Clinical Trial of Chemotherapy Combination Cisplatin-Fluorouracil-Afatinib in Patients With Inoperable Gastric Cancer (A-GAPP)

September 2, 2019 updated by: Hellenic Cooperative Oncology Group

A Phase II, Single-arm Clinical Trial of Administration of Cisplatin and 5- Fluorouracil With Afatinib as First-line Therapy in Patients With Inoperable Gastric or Gastroesophageal Junction Cancer

The purpose of this study is to evaluate the efficacy and safety of the combination of Cisplatin,5-Fluorouracil(5FU) and Afatinib as first-line therapy in patients with advanced gastric or gastroesophageal junction cancer. The study will include 55 patients in all. The patients will receive open-label Cisplatin intravenous 75mg/m2 on Day 1, 5FU 750mg/m2 at 24-hour intravenous infusion on Days 1-4, and Afatinib 40mg per os on Days 3-5, 8-12, 15-19.

The administration of Afatinib will start on Day 3 of each therapy cycle with an administration interval on each weekend ("Weekday on, Weekend off") for 21 days. Instructions are given on the dose reduction scheme in the presence of toxicity. The administration of the combination Cisplatin-5FU-Afatinib will be continued until disease progression, appearance of significant toxicity, completion of 6 treatment cycles, or withdrawal of consent. At completion of 6 cycles of the combination, in the absence of disease progression, the administration of Afatinib as maintenance monotherapy will be continued until disease progression, appearance of significant toxicity, or withdrawal of consent at the weekday on-weekend off schedule. Imaging will be applied once every 8 weeks, and once every 12 weeks in the Afatinib maintenance therapy phase.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

55

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Greece
      • Athens, Greece, 11528
        • Oncology Section, Dept of Clinical Therapeutics, General Hospital of Athens "Alexandra"
      • Athens, Greece, 14564
        • 2nd Dept of Medical Oncology, Agii Anargiri Cancer Hospital
      • Athens, Greece, 14564
        • 3rd Dept of Medical Oncology, Agii Anargiri Cancer Hospital
      • Athens, Greece, 15123
        • 3rd Dept of Medical Oncology, Hygeia Hospital
      • Athens, Greece, 18547
        • 1st Dept of Medical Oncology, Metropolitan Hospital
      • Athens, Greece, 18547
        • 2nd Dept of Medical Oncology, Metropolitan Hospital
      • Athens, Greece, 11522
        • 2nd Dept of Internal Medicine, Agios Savvas Cancer Hospital
      • Athens, Greece, 11527
        • 2nd Dept of Internal Medicine, General Hospital of Athens "Hippokratio"
      • Athens, Greece, 11525
        • Dept of Medical Oncology, 251 Air Force Hospital
      • Athens, Greece, 12462
        • Division of Oncology, 2nd Dept of Internal Medicine, University Hospital "Attikon"
      • Heraklion, Greece, 71110
        • Dept of Medical Oncology, University Hospital of Heraklion
      • Ioannina, Greece, 45110
        • Dept of Medical Oncology, Ioannina University Hospital
      • Patras, Greece, 26504
        • Division of Oncology, Dept of Internal Medicine, University Hospital of Patras
      • Thessaloniki, Greece, 56429
        • Dept of Medical Oncology, Papageorgiou General Hospital
      • Thessaloniki, Greece, 57001
        • Dept of Medical Oncology, Thermi Clinic S.A

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with histological or cytological diagnosis of gastric and/or gastroesophageal junction adenocarcinoma/carcinoma.
  • Locally advanced or metastatic inoperable disease.
  • Life expectancy ≥12 weeks.
  • Patients who may have undergone any type of palliative treatment for localised disease, including surgical approaches and palliative radiotherapy, but not in the last four weeks before the trial.
  • Adequate bone marrow, hepatic and renal functional reserves (ANC≥1500mm3, PLT≥100mm3, GFR≥50ml/min by Gault Formula, bilirubin <1.5x, Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) <2.5x upper normal limit or 5x in the presence of hepatic metastases).
  • Patients must be able to swallow pharmaceutical tablets and to be eligible to receive intravenous chemotherapy.
  • Men or women patients must be at least 18 years old.
  • Performance Status Scale 0 or 1 (ECOG).
  • Measurable disease according to RECIST 1.1.
  • Left ventricular ejection fraction (LVEF) ≥50% (ECHO or MUGA).
  • Provision of patient informed consent for participation in the study and for the use of biological material for research purposes.
  • Willingness and ability to comply with scheduled medical visits, therapeutic treatment programmes, laboratory testing and other study procedures.

Exclusion Criteria:

  • Previous systemic first-line therapy.
  • Previous therapy with EGFR/HER Tyrosine Kinase Inhibitor (TKI) or other experimental agent.
  • Diagnosis of a second malignancy, except basal cell carcinoma of the squamous epithelium or in situ carcinoma of any organ, for which an appropriate treatment has been administered without indications of relapse for 12 months.
  • Presence of uncontrolled, active brain metastases (controlled brain metastases are considered those that have been irradiated and have remained stable for at least 4 weeks after radiation therapy).
  • Diagnosis of spinal cord compression or carcinomatous meningitis.
  • Any of the following that has occurred within 12 months before the start of the study treatment: myocardial infarction, serious or unstable angina pectoris, aortic-coronary or peripheral bypass surgery, symptomatic heart failure, vascular stroke, or transient ischemic attack, or pulmonary embolism.
  • Continuing grade ≥2 heart rate abnormalities; atrial fibrillation of any grade.
  • Hypertension uncontrolled by medication treatment (>150/100 mm/Hg despite the administration of best medical therapy).
  • In the case of previous irradiation of locally advanced disease, absence of measurable tumor sites outside the irradiation field.
  • Presence of any other disease which in the opinion of the doctor responsible constitutes a contraindication for the administration of cisplatin, 5FU or afatinib.
  • Diagnosed human immunodeficiency virus (HIV) or disease associated with Acquired Immunodeficiency Syndrome (AIDS).
  • Pregnancy or lactation. Female patients must be surgically sterilised, menopausal, or must consent to use effective contraception throughout the course of the trial.All female patients with reproduction ability must undergo a pregnancy test (serum or urine). The effective contraceptive technique will be determined by the main investigator or a person authorized by the investigator.
  • Any other serious, acute or chronic, medical or psychiatric condition or laboratory analysis finding which, in the investigator's opinion, could create excessive danger as regards the patient's participation in the trial or administration of the trial medication may render a patient ineligible for inclusion in the trial.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Cisplatin-5FU-Afatinib
Cisplatin 75mg/m2 iv administered on Day 1, 5FU 750mg/m2 at 24-hour iv infusion on Days 1-4, Afatinib (BIBW-2992) 40mg per os on Days 3-5, 8-12, 15-19 of each cycle. Administration of Afatinib will start on Day 3 of each cycle with an administration interval on each weekend ("Weekday on, Weekend off") for 21 days. The administration of the combination Cisplatin-5FU-Afatinib will be continued until disease progression, appearance of significant toxicity, completion of 6 cycles, or withdrawal of consent. At completion of 6 cycles of the combination, in the absence of disease progression, the administration of Afatinib as maintenance monotherapy will be continued until disease progression, appearance of significant toxicity, or withdrawal of consent at the weekday on-weekend off schedule.
Drug: Cisplatin-5FU-Afatinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Objective Response Rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Time Frame: At an average of 6 months for each patient
Imaging will be performed once every 8 weeks during treatment with cisplatin-5FU-afatinib (6 cycles), and once every 12 weeks in the Afatinib maintenance therapy phase.
At an average of 6 months for each patient

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluation of Overall Survival (OS)
Time Frame: OS will be calculated from the date of treatment initiation to the date of death from any cause assessed up to 36 months.
OS will be calculated from the date of treatment initiation to the date of death from any cause assessed up to 36 months.
Evaluation of Progression-Free Survival (PFS)
Time Frame: PFS will be calculated from the date of treatment initiation to the date of disease progression or date of death, assessed up to 36 months.
PFS will be calculated from the date of treatment initiation to the date of disease progression or date of death, assessed up to 36 months.
Assessment of safety and tolerability
Time Frame: Assessed up to 36 months

Distribution of Adverse Events (AEs) according to severity grade.

Evaluation of AEs will be performed:

On Day 1 and day 10 in cycle 1,on Day 1 in cycles 2-6 (every 21 days) and on Day 1 during maintenance treatment with afatinib (every 4 weeks).
Assessed up to 36 months
Value of prognostic and/or predictive biomarkers measured in tissue and blood samples
Time Frame: Tumor blocks and blood samples will be collected at baseline

Immunochemical expression of proteins/messenger ribonucleic acid (mRNA) of the tumor that can be linked to the efficacy / safety of the treatment, the tumor angiogenesis and the mechanism of action of the combination cisplatin/5FU/Afatinib.

In bioptic material for gastric or gastroesophageal adenocarcinoma:

  • Epidermal Growth Factor Receptor (EGFR) immunohistochemical expression;
  • EGFR gene amplification (chromosome 7 gene number by FISH);
  • mRNA levels of the EGFR ligands epiregulin and amphiregulin;
  • Kirsten Rat Sarcoma (KRAS) mutations;
  • Human Epidermal Growth Factor Receptor 2 (HER2) immunohistochemical expression and gene amplification
  • HER2 p95, Human Epidermal Growth Factor Receptor 3 (HER3), Human Epidermal Growth Factor Receptor 4 (HER4) immunohistochemical and mRNA expression

In peripheral blood and plasma:HER2 shed extracellular domain (ECD)

There may be additions to the biomarkers to be analysed, dependent on the clinical and bibliographical data.
Tumor blocks and blood samples will be collected at baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hellenic Cooperative Oncology Group

Collaborators

Boehringer Ingelheim

Investigators

  • Study Chair: George Pentheroudakis, Ass.Prof, Dept of Medical Oncology, Ioannina University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 11, 2013

Primary Completion (Actual)

June 15, 2019

Study Completion (Actual)

July 29, 2019

Study Registration Dates

First Submitted

November 28, 2012

First Submitted That Met QC Criteria

December 4, 2012

First Posted (Estimate)

December 6, 2012

Study Record Updates

Last Update Posted (Actual)

September 4, 2019

Last Update Submitted That Met QC Criteria

September 2, 2019

Last Verified

August 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HE7/12
  • 2011-006198-25 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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