PANORAMIC: Radio-chemotherapy With or Without Panitumumab (Vectibix®) in Irresectable Squamous Cell Carcinoma or Adenocarcinoma of the Oesophagus

Sponsor

Radboud University Medical Center (Other)

Overall Status

Terminated

CT.gov ID

NCT01262183

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

For esophageal cancer that can not be removed by surgery, the choice of treatment is a combination of chemotherapy and radiotherapy. We call this combination- (or concurrent) chemoradiotherapy. Chemotherapy is treatment with drugs that kill cancer cells. Both chemotherapy and radiotherapy make the tumour smaller and enhance each other's effect. The goal of treatment with chemotherapy and radiation therapy is to cure the cancer. Unfortunately only a small proportion of patients are cured with this treatment.

Improvements in the outcome of treatment may be expected by using the so-called "targeted" treatments. With esophageal cancer, a protein (the epidermal growth factor receptor (this is a kind of trap), the EGFR), is present in many tumours. This protein causes the tumor to grow. Panitumumab is a drug that blocks the functioning of this receptor (catcher), so that possibly the growth and spread of esophageal cancer is prevented.

The main objective of this trial is to see if survival of patients with inoperable esophageal cancer improves as panitumumab is added to standard treatment with chemoradiotherapy.

It will also investigate whether patients tolerate the addition of panitumumab to the standard treatment. Also, the biological characteristics of the tumor will be examined. In a proportion of patients it will be determined how the enhancement of the cancer is visible on an FDG-PET scan before the start of treatment and how this changes during the treatment. It will be also be evaluated how this treatment affects the survival.

Condition or Disease	Intervention/Treatment	Phase
Irresectable Squamous Cell or Adenocarcinoma of the Oesophagus	Drug: CRT + Panitumumab Drug: Concurrent chemoradiation therapy without panitumumab	Phase 2

Detailed Description

A complete response rate of approximately 30% is achieved for standard treatment of irresectable carcinoma of the oesophagus, consisting of concurrent chemoradiation therapy (50.5 Gy + cisplatin/5-FU). Attempts to improve outcome by intensifying conventional cytotoxic drugs or increasing the radiation dose have not been successful. Future improvements will likely require the incorporation of targeted agents that probably will not add significant toxicity, the use of molecular predictors of response and early identification of responders. In both squamous cell carcinoma and adenocarcinoma of the oesophagus expression of EGFR is correlated with poor outcome. Furthermore the addition of cetuximab, a chimaeric EGFR antibody, to radiation therapy in head and neck cancer and non-small cell lung cancer showed a gain in overall survival. In head and neck cancer studies with the addition of panitumumab to chemo-radiation therapy are currently ongoing. Therefore, we propose to perform a randomised phase II study of chemo-radiation therapy with or without the combination of panitumumab (human EGFR antibody) in irresectable squamous cell carcinoma or adenocarcinoma of the oesophagus without distant metastases.

Study Design

Study Type:

Interventional

Actual Enrollment :

4 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomised Phase II Study of Radio-chemotherapy With or Without Panitumumab (Vectibix®) in Irresectable Squamous Cell Carcinoma or Adenocarcinoma of the Oesophagus

Study Start Date :

Jan 1, 2011

Actual Primary Completion Date :

Apr 1, 2012

Anticipated Study Completion Date :

Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Concurrent chemoradiation therapy with panitumumab	Drug: CRT + Panitumumab Day -7, day +15 and day +36: panitumumab 9.0 mg/kg i.v. Day +1 to +39: radiation therapy 1.8 Gy fractions 5 times per week to a cumulative dose of 50.4 Gy Day +1 and +29: cisplatin 75 mg/m2 i.v. Day +1 to +4 and +29 to +32: 5-fluorouracil 1000 mg/m2 i.v.
Active Comparator: Concurrent chemoradiation therapy without panitumumab	Drug: Concurrent chemoradiation therapy without panitumumab Day +1 to +39: radiation therapy 1.8 Gy fractions 5 times per week to a cumulative dose of 50.4 Gy Day +1 and +29: cisplatin 75 mg/m2 i.v. Day +1 to +4 and +29 to +32: 5-fluorouracil 1000 mg/m2 i.v.

Arm

Intervention/Treatment

Experimental: Concurrent chemoradiation therapy with panitumumab

Drug: CRT + Panitumumab

Day -7, day +15 and day +36: panitumumab 9.0 mg/kg i.v. Day +1 to +39: radiation therapy 1.8 Gy fractions 5 times per week to a cumulative dose of 50.4 Gy Day +1 and +29: cisplatin 75 mg/m2 i.v. Day +1 to +4 and +29 to +32: 5-fluorouracil 1000 mg/m2 i.v.

Active Comparator: Concurrent chemoradiation therapy without panitumumab

Drug: Concurrent chemoradiation therapy without panitumumab

Day +1 to +39: radiation therapy 1.8 Gy fractions 5 times per week to a cumulative dose of 50.4 Gy Day +1 and +29: cisplatin 75 mg/m2 i.v. Day +1 to +4 and +29 to +32: 5-fluorouracil 1000 mg/m2 i.v.

Outcome Measures

Primary Outcome Measures

1-year overall survival [1-year]
To describe the 1-year OS rate after concurrent CRT with or without panitumumab in irresectable carcinoma of the oesophagus. The control arm is used to validate whether the historical cohort used for comparison is similar to our success-rate.

Secondary Outcome Measures

toxicity [during treatment and follow up]
Investigation of the acute and long-term toxicity of both study arms (according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0);
PFS [between randomisation and date of PD]
PFS: interval between randomisation date and the date at which disease progression is established being not suspicious for a second cancer (histologically confirmed when in doubt) or date of death from any cause but clearly not related to disease- or treatment (e.g. accident). Patients still disease-free after 18 months follow-up or lost to follow-up or death clearly not related to disease or treatment (e.g. accident)), are censored at the date of the most recent follow-up or at the analysis cut-off date, whichever comes first.
Response Rate [3 months after treatment]
Response rate: partial (PR) or complete response (CR) according to RECIST 1.1 at 3 months after treatment
pharmacodynamics of panitumumab [biopsy at baseline (standard) and the biopsy one week after start chemo-radiation therapy]
pharmacodynamics (PD) of panitumumab (EGFR, K-RAS, B-RAF, downstream signalling pathways ) compared between the biopsy at baseline (standard) and the biopsy one week after start chemo-radiation therapy
Quantification of baseline FDG uptake (SUV) with PET, and SUV changes [baseline 7 days after the first panitumumab dose or for start chemo-radiation therapy. during treatment with chemoradiation therapy after three weeks.]
baseline, 7 days after the first panitumumab dose or for start chemo-radiation therapy. during treatment with chemoradiation therapy after three weeks. 2-4 weeks after finishing treatment. 10-12 weeks after finishing treatment
CTCs and CECs [baseline,after 2 weeks during chemo-radiation therapy and 12 weeks after finishing treatment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 18 - 70years
Histology proven SCC or adenocarcinoma of the oesophagus
No proven (distant) metastases (ultrasonography, CT or MRI)
No prior treatment for carcinoma of the oesophagus
Karnofsky performance status ≥70% (appendix A)
Irresectable disease as assessed by the multidisciplinary tumour board
All patients (male and female) must use effective contraception methods according to CPMP/ICH/286/95 if of reproductive potential (e.g. implants, injectables, combined oral contraceptives, IUDs, sexual abstinence or vasectomised partner), for the whole duration of the study and until six months after they received the last treatment dose
No contraindications for cytotoxic therapy or panitumumab:
No known hypersensitivity/allergy to any of the compounds used
Haematology: Neutrophil count ≥ 1.5∙109 /L Thrombocyte count ≥ 100∙109 /L Haemoglobin ≥ 6.2 mmol/L (100 g/L)
No known HIV infection or other condition of persistent immunodeficiency
Renal function:
Creatinine clearance (MDRD) ≥ 60 mL/min
Hepatic function:
Total bilirubin ≤ 1.5∙ULN
AST, ALT, AP ≤ 2.5∙ULN
Electrolyte balance:
(albumin corrected) calcium ≤ 2.87 mmol/L (=11.5 mg/dl) but ≥ lower limit of normal (LLN)
Magnesium ≥ LLN
History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan.
No known other serious illness or medical condition present at entry in the study including: Unstable cardiac disease despite treatment, congestive heart failure NYHA grade 3 and 4 Clinically significantly abnormal electrocardiogram (ECG) or left ventricular ejection fraction (LVEF) below the institutional ULN
Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrolment/randomisation
Significant neurologic or psychiatric disorders
Active uncontrolled infection Active disseminated intravasal coagulation
Symptomatic peripheral neuropathy (CTCAE v3.0 term "neuropathy: sensory") ≥ grade 2 Ototoxicity (CTCAE v3.0 any term in "auditory/ear") ≥ grade 2 except if due to trauma or mechanical impairment due to tumour mass
Other serious underlying medical condition which could impair the ability of the patient to participate in the study No or insufficient oral nutrient intake
No prior exposure to EGFR pathway targeting agents
No known drug abuse
Absence of any psychological, familial, sociological (e.g. severe alcohol addiction expected to hamper protocol compliance) or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
No participation in another interventional clinical trial in the preceding 30 days
Written informed consent to participate to study must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

Prior treatment for this tumour
Prior treatment with radiation therapy in the area of the oesophagus or other site that will interfere with proposed treatment
Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the 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.
History of other prior malignancy in past 5 years, other than basal cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ.

Exclusion criteria for the PET-scan (secondary endpoint)