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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Hellenic Cooperative Oncology Group
Sponsor:
Collaborator:
Boehringer Ingelheim
Information provided by (Responsible Party):
Hellenic Cooperative Oncology Group
ClinicalTrials.gov Identifier:
NCT01743365
First received: November 28, 2012
Last updated: February 7, 2014
Last verified: February 2014
  Purpose

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.


Condition Intervention Phase
Gastric Cancer
Gastroesophageal Junction Cancer
Drug: Cisplatin-5FU-Afatinib
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Hellenic Cooperative Oncology Group:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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. ] [ Designated as safety issue: No ]
  • 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. ] [ Designated as safety issue: No ]
  • Assessment of safety and tolerability [ Time Frame: Assessed up to 36 months ] [ Designated as safety issue: Yes ]

    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).


  • 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 ] [ Designated as safety issue: No ]

    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.



Estimated Enrollment: 55
Study Start Date: January 2013
Estimated Study Completion Date: November 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01743365

Contacts
Contact: George Pentheroudakis, Ass.Prof 0030 26510 99394 gpenther@otenet.gr

Locations
Greece
Oncology Section, Dept of Clinical Therapeutics, General Hospital of Athens "Alexandra" Recruiting
Athens, Greece, 11528
Contact: Christos Papadimitriou, Ass.Prof       chr_papadim@yahoo.gr   
Principal Investigator: Christos Papadimitriou, Ass.Prof         
Division of Oncology, 2nd Dept of Internal Medicine, University Hospital "Attikon" Recruiting
Athens, Greece, 12462
Contact: Nikolaos Xiros, MD       nxiros@otenet.gr   
Principal Investigator: Nikolaos Xiros, MD         
3rd Dept of Medical Oncology, Hygeia Hospital Recruiting
Athens, Greece, 15123
Contact: Evangelia Razis, MD       e.razis@hygeia.gr   
Principal Investigator: Evangelia Razis, MD         
2nd Dept of Internal Medicine, Agios Savvas Cancer Hospital Recruiting
Athens, Greece, 11522
Contact: Dimitrios Tryfonopoulos, MD       tryf@hol.gr   
Principal Investigator: Dimitrios Tryfonopoulos, MD         
1st Dept of Medical Oncology, Metropolitan Hospital Recruiting
Athens, Greece, 18547
Contact: Elena Linardou, MD       elinardou@otenet.gr   
Principal Investigator: Elena Linardou, MD         
2nd Dept of Medical Oncology, Agii Anargiri Cancer Hospital Recruiting
Athens, Greece, 14564
Contact: Gerassimos Aravantinos, MD       bpstudies@yahoo.gr   
Principal Investigator: Gerassimos Aravantinos, MD         
2nd Dept of Medical Oncology, Metropolitan Hospital Recruiting
Athens, Greece, 18547
Contact: Dimosthenis V. Skarlos, MD       hecogiat@otenet.gr   
Principal Investigator: Dimosthenis V. Skarlos, MD         
2nd Dept of Internal Medicine, General Hospital of Athens "Hippokratio" Recruiting
Athens, Greece, 11527
Contact: Dimitrios Pectasides, Prof.       pectasid@otenet.gr   
Principal Investigator: Dimitrios Pectasides, Prof.         
3rd Dept of Medical Oncology, Agii Anargiri Cancer Hospital Recruiting
Athens, Greece, 14564
Contact: Joseph Sgouros, MD       josephsgouros@yahoo.co.uk   
Principal Investigator: Joseph Sgouros, MD         
Dept of Medical Oncology, University Hospital of Heraklion Recruiting
Heraklio, Greece, 71110
Contact: Ioannis Souglakos, MD       johnsougl@gmail.com   
Principal Investigator: Ioannis Souglakos, MD         
Dept of Medical Oncology, Ioannina University Hospital Recruiting
Ioannina, Greece, 45110
Contact: George Pentheroudakis, Ass.Prof       gpenther@otenet.gr   
Principal Investigator: George Pentheroudakis, Ass.Prof         
University Hospital of Larissa, Oncology Dept Recruiting
Larissa, Greece, 41110
Contact: Christos Papandreou, Professor    0030 2413502785    cpapandreou@med.uth.gr   
Principal Investigator: Christos Papandreou, Professor         
Division of Oncology, Dept of Internal Medicine, University Hospital of Patras Recruiting
Patras, Greece, 26504
Contact: Thomas Makatsoris, MD       maktom@yahoo.com   
Principal Investigator: Thomas Makatsoris, MD         
Dept of Medical Oncology, Papageorgiou General Hospital Recruiting
Thessaloniki, Greece, 56429
Contact: George Fountzilas, Professor       fountzil@auth.gr   
Principal Investigator: George Fountzilas, Professor         
Sponsors and Collaborators
Hellenic Cooperative Oncology Group
Boehringer Ingelheim
Investigators
Study Chair: George Pentheroudakis, Ass.Prof Dept of Medical Oncology, Ioannina University Hospital
  More Information

No publications provided

Responsible Party: Hellenic Cooperative Oncology Group
ClinicalTrials.gov Identifier: NCT01743365     History of Changes
Other Study ID Numbers: HE7/12, 2011-006198-25
Study First Received: November 28, 2012
Last Updated: February 7, 2014
Health Authority: Greece: National Organization for Medicines
Greece: National Ethics Committee
Greece: Ministry of Health and Welfare

Additional relevant MeSH terms:
Stomach Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Cisplatin
Fluorouracil
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Radiation-Sensitizing Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 22, 2014