 0/8 (0%) | 0 | 7/93 (7.5%) | 16 | 0/7 (0%) | 0 |
| Skin infection | 1/8 (12.5%) | 1 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Pelvic infection | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Peritoneal infection | 0/8 (0%) | 0 | 0/93 (0%) | 0 | 1/7 (14.3%) | 1 |
| Yersinia enterocolitica gastroenteritis | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Sepsis | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| Anorexia | 1/8 (12.5%) | 1 | 2/93 (2.2%) | 3 | 0/7 (0%) | 0 |
| Diabetes angiopathy | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Hypokalemia | 2/8 (25%) | 4 | 2/93 (2.2%) | 7 | 0/7 (0%) | 0 |
| Dehydration | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Hyperglycemia | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Hypophosphatemia | 0/8 (0%) | 0 | 2/93 (2.2%) | 2 | 0/7 (0%) | 0 |
| Hyponatremia | 1/8 (12.5%) | 2 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Hypomagnesemia | 1/8 (12.5%) | 1 | 0/93 (0%) | 0 | 0/7 (0%) | 0 |
| Severe undernutrition | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Nervous system disorders | ||||||
| Peripheral sensory neuropathy | 1/8 (12.5%) | 1 | 0/93 (0%) | 0 | 0/7 (0%) | 0 |
| Syncope | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 1/7 (14.3%) | 1 |
| Renal and urinary disorders | ||||||
| Acute kidney injury | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Pulmonary edema | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Respiratory failure | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Dyspnea | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Respiratory insufficiency | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||
| Hypertrichosis | 1/8 (12.5%) | 1 | 0/93 (0%) | 0 | 0/7 (0%) | 0 |
| Fissure/feet | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Fissure/fingers | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Pruritus | 0/8 (0%) | 0 | 2/93 (2.2%) | 3 | 0/7 (0%) | 0 |
| Rash maculo-papular | 0/8 (0%) | 0 | 2/93 (2.2%) | 2 | 0/7 (0%) | 0 |
| Rash acneiform | 0/8 (0%) | 0 | 17/93 (18.3%) | 25 | 0/7 (0%) | 0 |
| Skin hyperpigmentation | 1/8 (12.5%) | 1 | 0/93 (0%) | 0 | 0/7 (0%) | 0 |
| Vascular disorders | ||||||
| Circulatory failure | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
| Thromoembolic event | 0/8 (0%) | 0 | 1/93 (1.1%) | 1 | 0/7 (0%) | 0 |
Limitations/Caveats
Insufficient population in escalation arm A as early skin toxicity in most patients; study not powered for formal comparison between arms. Systematic error sources: some AEs re-coded by sponsor, misclassification bias (local response assessment).
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Prof Dr Eric Van Cutsem |
|---|---|
| Organization | UZ Leuven |
| Phone | 003216344218 |
| eric.vancutsem@uzleuven.be |
Responsible Party:
Universitaire Ziekenhuizen Leuven
ClinicalTrials.gov Identifier:
NCT01251536
Other Study ID Numbers:
- S51532
- 2009-009992-36
First Posted:
Dec 2, 2010
Last Update Posted:
Oct 11, 2019
Last Verified:
Oct 1, 2019