A Study of Chemoradiation Associated With Nimotuzumab as the Treatment of Locally Advanced Esophageal Cancer

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to assess the efficacy of nimotuzumab in combination with chemotherapy and radiotherapy for the treatment of locally advanced esophageal cancer, comparing it to that of the conventional treatment with radiation and chemotherapy. The secondary objective of this study is to assess the health-related quality of life for the nimotuzumab in combination with chemotherapy and radiotherapy regimen, compared to the standard chemoradiation regimen in the treatment of inoperable locally advanced esophageal cancer.

Detailed Description
-----------------
This will be a phase II, randomized, controlled, open-label, multicenter, and two-arm study. The study will be conducted in Brazil and has the purpose of determining the activity and safety of nimotuzumab in terms of overall survival, TTP, clinical and endoscopic response rates, resectability rate, toxicity profile, and quality of life. All participating patients will sign a consent form before they undergo any study-related procedure. The eligible patients will have locally advanced esophageal cancer, and they will be randomized to one of two treatment groups. Randomization will be centrally coordinated by the sponsor and performed by means of the electronic CRF itself.

Official Title
-----------------
A Phase II, Randomized, Controlled, Open-Label Study Comparing Standard Chemoradiation Versus Chemoradiation Associated With Nimotuzumab as the Treatment of Locally Advanced Esophageal Cancer

Conditions
-----------------
Esophageal Cancer, Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: Nimotuzumab
* Drug: Cisplatin
* Drug: Fluorouracil
* Radiation: Radiotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years; Histological prove of SCC or esophageal adenocarcinoma; T1N1M0, T2N1M0, T3N0M0, T4N0M0, T3N1M0, T4N1M0, qqTqqNM1a stage, according to the TNM system42; Life expectation above 6 months; Inoperable superior, medial, or distal third esophageal cancer, including GE junction tumors, defined as type I and II tumors in the Siewert classification43 (see Appendix B); Performance status 0, 1, or 2, according to the Eastern Cooperative Oncology Group criteria44 (ECOG) (see Appendix C); Creatinine clearance ≥ 60 ml/min, according to the Cockcroft and Gault formula45 (see Appendix D); Adequate body functions, indicated by Creatinine clearance ≥ 60 ml/min; Bilirubin, transaminase, alkaline phosphatase, and gamma-GT < 1,5 x the upper limit of normal; leucocytes ≥ 3000/μl; granulocytes ≥ 1500/ μl; hemoglobin ≥ 9 g/dl; platelets ≥ 80000/ μl; Adequate calorie ingestion, at the investigator's discretion; He/she must have signed the informed consent form Exclusion Criteria: Previous or planned treatment of esophageal carcinoma with surgery, radiotherapy, chemotherapy, or antineoplastic biological therapy; Presence of active infection; Knowledge of the presence of HIV seropositivity; Presence of severe comorbidities that, in the investigator's opinion, will put the patient at a significantly higher risk or will damage the protocol compliance; Presence of a significant neurological or psychiatric disease, including dementia and seizures, as per the investigator's judgment; History of malignant neoplasm, except for adequately treated skin basal carcinoma or SCC, and cervical carcinoma in situ; Presence of peripheral neuropathy; Knowledge of the presence of hypersensitivity or allergy to drugs that will be administered in this protocol; History of severe allergic reaction; Pregnancy or lactation; Presence of aerodigestive fistula (trachea and/or bronchia); Evident presence of trachea and/or bronchia infiltration by the tumor; Presence of uncontrolled hypercalcaemia ≥ 2.9 mmol/L (or grade >1, according to the NCI-CTCAE, version 3.0).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: STANDARD CHEMORADIATION<br>Cisplatin 75 mg/m2, IV IV doses on D1 of each chemotherapy cycle, for 4 cycles Fluorouracil 1000 mg/m2, IV IV doses in a 24-hour continuous infusion, from D1 to D4 of each chemotherapy cycle, for 4 cycles. Radiotherapy 50.4 Gy, fractions of 1.8 Gy/day Equivalent to 28 fractions for 5 and a half weeks. | Drug: Nimotuzumab<br>* 200 mg, IV Weekly IV dose for up to 26 weeks.<br>Drug: Cisplatin<br>* 75 mg/m2, IV dose on D1 of each chemotherapy cycle, for 4 cycles, always after nimotuzumab.<br>Drug: Fluorouracil<br>* 1,000 mg/m2, IV dose in a 24-hour continuous infusion, from D1 to D4, every chemotherapy cycle, for 4 cycles.<br>Radiation: Radiotherapy<br>* Radiotherapy 50.4 Gy, fractions of 1.8 Gy/day<br>|
| Experimental: CHEMORADIATION + NIMOTUZUMAB<br>Nimotuzumab 200 mg, IV weekly IV doses for up to 26 weeks. Cisplatin 75 mg/m2, IV IV dose on D1 of each chemotherapy cycle, for 4 cycles, always after nimotuzumab. Fluorouracil 1000 mg/m2, IV IV dose in a 24-hour continuous infusion, from D1 to D4 of each chemotherapy cycle, for 4 cycles. Radiotherapy 50.4 Gy, fractions of 1.8 Gy/day Equivalent to 28 fractions for 5 and a half weeks. | Drug: Nimotuzumab<br>* 200 mg, IV Weekly IV dose for up to 26 weeks.<br>Drug: Cisplatin<br>* 75 mg/m2, IV dose on D1 of each chemotherapy cycle, for 4 cycles, always after nimotuzumab.<br>Drug: Fluorouracil<br>* 1,000 mg/m2, IV dose in a 24-hour continuous infusion, from D1 to D4, every chemotherapy cycle, for 4 cycles.<br>Radiation: Radiotherapy<br>* Radiotherapy 50.4 Gy, fractions of 1.8 Gy/day<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival and assessment of the complete endoscopic response | The primary endpoint of this study is the overall survival at the end of Phase II. At the end of Phase II, the assessment of the complete endoscopic response, and the regimen safety will be used to decide if the study will continue to Phase III. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete clinical response rate | Time to tumor progression (TTP); Complete clinical response rate, defined as the proportion of patients with absence of visible disease in the high endoscopy and in the chest and abdomen computerized tomography, in the population assessable for response; Complete endoscopic response rate, defined as the absence of visible disease in the high endoscopy; Resectability rate; Safety: Quality of life, according to the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire; Relationship between efficacy and safety and the tumor characteristics. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Esophageal Cancer, Nimotuzumab, EF024, EF024-201