Colorectal Cancer (CRC) Cetuximab Elderly Frail

Study Overview
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Brief Summary
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OBJECTIVE: The principal objective of the trial is to evaluate whether the addition of cetuximab associated with 5-fluorouracil in elderly patients with KRAS wild type advanced colorectal cancer (CRC) prolongs Progression Free Survival, compared with 5-fluorouracil alone.

Detailed Description
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The primary efficacy analyses will be performed on the Intention-to-treat population. The safety analyses will be performed on the Safety population. Median PFS and OS in each treatment arm with its 95% CI, estimated by the Kaplan-Meier technique Response rates by treatment arm with their exact 95% CI IADL sum score, G8 sum score and social situation by treatment arm at baseline and at each timepoint of assessment QoL scores from the EORTC QLQ-C30 and QLQ-ELD14 modules by treatment arm at baseline and at each timepoint of assessment Safety data by treatment arm in the Safety population. Worst toxicity grade over all cycles according to the CTCAE criteria version 4.0 by treatment arm. Pharmaco-economics evaluation Summary of proposed Phase II trial characteristics: Total number of randomized patients: 150. Total number of events at phase II analysis for primary endpoint: 110. Total number of patients screened over the phase II: 250. Total number of patients treated with cetuximab for the Phase II study: 75. Maximum study duration: 19 months. In the present study, HRQoL is an important secondary endpoint. The objective of the HRQoL data collection in this Phase II trial is to assess the impact of the addition of cetuximab on patients' HRQoL during treatment. The hypothesis is that there will be no difference in patients' HRQoL between both treatment arms during treatment. The HRQoL domains (from the EORTC QLQ-C30 module) which are expected to be affected by treatment (to the same extent in both arms) are Global health status, Fatigue, Pain and Stool habits.

Official Title
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Treatment of Patients With KRAS Wild Type Advanced Colorectal Cancer (CRC) With 5-Fluorouracil (5-FU) or 5- FU Plus an Epidermal Growth Factor Receptor (EGFR) Inhibitor (Cetuximab) Based on a Comprehensive Geriatric Assessment (CGA).

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Drug: Cetuximab
* Drug: 5-fluorouracil
* Drug: leucovorin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed metastatic colorectal cancer Measurable disease according to RECIST V1.1 Histological local review and analysis of KRAS Age ≥ 80 or ≥ 70 in combination with functional restrictions defined as limitation in at least 2 of 8 IADL WHO performance status 0, 1 or 2 Adequate bone marrow reserves, hepatic function & renal function Normal 12 lead ECG without clinically significant abnormalities Written informed consent before randomization according to ICH/EU GCP, and local, national and international regulations Exclusion Criteria: Prior systemic chemotherapy for metastatic disease Previous exposure to EGFR or VEGF/VEGFR targeted therapy Patients may have received chemotherapy in the adjuvant or neoadjuvant setting (CRC). The treatment-free interval should be 6 months or more from the end of (neo-)adjuvant therapy Previous radiotherapy, either in the adjuvant setting or for the treatment of bone metastases, is allowed provided that the measurable lesions are outside the radiation fields Persistence of clinically relevant treatment-related toxicities from previous chemotherapy and/or radiotherapy (adjuvant or neo-adjuvant setting) Treatment with other investigational drugs or treatment in another clinical trial within the past four weeks before start of treatment or concomitantly with this trial Known alcohol or drug abuse Clinically significant cardiovascular disease Evidence of uncontrolled medical comorbidities despite adequate treatment Patients who have suffered a cerebrovascular accident or transient ischemic attack within the past 12 months History, within the past 5 years, of malignancies other than CRC Psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and followup schedule

Ages Eligible for Study
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Minimum Age: 70 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5-fluorouracil/leucovorin plus cetuximab<br> | Drug: Cetuximab<br>* 500 mg/m2 on day 1, Every 14 days Intravenously<br>* Other names: Erbitux;Drug: 5-fluorouracil<br>* Every 2 weeks, 400 mg/m2 on day 1; 2400 mg/m2 from day 1 to day 3, intravenously<br>* Other names: 5-FU;Drug: leucovorin<br>* Every 2 weeks, Racemic leucovorin 200 mg/m2 or l-leucovorin 100 mg/m2 on day 1, intravenously<br>* Other names: Folinic Acid;|
| Active Comparator: 5-fluorouracil/leucovorin alone<br> | Drug: 5-fluorouracil<br>* Every 2 weeks, 400 mg/m2 on day 1; 2400 mg/m2 from day 1 to day 3, intravenously<br>* Other names: 5-FU;Drug: leucovorin<br>* Every 2 weeks, Racemic leucovorin 200 mg/m2 or l-leucovorin 100 mg/m2 on day 1, intravenously<br>* Other names: Folinic Acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Progression will be defined according to the RECIST V1.1 | 19 months from first patient in | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | 19 months from first patient in | 
| Response Rate | according to the RECIST V1.1 | 19 months from first patient in | 
| Change in Instrumental Activities of Daily Living (IADL) score |  | 19 months from first patient in | 
| Change in G8 geriatric assessment screening tool |  | 19 months from first patient in | 
| Change in social situation |  | 19 months from first patient in | 
| Score of Quality of Life (EORTC-QLQ C30 and QLQ-ELD14) |  | 14 days before randomization; 6 weeks, 14 weeks, 22 weeks and 38 weeks after randomization; 30 days after last treatment administration | 
| Occurrence of adverse events | Adverse events will be graded according to the Common Terminology Criteria for Adverse events CTCAE,version 4.0. | 19 months from first patient in | 
| Health Economy assessments |  | 19 months from first patient in | 
| Score of elderly minimal dataset comprehensive geriatric assessment (EMDCGA), as evaluated by G8 instrument |  | 14 days before randomization; 6 weeks, 14 weeks, 22 weeks and 38 weeks after randomization; 30 days after last treatment administration | 
| Score of elderly minimal dataset comprehensive geriatric assessment (EMDCGA), as evaluated by Instrumental Activities of Daily Life (IADL) questionnaire |  | 14 days before randomization; 6 weeks, 14 weeks, 22 weeks and 38 weeks after randomization; 30 days after last treatment administration | 
| Score of elderly minimal dataset comprehensive geriatric assessment (EMDCGA), as evaluated by social situation questionnaire |  | 14 days before randomization; 6 weeks, 14 weeks, 22 weeks and 38 weeks after randomization; 30 days after last treatment administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KRAS Wild Type, Frail Elderly, QLQ-C30, QLQ-ELD14, CGA, EGFR, Cetuximab, 5-FU