Explorative Phase II Study of Perioperative Treatment in Patients With Adenocarcinoma of the Gastroesophageal Junction or Stomach (HerFLOT)

• ClinicalTrials.gov Identifier: NCT01472029
• Recruitment Status: Completed
• First Posted: November 16, 2011
• Last Update Posted: June 19, 2017
• Sponsor: AIO-Studien-gGmbH
• Collaborator: Roche Pharma AG
• Information provided by (Responsible Party): AIO-Studien-gGmbH

Study Description

Brief Summary:

The purpose of this study is 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.

Condition or disease	Intervention/treatment	Phase
Adenocarcinoma of the Gastroesophageal Junction; Adenocarcinoma of the Stomach	Drug: 5-FU, leucovorin, docetaxel, oxaliplatin (FLOT), trastuzumab; Drug: Post-operative treatment trastuzumab mono therapy	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 53 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: December 2011
• Actual Primary Completion Date: August 25, 2014
• Actual Study Completion Date: September 12, 2016

Arms and Interventions

Arm

Intervention/treatment

Experimental: 5-FU, leucovorin, docetaxel, oxaliplatin (FLOT), trastuzumab

Drug: 5-FU, leucovorin, docetaxel, oxaliplatin (FLOT), trastuzumab; Pre-operative treatment 4 cycles and post-operative treatment 4 cycles: Trastuzumab 4 mg/kg BW (6 mg loading dose at 1st administration), iv over 1 h on day 1 of each 14 day cycle Docetaxel 50 mg/m², iv over 2 h on day 1 of each 14 day cycle Oxaliplatin 85 mg/m² in 500 ml G5%, iv over 2h on day 1 of each 14 day cycle Leucovorin 200 mg/m² in 250 ml NaCl 0,9%, iv over 1 h on day 1 of each cycle 5-FU 2600 mg/m², iv over 24 h on day 1 of each 14 day cycle; Drug: Post-operative treatment trastuzumab mono therapy; Trastuzumab mono therapy for 9 cycles: Trastuzumab 6 mg/kg BW, iv over 1 h on day 1 of each 21 day cycle

Outcome Measures

Primary Outcome Measures :

1. 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. [ Time Frame: From enrollment to surgery after pre-operative treatment (4 cycles = 8 weeks) for 9 weeks. ]

   The experimental therapy would be rated as insufficiently active, if the observed pCR rate is 10 % or lower, as this corresponds to the expectations after chemotherapy alone.

   The experimental therapy would be considered to be a promising candidate for further development (e.g. in a phase III trial), if the true pCR rate amounted to 20% or more.

Secondary Outcome Measures :

1. R0 resection rate [ Time Frame: From enrollment to surgery after pre-operative treatment (4 cycles = 8 weeks) for 9 weeks. ]
   The R0 rate is defined as the number of patients with negative surgical margins and no tumor left macroscopically, divided by the total number of recruited eligible patients.
2. Relapse-free survival [ Time Frame: From enrollment to end of follow up assessed up to 58 months ]
   Relapse-free survival (RFS) will be defined as the time from enrolment to the time of disease progression or relapse or death, or to the date of last tumor assessment without any such event (censored observation)
3. Overall survival [ Time Frame: From enrollment to end of follow up assessed up to 58 months. ]
   The duration of overall survival (OS) will be determined by measuring the time interval from enrolment to the date of death or last observation, including survival rates after 1, 2 and 3 years.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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
• Normal cardiac ejection fraction, as assessed by echocardiography
• Written patient consent form

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

Contacts and Locations

Locations

Germany

Tagestherapiezentrum am ITM & III. Medizinische Klinik Universitätsmedizin Mannheim

Mannheim, Germany, D-68167

Sponsors and Collaborators

AIO-Studien-gGmbH

Roche Pharma AG

Investigators

• Principal Investigator: Ralf D Hofheinz, Prof. Dr.; Tagestherapiezentrum am ITM & III. Medizinische Klinik, Universitätsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hofheinz RD, Hegewisch-Becker S, Kunzmann V, Thuss-Patience P, Fuchs M, Homann N, Graeven U, Schulte N, Merx K, Pohl M, Held S, Keller R, Tannapfel A, Al-Batran SE. Trastuzumab in combination with 5-fluorouracil, leucovorin, oxaliplatin and docetaxel as perioperative treatment for patients with human epidermal growth factor receptor 2-positive locally advanced esophagogastric adenocarcinoma: A phase II trial of the Arbeitsgemeinschaft Internistische Onkologie Gastric Cancer Study Group. Int J Cancer. 2021 Sep 15;149(6):1322-1331. doi: 10.1002/ijc.33696. Epub 2021 May 29.

• Responsible Party: AIO-Studien-gGmbH
• ClinicalTrials.gov Identifier: NCT01472029
• Other Study ID Numbers: AIO-STO-0310; 2011-001507-13 ( EudraCT Number )
• First Posted: November 16, 2011
• Last Update Posted: June 19, 2017
• Last Verified: June 2017

Keywords provided by AIO-Studien-gGmbH:

Adenocarcinoma; Gastroesophageal junction; Stomach; HER2

Additional relevant MeSH terms:

Adenocarcinoma; Esophageal Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Head and Neck Neoplasms; Digestive System Diseases; Esophageal Diseases; Gastrointestinal Diseases; Leucovorin; Docetaxel; Oxaliplatin; Trastuzumab; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Antidotes; Protective Agents; Physiological Effects of Drugs; Vitamin B Complex; Vitamins; Micronutrients