Multicenter, explorative phase II study of perioperative 5-FU, leucovorin, docetaxel, and oxaliplatin (FLOT) in combination with Trastuzumab in patients with HER2-positive, locally advanced resectable adenocarcinoma of the gastroesophageal junction or stomach (HerFLOT) - HerFLOT

Phase 1

• Conditions: HER2-positive, locally advanced, resectable adenocarcinoma of the gastroesophageal junction or stomch; MedDRA version: 16.0Level: LLTClassification code 10066354Term: Adenocarcinoma of the gastroesophageal junctionSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 16.0Level: PTClassification code 10001150Term: Adenocarcinoma gastricSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2011-001507-13-DE
• Lead Sponsor: AIO-Studien-gGmbH

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2011-07-05
• Last Update Posted: 31 January 2017

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 265

Inclusion Criteria

• Histologically confirmed adenocarcinoma of the gastroesophageal junction (AEG I-III) or the stomach (uT2, uT3, uT4, any N category, M0), or any T N+ M0 patient, with the following specifications:
- Endosonography and an esophageal-gastro-duodenoscopy
- Categorization of gastroesophageal junction tumors according to the classification by Siewert (1987, cf. appendix 2)
• Detection of an adenocarcinoma with HER2 3+ (IHC) or HER2 2+ (IHC) with amplification proven by FISH, SISH or CISH by an accredited local pathologist (for quality assurance tumor samples have to be available for a subsequent central review)
• No preceding cytotoxic or targeted therapy
• Male and female patients aged = 18 years. If able to reproduce, patients must be willing to use highly effective methods of contraception during treatment and for 6 months after the end of treatment (adequate: methods fulfilling the requirements of the Note for guidance on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals [CPMP/ICH/286/95 mod]). Female patients with reproductive ability must have performed a negative pregnancy test within 7 days of study entry.
• ECOG = 2
• Exclusion of distant metastasis by CT of thorax and abdomen, bone scan or MRI (if osseous lesions are suspected due to clinical signs)
• Laparoscopic exclusion of peritoneal carcinomatosis, if suspected clinically
• Adequate haematological, hepatic and renal function parameters:
Leukocytes = 3000/mm³, platelets = 100,000/mm3
Serum creatinine = 1.5 x upper limit of normal, or GFR > 40 ml/min
Bilirubin = 1.5 x upper limit of normal, AST and ALT = 3.5 x upper limit of normal, alkaline phosphatase = 6 x upper limit of normal
• Written patient consent form
• Normal cardiac ejection fraction, as assessed by echocardiography
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 265
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 265

Exclusion Criteria

• Known hypersensitivity against trastuzumab, murine proteins, 5-FU, leucovorin, oxaliplatin, or docetaxel
• Other known contraindications against trastuzumab, 5-FU, leucovorin, oxaliplatin, or docetaxel
• Clinically significant active coronary heart disease, cardiomyopathy or congestive heart failure, NYHA III-IV
• Clinically significant valvular defect
• Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated basal cell carcinoma of the skin and in situ carcinoma of the cervix
• Known brain metastases
• Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy
• Other severe internal disease or acute infection
• Peripheral polyneuropathy > NCI Grade II
• Chronic inflammatory bowel disease
• On-treatment participation in another clinical study in the period 30 days prior to inclusion and during the study
• Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
• Patients in a closed institution according to an authority or court decision (AMG § 40, Abs. 1 No. 4)
• Any other concurrent antineoplastic treatment including irradiation

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Primary objective of the study is to estimate the efficacy of the trastuzumab/FLOT combination consisting of 5-FU/leucovorin, oxaliplatin, docetaxel and the antibody in locoregional cancer of the stomach or gastroesophageal junction, based on the rate of complete pathological responses (percentage of patients with pCR referring to the total number of enrolled and eligible patients), as evaluated centrally by a reference pathologists.;Secondary Objective: • Safety and tolerability of the trastuzumab/FLOT regimen<br>• Evaluation of prognostic and predictive markers<br>• Perioperative morbidity and mortality;Primary end point(s): To determine the rate of complete pathological responses (percentage of patients with pCR referring to the total number of enrolled and eligible patients), as evaluated centrally by a reference pathologist;Timepoint(s) of evaluation of this end point: Surgery after 4 pre-operative Cycles with FLOT + Trastuzumab

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1) R0 resection rate<br>2) Relapse-free survival<br>3) Overall survival, including survival rates after 1, 2 and 3 years<br>4) Evaluation of pCR as a surrogate endpoint<br>;Timepoint(s) of evaluation of this end point: 1) Surgery after 4 pre-operative Cycles with FLOT + Trastuzumab<br>2) Last survey without relaps before relaps or death<br>3) Date of death or last confirmed date alive<br>4) Surgery after 4 pre-operative Cycles with FLOT + Trastuzumab