HER2 Imaging Study to Identify HER2 Positive Metastatic Breast Cancer Patient Unlikely to Benefit From T-DM1 (ZEPHIR)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2016 by Jules Bordet Institute
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
Jules Bordet Institute
ClinicalTrials.gov Identifier:
NCT01565200
First received: March 22, 2012
Last updated: April 4, 2016
Last verified: April 2016
  Purpose

T-DM1 , which is a highly innovative but also expensive antiHER2 agent consisting in the coupling of the humanised monoclonal antibody trastuzumab with a cytotoxic agent (maytansine derivate) has shown an encouraging antitumor activity evaluated by Recist criteria (35% objective response rate, 44% stable disease, 18% progressive disease) in patients with advanced HER2 positive Breast Cancer pretreated with several cytotoxic drugs, trastuzumab and lapatinib.

Rationale I :For TDM1 to be active, the presence of an intact HER2 receptor is "key" since the internalization of the cytotoxic moiety depends on the binding of trastuzumab to the external domain of HER2.

The zirconium 89 labelled trastuzumab PET/CT (or HER2 immunoPET/CT) is a non invasive test which shows promise in measuring HER2 expression (extracellular domain) for the entire disease burden and which could identify non responding patients prior to TDM1 administration.

Rationale II: As for many such agents, it is desirable to identify early on (here with the use of FDG-PET/CT) which patients are unlikely to benefit from the therapy


Condition Intervention Phase
HER-2 Positive Breast Cancer
Drug: T-DM1
Procedure: 89Zr-trastuzumab
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Phase II Prospective Imaging Study Evaluating the Utility of Pre-treatment zr89 Labelled Trastuzumab PET/CT and an Early FDG-PET/CT Response to Identify Patients With Advanced HER2+ BC Unlikely to Benefit From a Novel antiHER2 Therapy: TDM1

Resource links provided by NLM:


Further study details as provided by Jules Bordet Institute:

Primary Outcome Measures:
  • negative predictive value of the 89Zr-trastuzumab PET/CT [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The primary objective is to show that pre-treatment 89Zr-trastuzumab PET/CT is able to select lesions not responding morphologically from treatment with T-DM1 (applying RECIST 1.0 criteria).


Secondary Outcome Measures:
  • negative predictive value of the early FDG PET/CT [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The first secondary objective is to show that early FDG PET/CT (performed after one cycle of T-DM1 just before the second cycle) is able to select lesions not responding from treatment with T-DM1 according to metabolic and morphological response criteria post 3 cycles of T-DM1.

  • negative predictive value of the 89Zr-trastuzumab PET/CT [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The second secondary objective is to show that 89Zr-trastuzumab PET/CT is able to select lesions not responding from treatment with T-DM1 according to metabolic response criteria post 3 cycles of T-DM1.

  • negative predictive value of the combined 89Zr-trastuzumab PET/CT and early PET/CT [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The third secondary objective is to show that a lesion with no/faint uptake on 89Zr-trastuzumab PET/CT and not responding metabolically on the early FDG-PET/CT will not respond according to metabolic and morphological criteria after 3 cycles of T-DM1.


Estimated Enrollment: 105
Study Start Date: May 2012
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
T-DM1
After an imaging phase, the patient will receive T-DM1 iv every 3 weeks until progression or toxicity
Drug: T-DM1
3.6 mg/kg iv every 3 weeks
Other Name: Trastuzumab-DM1
Procedure: 89Zr-trastuzumab
Injection of 89Zr-trastuzumab for HER2 imaging
Other Name: Zirconium 89 labelled trastuzumab

Detailed Description:

The main objective of the trial is to prospectively evaluate the ability of a zirconium 89 labelled trastuzumab PET, to predict, before initiation of the treatment, treatment failure to a new targeted drug: T-DM1.

At the same time, the early FDG-PET/CT, performed after 1 course of T-DM1, will also evaluated for its ability to predict non response to TDM1.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. The patient must have histologically confirmed HER2 positive invasive carcinoma of the breast in the reference laboratory of the participating center. HER2 positive criteria to be applied are those used in the participating countries:

    • Belgium: FISH amplification ratio ≥ 2 in the reference laboratory of the participating center
    • The Netherlands: IHC 3+ or FISH ratio ≥ 2 in the reference laboratory of the participating center
  2. The patient must have documented progressive disease and present with at least 2 non-bone "target" metastatic lesions, unequivocally of neoplastic origin with

    • a transaxial diameter greater than 2 cm on the screening diagnostic CT/MRI for all non-bone lesions except lymphnodes
    • a short axis greater than 1,5 cm for lymphnodes on the screening diagnostic CT/MRI These two lesions should not be confluent with adjacent lesions and not have been irradiated previously.
  3. A concurrent biopsy of a metastatic site is mandatory (with two formalin fixed paraffin embedded (FFPE) core sample and two snap frozen tumor sample) after progression has been documented and before inclusion and the patient agrees with the procedure.
  4. Primary tumor blocks (or 11 unstained slides) available for confirmatory central laboratory HER2 testing in Institut Jules Bordet. If available, a snap frozen sample of the primary tumor will also be centralized in Institut Jules Bordet.
  5. Age ≥ 18 years
  6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1
  7. No significant cardiac history and current LVEF ≥ 50%
  8. Adequate organ function, evidenced by the following laboratory results:

    • Absolute neutrophil count > 1,500 cells/mm3
    • Platelet count > 100,000 cells/mm3
    • Hemoglobin > 9 g/dL
    • AST(SGOT) and ALT (SGPT) < 2.5 x ULN
    • Total Bilirubin ≤ 1.5 x ULN unless the patient has documented Gilbert's syndrome. Patients with known Gilbert's Syndrome should have direct bilirubin within normal limits.
    • Serum alkaline phosphatase ≤ 2.5 x ULN. Patients with bone metastases: alkaline phosphatase ≤ 5 x ULN
    • Serum creatinine < 2.0 mg/dL or 177 μmol/L
    • International normalized ratio (INR) and activated partial thromboplastin time or partial thromboplastin time (aPTT or PTT) < 1.5 x ULN (unless on therapeutic anti-coagulation except vitamin K antagonists which are prohibited in this study)
  9. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
  10. For women of childbearing potential a serum pregnancy test will be done (and it must be negative) and an agreement to use a highly-effective form of contraception during all the study and at least the following 7 months will be obtained.
  11. Signed written informed consent obtained prior to any study specific procedure.
  12. Completion of all necessary baseline surgical, laboratory and imaging investigations prior to patient inclusion.

Exclusion Criteria:

  1. Patients with bone only metastases are not eligible.
  2. Diffuse liver (≥50%) involvement on imaging.
  3. Patients with brain metastasis as the sole site of metastatic disease and/or are symptomatic or require therapy to control symptoms NB: Brain metastasis are allowed provided they are asymptomatic and/or controlled by previous radiotherapy. In case of recent prior brain radiotherapy, there must be evidence on MRI imaging of brain metastatic control for at least 6 weeks since the end of radiotherapy. Moreover, the patient should be at the end of corticosteroid therapy and be clinically asymptomatic.
  4. Current uncontrolled hypertension despite medication intake (systolic > 150 mmHg and/or diastolic > 100 mmHg)
  5. Current unstable angina
  6. History of symptomatic CHF of any New York Heart Association (NYHA) criteria or ventricular arrhythmia that requires treatment
  7. History of myocardial infarction within the last 6 months
  8. History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab treatment
  9. Current dyspnea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy
  10. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures)
  11. History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other cancers with a similar outcome as those previously mentioned
  12. Pregnant or lactating women
  13. Concurrent, serious, uncontrolled infections or current known infection with HIV, active hepatitis B and/or hepatitis C.
  14. Known prior severe hypersensitivity to trastuzumab
  15. Patient who received lapatinib within the 15 days prior to 89Zr-Trastuzumab injection
  16. Patient under a prohibited concomitant therapy, including vitamine K antagonist
  17. Patients with a peripheral neuropathy Grade 3 or higher
  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: NCT01565200

Contacts
Contact: Geraldine Gebhart, MD 0032 2 541 3240 geraldine.gebhart@bordet.be
Contact: Chloé Velghe, Ir 0032 2 541 3473 chloe.velghe@bordet.be

Locations
Belgium
Universitair Ziekenhuis Antwerpen (UZA) Recruiting
Antwerpen, Edegem, Belgium, 2650
Contact: Sigrid Stroobants, MD, PhD    + 32 3 8213696    Sigrid.Stroobants@uza.be   
Principal Investigator: Sigrid Stroobants, MD, PhD         
Sub-Investigator: Manon Huizing, MD         
Sub-Investigator: Sarah Ceyssens, MD         
Institut Jules Bordet Recruiting
Brussels, Belgium, 1000
Contact: Geraldine Gebhart, MD    0032 2 5413240    geraldine.gebhart@bordet.be   
Contact: Chloé Velghe, MSc    0032 2 541 3473    chloe.velghe@bordet.be   
Principal Investigator: Patrick Flamen, MD, PhD         
Sub-Investigator: Geraldine Gebhart, MD         
Sub-Investigator: Martine Piccart, MD, PhD         
Sub-Investigator: Ahmad Awada, MD, PhD         
Sub-Investigator: Philippe Aftimos, MD         
Netherlands
Vrije Universiteit Amsterdam (VUMC) Recruiting
Amsterdam, Netherlands, 1081HV
Contact: Willemien Menke, MD       w.menke@vumc.nl   
Contact: Otto S Hoekstra, MD    +31-20-4444214    os.hoekstra@vumc.nl   
Sub-Investigator: Henk Verheul, MD         
Principal Investigator: willemien Menke, MD         
Sub-Investigator: Otto Hoekstra, MD         
University Medical Center Groningen (UMCG) Recruiting
Groningen, Netherlands, 9700RB
Contact: Suzanne Van Es, MD       s.c.van.es@umcg.nl   
Principal Investigator: Elisabeth De Vries, MD, PhD         
Sub-Investigator: C.P Schroder, MD         
Sub-Investigator: Adrienne Brouwers, MD         
Sub-Investigator: S Gaykema, MD         
Radboud University Medical Centre Nijmegen (UMCN) Terminated
Nijmegen, Netherlands, 6525 GA
Sponsors and Collaborators
Jules Bordet Institute
Roche Pharma AG
Investigators
Study Chair: Patrick Flamen, MD/PhD Jules Bordet Institute
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Jules Bordet Institute
ClinicalTrials.gov Identifier: NCT01565200     History of Changes
Other Study ID Numbers: IJBMNTDM1  2011-005437-39 
Study First Received: March 22, 2012
Last Updated: April 4, 2016
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Belgium: Federal Agency of Nuclear Control
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by Jules Bordet Institute:
HER2
Metastatic Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Ado-trastuzumab emtansine
Trastuzumab
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 28, 2016