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
Overview
- Phase
- Phase 2
- Intervention
- Standard first line treatment with cetuximab + Folfiri
- Conditions
- Colorectal Cancer
- Sponsor
- Universitaire Ziekenhuizen KU Leuven
- Enrollment
- 108
- Locations
- 30
- Primary Endpoint
- PFS Probability Rate at 9 Months in the Dose Escalation Arm
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
The purposes of this study are to determine whether administering escalating doses of cetuximab in patients with no early skin toxicity could delay the progression of disease in a significant proportion of patients and to study the molecular signatures of response.
Detailed Description
Colorectal carcinoma (CRC) is the third most common form of cancer worldwide and remains a leading malignancy both in incidence and mortality. In the light of existing knowledge, the investigators propose a phase II open label, two arm study in patients presenting with K-Ras wild-type metastatic colorectal tumours in the first line setting. The standard combination of irinotecan plus infusional 5-FU/LV (FOLFIRI) and cetuximab will be given to all patients entering the study. As the investigators hypothesize that increasing the dose of cetuximab might increase the intensity of skin reactions that directly correlates with outcome, in patients experiencing no skin toxicity, the dose of cetuximab will be escalated from 250 mg/m2 to 350 mg/m2 and then up to 500 mg/m2, in order to better define the effect of dose escalation in the first-line setting in a K-Ras wild type tumour population and in an attempt to increase efficacy. Pharmacokinetic studies will be performed to document PK parameters of cetuximab in patients from both arms in selected centers. Translational research studies are planned for all patients. Some more in depth molecular testing will be performed in a subset of patients from whom three serial tissue samples from accessible metastases by biopsy are available.
Investigators
Eligibility Criteria
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
- •Effective contraception for both male and female patients if the risk of conception exists.
- •Adequate organ function.
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
- •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.
Arms & Interventions
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.
Intervention: Standard first line treatment with cetuximab + Folfiri
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.
Intervention: Dose escalation of cetuximab
Outcomes
Primary Outcomes
PFS Probability Rate at 9 Months in the Dose Escalation Arm
Time Frame: 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 Outcomes
- Duration of Response in Liver-limited Disease Patients(Treatment + follow-up (3 years from database lock))
- Progression Free Survival (PFS) Median Time(Treatment + follow-up (3 years from database lock))
- Progression Free Survival (PFS) Median Time for Resected Patients(Treatment + follow-up (3 years from database lock))
- Progression Free Survival (PFS) Time for Resected Versus Non-resected Patients (Hazard Ratio)(Treatment + follow-up (3 years from database lock))
- Death Rates by 3 Years Follow-up(Treatment + follow-up (3 years from database lock))
- Overall Survival (OS) Median Time(Treatment + follow-up (3 years from database lock))
- Overall Survival (OS) Median Time for Resected Patients(Treatment + follow-up (3 years from database lock))
- Overall Response(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(Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.)
- Disease Control(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(Treatment duration (interval from first infusion to last infusion on study for each patient), an average of 8.5 months.)
- Duration of Response(Treatment + follow-up (3 years from database lock))
- Resections for Metastatic Lesions(Treatment + follow-up (3 years from database lock))
- R0 Rate (Free of Tumor After Resection for Metastatic Lesions)(Treatment + follow-up (3 years from database lock))
- 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.)
- 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.)
- 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.)