Clinical trial NCT01262183: Radio-chemotherapy With or Without Panitumumab (Vectibix®) in Irresectable Squamous Cell Carcinoma or Adenocarcinoma of the Oesophagus
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Irresectable Squamous Cell or Adenocarcinoma of the Oesophagus
Keywords: oesophagus cancer
chemoradiotherapy
panitumumab
irresectable
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2010-12-17
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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)

For the PET-scan the following exclusion criteria are used:

* Severe claustrophobia
* Diabetes mellitus (type I and II)
* Serum glucose level \>11 mmol/L

Primary outcomes:
measure: 1-year overall survival
timeFrame: 1-year
Secondary outcomes:
measure: toxicity
timeFrame: during treatment and follow up
measure: PFS
timeFrame: between randomisation and date of PD
measure: Response Rate
timeFrame: 3 months after treatment
measure: pharmacodynamics of panitumumab
timeFrame: biopsy at baseline (standard) and the biopsy one week after start chemo-radiation therapy
measure: Quantification of baseline FDG uptake (SUV) with PET, and SUV changes
timeFrame: baseline 7 days after the first panitumumab dose or for start chemo-radiation therapy. during treatment with chemoradiation therapy after three weeks.
measure: CTCs and CECs
timeFrame: baseline,after 2 weeks during chemo-radiation therapy and 12 weeks after finishing treatment
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: University Medical Centre Nijmegen
state: Gelderland
Study officials:
affiliation: University Medical Centre Nijmegen
name: C.M.L. van Herpen, Md PhD
role: PRINCIPAL_INVESTIGATOR
References: