Panitumumab After Resection of Liver Metastases From Colorectal Cancer in KRAS Wild-type Patients

Sponsor

PD Dr. med. Volker Heinemann (Other)

Overall Status

Unknown status

CT.gov ID

NCT01384994

Collaborator

Amgen (Industry)

111

Enrollment

Location

Arms

Duration (Months)

3.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Up to 50% of patients with colorectal cancer (CRC) develop liver metastasis during the course of their disease. In 30-40% of patients metastasis is confined to the liver. In these patients R0-resection of metastases may contribute to marked improvement of overall survival. Primary resection of liver metastasis is possible in about 15-20% of patients (Scheele 2005, Petrelli 2005). Recent studies indicate that perioperative chemotherapy may improve survival after resection of liver metastases (Portier 2007, Nordlinger 2007). Nevertheless, there is evidence that 70-80% of patients have recurrent disease after resection of liver metastasis. Stratification for the risk of recurrence may be performed using the FONG-score (Fong 1999).

This study is designed to investigate the efficacy of postoperative chemotherapy combined with an anti-EGFR treatment using panitumumab.

The majority of patients present to the surgeon after chemotherapeutic pretreatment with various not necessarily standardized regimens. Also postoperative therapy after resection of liver metastasis is not a clearly defined standard of care in Germany.

Based on the study by Nordlinger et al. an oxaliplatin-based regimen is chosen for postoperative therapy (Nordlinger 2008). For reasons of practicability mFOLFOX6 was selected as the chemotherapy backbone for additive treatment (Allegra 2010).

Also, there is evidence that the combination of FOLFOX with panitumumab is associated with enhanced antitumor activity (Douillard et al. ESMO 2009). The experimental treatment arm will therefore evaluate the combination of FOLFOX plus panitumumab. Since in colorectal cancer monoclonal antibodies directed against the EGFR are not active in KRAS mutant patients, the experimental arm including panitumumab will only be performed in KRAS wild-type patients (Amado 2008).

The planned study aims to assess the efficacy of postoperative therapy with FOLFOX plus panitumumab followed by maintenance with panitumumab for 3 months in KRAS wild-type patients, compared to the historical data for standard FOLFOX chemotherapy alone, which are verified by a randomised control group without the antibody. (Figure 1: Study Design).

The study will allow preoperative treatment with regimens such as FOLFIRI, XELIRI, FOLFOX or XELOX +/-bevacizumab or +/- cetuximab. However, only those patients will be considered eligible who did not progress during preoperative therapy.

After surgery, a treatment-free interval of at least 4 weeks, but no longer than 8 weeks will be granted.

KRAS-wild-type patients (60% of all pts) will then be randomized in a 2:1 ratio to an experimental arm with FOLFOX + panitumumab or to a reference arm with FOLFOX alone. Combination treatment will be performed for a duration of 3 months, after which patients in the experimental arm will receive maintenance therapy with panitumumab for further 3 months. In the reference arm, treatment will, however, be ended after 3 months.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer KRAS Wildtype After Resection of Liver Metastases	Drug: Folic Acid Drug: 5-FU Drug: 5-FU Drug: Oxaliplatin Drug: Panitumumab Drug: Panitumumab Drug: Folic Acid Drug: 5-FU Drug: 5-FU Drug: Oxaliplatin	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

111 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Study Start Date :

Aug 1, 2011

Anticipated Primary Completion Date :

Aug 1, 2013

Anticipated Study Completion Date :

Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FOLFOX + Panitumumab	Drug: Folic Acid 400 mg/m2, 2h infusion, d1, q2w Drug: 5-FU 400 mg/m2 bolus iv, d1, q2w Drug: 5-FU 2400 mg/m2 46-h infusion, d1-2, q2w Drug: Oxaliplatin 85 mg/m2 d1, q2w Drug: Panitumumab 6 mg/kg BW every 2 weeks Drug: Panitumumab Panitumumab maintenance phase (3 months) 9mg/kg BW every 3 weeks
Active Comparator: FOLFOX	Drug: Folic Acid 400 mg/m2, 2-h infusion, d1, q2w Drug: 5-FU 400 mg/m2 bolus iv, d1, q2w Drug: 5-FU 2400 mg/m2 46-h infusion, d1-2, q2w Drug: Oxaliplatin 85 mg/m2 d1, q2w

Arm

Intervention/Treatment

Experimental: FOLFOX + Panitumumab

Drug: Folic Acid

400 mg/m2, 2h infusion, d1, q2w

Drug: 5-FU

400 mg/m2 bolus iv, d1, q2w

Drug: 5-FU

2400 mg/m2 46-h infusion, d1-2, q2w

Drug: Oxaliplatin

85 mg/m2 d1, q2w

Drug: Panitumumab

6 mg/kg BW every 2 weeks

Drug: Panitumumab

Panitumumab maintenance phase (3 months) 9mg/kg BW every 3 weeks

Active Comparator: FOLFOX

Drug: Folic Acid

400 mg/m2, 2-h infusion, d1, q2w

Drug: 5-FU

400 mg/m2 bolus iv, d1, q2w

Drug: 5-FU

2400 mg/m2 46-h infusion, d1-2, q2w

Drug: Oxaliplatin

85 mg/m2 d1, q2w

Outcome Measures

Primary Outcome Measures

Progression Free Survival [2 years after randomisation]

Secondary Outcome Measures

Tolerability and side effects [approximate 6 months after randomisation]
Overall Survival [2 years after randomisation]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient has provided written informed consent.
R0-resection of liver metastasis, at least four weeks but not longer than 8 weeks ago.
Histologically confirmed diagnosis of metastatic colorectal cancer confined to the liver
KRAS-wildtype of the tumor
Age 18 years or older
ECOG performance status 0-1
Females with child-bearing potential must use adequate contraceptive measures
Exclusion of pregnancy
Relevant toxicities of previous treatments must have subsided
Magnesium >= lower limit of normal; Calcium >= lower limit of normal
Normal cardiac function demonstrated by ECG and echocardiogram (LVEF ≥ 55%)
No symptomatic congestive heart failure
No unstable angina pectoris
No cardiac arrhythmia
Adequate organ function as defined by Table 1:
Hematologic: ANC (absolute neutrophil count) >= 1.5 G/L, Leucocytes > 3.0 G/L, Hemoglobin >= 9 g/dL, Platelets >= 100 G/L
Hepatic: Albumin >= 2.5 g/dL, Serum bilirubin <= 2 mg/dL, AST and ALT <= 3 x ULN
Renal: Serum Creatinine <= 1.5 mg/dL

Exclusion Criteria:

Known manifestations of metastatic disease
Progression during preoperative treatment
Missing KRAS mutation status of the tumor
Contraindication against therapy with 5-fluorouracil/ folinic acid or oxaliplatin
Known intolerability of panitumumab
Known DPD deficiency
Polyneuropathy > grade 1 (NCI-CTCv4) which precludes the use of oxaliplatin
Evidence of ascites or cirrhosis
Patient is pregnant or lactating or planning to become pregnant within 6 months after end of treatment
Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment
Has had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrolment, or there is an anticipated need for major surgical procedure during the course of the study
Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) <= 1 year before enrolment/randomization
History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan
Has a concurrent disease or condition that would make the subject inappropriate for study participation or would interfere with the subject's safety.
Has any psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
Requires concurrent cancer therapy (chemotherapy, radiation therapy, biologic therapy, immunotherapy, or hormonal therapy) while on study.
Requires concurrent treatment with an investigational agent, participation in another clinical trial, or any specifically prohibited medication while on study.
Has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to 5-fluorouracil, folinic acid, oxaliplatin, or panitumumab.
Other active malignancy
Known alcohol abuse or drug addiction
Incapability to give informed consent