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

Primary Purpose

Adenocarcinoma of the Gastroesophageal Junction, Adenocarcinoma of the Stomach

Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
5-FU, leucovorin, docetaxel, oxaliplatin (FLOT), trastuzumab
Post-operative treatment trastuzumab mono therapy
Sponsored by
AIO-Studien-gGmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adenocarcinoma of the Gastroesophageal Junction focused on measuring Adenocarcinoma, Gastroesophageal junction, Stomach, HER2

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Tagestherapiezentrum am ITM & III. Medizinische Klinik Universitätsmedizin Mannheim

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

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

Arm Description

Outcomes

Primary Outcome Measures

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.
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

R0 resection rate
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.
Relapse-free survival
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)
Overall survival
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.

Full Information

First Posted
October 24, 2011
Last Updated
June 16, 2017
Sponsor
AIO-Studien-gGmbH
Collaborators
Roche Pharma AG
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1. Study Identification

Unique Protocol Identification Number
NCT01472029
Brief Title
Explorative Phase II Study of Perioperative Treatment in Patients With Adenocarcinoma of the Gastroesophageal Junction or Stomach
Acronym
HerFLOT
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 Type
Interventional

2. Study Status

Record Verification Date
June 2017
Overall Recruitment Status
Completed
Study Start Date
December 2011 (undefined)
Primary Completion Date
August 25, 2014 (Actual)
Study Completion Date
September 12, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AIO-Studien-gGmbH
Collaborators
Roche Pharma AG

4. Oversight

Data Monitoring Committee
Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adenocarcinoma of the Gastroesophageal Junction, Adenocarcinoma of the Stomach
Keywords
Adenocarcinoma, Gastroesophageal junction, Stomach, HER2

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
53 (Actual)

8. Arms, Groups, and Interventions

Arm Title
5-FU, leucovorin, docetaxel, oxaliplatin (FLOT), trastuzumab
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
5-FU, leucovorin, docetaxel, oxaliplatin (FLOT), trastuzumab
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Post-operative treatment trastuzumab mono therapy
Intervention Description
Trastuzumab mono therapy for 9 cycles: Trastuzumab 6 mg/kg BW, iv over 1 h on day 1 of each 21 day cycle
Primary Outcome Measure Information:
Title
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.
Description
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.
Time Frame
From enrollment to surgery after pre-operative treatment (4 cycles = 8 weeks) for 9 weeks.
Secondary Outcome Measure Information:
Title
R0 resection rate
Description
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.
Time Frame
From enrollment to surgery after pre-operative treatment (4 cycles = 8 weeks) for 9 weeks.
Title
Relapse-free survival
Description
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)
Time Frame
From enrollment to end of follow up assessed up to 58 months
Title
Overall survival
Description
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.
Time Frame
From enrollment to end of follow up assessed up to 58 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ralf D Hofheinz, Prof. Dr.
Organizational Affiliation
Tagestherapiezentrum am ITM & III. Medizinische Klinik, Universitätsmedizin Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim
Official's Role
Principal Investigator
Facility Information:
Facility Name
Tagestherapiezentrum am ITM & III. Medizinische Klinik Universitätsmedizin Mannheim
City
Mannheim
ZIP/Postal Code
D-68167
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
34019698
Citation
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.
Results Reference
derived

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

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