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
18 Years
N/A
Both
Colorectal Cancer
Trial Information
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
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.
Inclusion Criteria:
1. Written informed consent (+ optional for PK and TR) must be given according to
ICH/GCP and national/local regulations.
2. Patient is at least 18 years of age.
3. Patient's body weight is ≤ 120 kg.
4. Histologically proven and measurable (RECIST criteria v.1.1) metastatic
adenocarcinoma of the colon or rectum, not in a previously irradiated area.
5. K-Ras wild type tumour eligible for treatment with cetuximab.
6. Unresectable metastatic disease.
7. Life expectancy of at least 12 weeks.
8. WHO ECOG performance status: 0 or 1.
9. Effective contraception for both male and female patients if the risk of conception
exists.
10. Adequate organ function.
11. Adequate bone marrow, hepatic and renal function (assessed within 14 days prior to
study entry):
- Hemoglobin > 10.0 g/dL, absolute neutrophil count > 1.5 x 109/L, platelet count
> 100 x 109/L
- ALAT, ASAT < 2.5 x ULN, up to < 5 x ULN in case of liver metastases
- Alkaline phosphatase < 2.5 x ULN
- Total bilirubin < 1.5 x ULN
- Creatinine clearance > 50 mL/min (calculated according to Cockroft and Gault)
Exclusion Criteria:
1. Prior treatment for metastatic disease (adjuvant therapy with fluoropyrimidines
+/-oxaliplatin based regimens allowed if stopped 6 months prior to registration on
study).
2. Prior treatment with EGFR inhibitor or chemotherapy with irinotecan in adjuvant
settings.
3. Surgery (excluding diagnostic biopsy) or irradiation within 4 weeks prior to study
entry.
4. Administration of any investigational drug or agent/procedure, i.e. participation in
another trial within 4 weeks before beginning treatment.
5. Concurrent chronic systemic immune therapy, chemotherapy, radiation therapy or
hormone therapy not indicated in the study protocol.
6. Any active dermatological condition > grade 1.
7. Brain metastasis (known or suspected).
8. Significant impairment of intestinal absorption (e.g. chronic diarrhea, inflammatory
bowel disease).
9. Other uncontrolled concomitant illness, including serious uncontrolled intercurrent
infection.
10. Uncontrolled coronary artery disease and/or unstable angina, a history of a
myocardial infarction within the last 12 months or heart failure NYHA class III or
IV. High risk of uncontrolled arrhythmia.
11. Known allergy or any other adverse reaction to any of the drugs or to any related
compound.
12. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
13. Gilbert disease.
14. Previous (within 5 years) or concurrent malignancies at other sites with the
exception of surgically cured or adequately treated carcinoma in-situ of the cervix
and basal cell carcinoma of the skin.
15. Organ allografts requiring immunosuppressive therapy.
16. Pregnancy (absence confirmed by serum/urine beta human choriongonadotrophin in
pre-menopausal women) or breast-feeding.
17. Medical, social or psychological condition which, in the opinion of the investigator,
would not permit the patient to complete the study or sign meaningful informed
consent.
Type of Study:
Interventional
Study Design:
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
PFS rate at 9 months in the dose escalation arm
Outcome Description:
To provide a precise estimate (+/- 10%) of the progression-free survival rate at 9 months, in patients without skin toxicity at 3 weeks (according to NCI CTCAE v. 4.0), treated with FOLFIRI + escalating dose of cetuximab (arm A). It is expected that the PFS rate will be similar to that observed after standard cetuximab treatment + FOLFIRI in patients with grade 1-4 skin toxicity in a K-Ras wild type population (CRYSTAL study)
Outcome Time Frame:
9 months
Safety Issue:
No
Principal Investigator
Eric Van Cutsem, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
UZ Leuven
Authority:
Belgium: Federal Agency for Medicinal Products and Health Products
Study ID:
S51532
NCT ID:
NCT01251536
Start Date:
December 2010
Completion Date:
December 2014
Related Keywords:
- Colorectal Cancer
- colorectal cancer
- K-Ras wildtype
- first line metastatic
- standard cetuximab + FOLFIRI
- dose escalation cetuximab
- Colorectal Neoplasms
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