Study Comparing Pathological Responses Observed on Colorectal Cancer Metastases Resected After Preoperative Treatment Combining Cetuximab With FOLFOX or FOLFIRI in RAS and B-RAF WT Tumors

Metastatic Colorectal Cancer Clinical Trial

Official title:

Randomised Phase 2 Study Comparing Pathological Responses Observed on Colorectal Cancer Metastases Resected After Preoperative Treatment Combining Cetuximab With FOLFOX or FOLFIRI in RAS and B-RAF WT Tumors

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01858662
• Other study ID #: CET-ONCO2012
• Secondary ID: 2012-005249-19
• Status: Terminated
• Phase: Phase 2
• First received: May 7, 2013
• Last updated: April 13, 2016
• Start date: January 2014
• Est. completion date: November 2015

Study information

• Verified date: April 2016
• Source: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicinal Products and Health Products
• Study type: Interventional

Clinical Trial Summary

To analyze the pathological tumor response on resected colorectal cancer metastases after preoperative treatment with cetuximab combined with FOLFOX or FOLFIRI regimen in a prospective cohort (RAS and B-RAF WT tumors) and to correlate this response with patient's outcome.

Description:

This is a phase II , openlabel, randomized study in patients with confirmed diagnosis of potentially or borderline resectable metastatic colorectal adenocarcinoma (RAS and B-RAF WT tumors ), who have not received prior chemotherapy for their metastatic disease.

The study is designed to compare pathological responses observed after pre-operative chemotherapy cetuximab with FOLFOX or FOLFIRI.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 4
• Est. completion date: November 2015
• Est. primary completion date: November 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Female or male patients with at least 18 years at the time the informed consent is signed

2. ECOG performance status 0 or 1

3. Histological or cytological confirmed diagnostic of adenocarcinoma of the colon or rectum, with or without primary tumour in situ. Wild-type RAS and B-RAF tumor status.

4. Patients with potentially resectable metastatic disease at diagnosis and for whom a chemotherapy first in a curative intent is recommended . Resectability could be planed in one or multiple stage if indicated. As commonly admitted, resectability means the surgical clearance (+/- radiofrequency ablation) of all detectable (liver) lesions with tumor-free margins and compatible with an adequate hepatic reserve. Practically, bilateral tumor location, number and location of lesions, and inadequate hepatic reserve remain the main decisional factors.

5. Partial and minor resection of metastatic disease is allowed within 3 months before inclusion if patient has never received chemotherapy for mCRC.

6. Extra hepatic metastatic location is limited to 1 site.

7. Patients may have received adjuvant chemotherapy or (neo-) adjuvant chemo-radiotherapy to the pelvis, provided the last dose of chemotherapy was administered at least 6 months prior to inclusion (12 months for oxaliplatin). Previous radiotherapy to the pelvis is not an exclusion criterion.

8. Adequate haematological, renal and hepatic function as follows:

Haematological:

haemoglobin >9g/dl Neutrophils > 1.5 x 109/L Platelets > 100 x 109/L

Renal:

Creatinine< 1.5 x ULN (Upper Limit of Normal)

Hepatic:

Bilirubin < or equal 1.5 X ULN AST (Aspartate Aminotransferase),and ALT (Alanine Aminotransferase)< or equal 5 x ULN, Phos Alc< or equal 5 x ULN

9. Female patients must either be postmenopausal, sterile (surgically or radiation- or chemically-induced), or if sexually active using an acceptable method of contraception.

10. Male patients must be surgically sterile or if sexually active and having a pre-menopausal partner must be using an acceptable method of contraception.

11. Life expectancy of at least 3 months without any active treatment.

Exclusion Criteria:

• 1.Definitively non resectable mCRC at diagnosis

• 2.Prior chemotherapy or systemic therapy for mCRC. Adjuvant chemotherapy for colorectal cancer is not an exclusion criterion provided that it was completed more than 6 months prior to inclusion. Oxaliplatin-based chemotherapy must be completed more than 1 year prior to inclusion.

• 3.Prior utilization of cetuximab, panitumumab (or other anti-EGFR (epidermal growth factor receptor)therapy).

• 4.Previous radiotherapy delivered to the upper abdomen.

• 5 Non mesurable disease( RECIST 1.1 criteria)

• 6.Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or thrombosis as determined by clinical or radiologic assessment.

• 7.Prior major liver resection: remnant liver < 50% of the initial liver volume.

• 8.Non-malignant disease that would render the patient unsuitable for treatment according to this protocol.

• 9.Concurrent central nervous systems metastases

• 10.Peripheric neuropathy = grade 2.

• 11.Interstitial lung disease

• 12.Pregnant or breast feeding.

• 13.The patient has previous or concomitant malignancies, except: Invasive malignancies in remission for more than 5 years and non melanoma skin cancer or carcinoma in situ of the cervix.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Procedure:
• Metastases Resection ( multiple steep surgery possible)
Metastases resection will be process by surgery, after a randomized chemotherapy (FOLFOX or FOLFIRI) + Target therapy (Cetuximab). The surgery will allow to compare the pathological response on the resected metastases by the chemotherapy + target therapy type.

Drug:
• 5-Fluorouracile
5-FU bolus 400 mg/m2, IV bolus every 2 weeks 5-FU continuous infusion 2400 mg/m2, 46-hour cont. IV infusion every 2 weeks
• leucovorin L
Leucovorin L (levoleucovorin) 200 mg/m2 (or folinic acid 400 mg/m²) in 250 ml glucose 5%, 2-hour IV infusion
• Oxaliplatin
Oxaliplatin 85 mg/m² in 150 ml NaCl 0.9%, 2-hour IV infusion every 2 weeks
• Irinotecan
Irinotecan 180 mg/m² in 150 ml NaCl 0.9%, 1.30-hour IV infusion every 2 weeks
• Cetuximab
Cetuximab 400 mg/m² in 100 ml NaCl 0.9% 2-hour IV infusion for 1rst cycle and after the 1rst cycle 250 mg/m² in 100 ml NaCl 0.9% 1-hour IV infusion

Locations

Country	Name	City	State
Belgium	clinique Saint Luc	Bouge
Belgium	Cliniques universitaires Saint-Luc - UCL	Brussels
Belgium	Grand Hôpital de Charleroi	Charleroi	Hainaut
Belgium	Centre Hospitalier Jolimont Lobbes	La Louvière
Belgium	CHU liège (Sart Timan)	Liège
Belgium	Clinique Saint Pierre Ottignies	Ottignies
Belgium	CHU-UCL Dinant-Godinne	Yvoir

Sponsors (2)

Lead Sponsor	Collaborator
Cliniques universitaires Saint-Luc- Université Catholique de Louvain	Grand Hôpital de Charleroi

Country where clinical trial is conducted

Belgium, 

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Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Major Pathological Response Rate	Major pathological response rate (MPRR) is defined as the proportion of patients presenting a major pathological response. Pathologic response will be evaluated according the Rubbia-Brandt Tumor Regression Grade classification .For patients with multiple colorectal metastases the global pathological response will be categorized based on the mean TRG of all metastases.: a major response is defined as a mean TRG < 3, a partial response is defined for patient presenting a mean TRG =3 and <4, and a no response for patient with a mean TRG =4.	Average 3 months (after resection of metastases)	Yes
Secondary	progression free survival	-Progression Free Survival (PFS) is defined as the time from randomization to the time of first event (relapse of the original mCRC, development of a new colorectal cancer or death due to any cause). Patients without any such event at the time of data analysis will be censored at the last date they were known to be event-free. PFS analysis will be based on tumour assessments and survival follow-up assessments.	at 6 months and at 12 months after randomization	Yes
Secondary	Overall survival	The overall survival will be analyzed at the end of study (3 year of recruitment and one year of follow-up).	At the end of the study	No
Secondary	Clinical response rate	Clinical response rate at time of surgery: Clinical tumour response will be measured according to the RECIST 1.1 criteria	at time of surgery -	No
Secondary	Metabolic response rate	Metabolic response rate at time of surgery (in selected centres only, optional): Metabolic tumour response will be measured according to the EORTC criteria . PET-Scan evaluation remains optional to selected centres only.	At time of surgery - average 3 months	No
Secondary	post operative complications	. Severe pre- or postoperative complications within 30 days of surgery: surgery-associated bleeding requiring replacement with > 4 units of erythrocyte concentrates,; wound infection,; intra-abdominal infection,; severe sepsis (American College of Chest physicians/Society of Critical Care Medicine, 1992),; impaired wound healing,; subphrenic or perihepatic abscess requiring drainage during hospital stay or within 30 days after the operation,; re-laparotomy connected with the resection,; a biliary fistula for more than 10 days with a discharge of > 100 mL/day,; transient liver failure (bilirubin > 10 mg/dL lasting > 3 days),; renal failure requiring dialysis,; respiratory failure with renewed necessary mechanical ventilation, venous thromboembolism,; cardiac failure,; death of the patient as a result of the operation.	one month after surgery	Yes
Secondary	Curative resection rate	Curative resection rate (R0 resection) is defined by the surgical clearance (+/- radiofrequency ablation) of all detectable hepatic lesions with tumor-free margins at histo-pathological evaluation.	At time of surgery	No
Secondary	Chemotherapy-associated hepatotoxicity:	Systemic neo-adjuvant chemotherapy in mCRC frequently causes morphological lesions involving hepatic microvasculature . Sinusoidal obstruction, complicated by perisinusoidal fibrosis and veno-occlusive lesion of the non tumoral liver, should be included in the list of the adverse side-effects of colorectal systemic chemotherapy, in particular related to the use of oxaliplatin.	at time of surgery	No