Cetuximab Standard or Dose Escalation in First Line Colorectal Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Dose escalation of cetuximab
* Drug: Standard first line treatment with cetuximab + Folfiri


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Arm B - standard dose of cetuximab<br>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<br>* 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.<br>* Other names: Erbitux;|
| Experimental: Arm A - dose escalation of cetuximab<br>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<br>* 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<br>* Other names: Erbitux;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Treatment + follow-up (3 years from database lock) | 
| 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. | Treatment + follow-up (3 years from database lock) | 
| 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. | Treatment + follow-up (3 years from database lock) | 
| Death Rates by 3 Years Follow-up | Deaths by 3 years follow-up after last cetuximab administration + 30 days. All patients (ITT). | Treatment + follow-up (3 years from database lock) | 
| Overall Survival (OS) Median Time | Overall survival was considered from start of treatment to death. All patients (ITT). | Treatment + follow-up (3 years from database lock) | 
| 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. | Treatment + follow-up (3 years from database lock) | 
| 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). | Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months. | 
| 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. | Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months. | 
| 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). | Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months. | 
| 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. | Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months. | 
| 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. | Treatment + follow-up (3 years from database lock) | 
| 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. | Treatment + follow-up (3 years from database lock) | 
| 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'. | Treatment + follow-up (3 years from database lock) | 
| 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'. | Treatment + follow-up (3 years from database lock) | 
| 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. | From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months. | 
| Laboratory Safety Assessments | Severe laboratory abnormalities (hematology and biochemistry grade 3 and higher). Worst grade per patient. All patients treated (Safety set). | From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months. | 
| 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. | From signature of informed consent to last cetuximab administration on study plus 30 days for each patient, an average of 9.5 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colorectal cancer, K-Ras wildtype, first line metastatic, standard cetuximab + FOLFIRI, dose escalation cetuximab