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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
Jules Bordet Institute
ClinicalTrials.gov Identifier:
NCT01565200
First received: March 22, 2012
Last updated: March 10, 2014
Last verified: March 2014
  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: Endpoint Classification: Pharmacodynamics Study
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 (NPV) 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 from treatment with T-DM1 according to the RECIST 1.1


Secondary Outcome Measures:
  • negative predictive value of the early FDG PET/CT [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The secondary objective is to show that early FDG PET/CT (performed after one cycle of T-DM1) is able to select lesions not responding from treatment with T-DM1 according to RECIST 1.1.


Estimated Enrollment: 60
Study Start Date: April 2012
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2015 (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
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed HER2+ according to national criteria invasive carcinoma of the breast with locally recurrent (not amenable to resection with curative intent) or metastatic disease scheduled for a first or any subsequent metastatic treatment line. A positive FISH test on a metastatic lesion will be acceptable (in case it is not available for the primary tumor).
  2. The patient must have at least 2 visceral or nodal "target" metastatic lesions fulfilling all of the following imaging criteria: on diagnostic CT scan/ MRI: lesion should be measurable according to RECIST 1.1; on FDG PET/CT: transaxial diameter of more than 15 mm or more and Standard Uptake Value (SUV) max ≥ 2 x SUVmean of the liver (as measured in a 3-cm-diameter spherical VOI located in the normal liver parenchyma). If liver is suspected to be diffusely infiltrated, the lesion should have a tracer uptake > 2.0 x SUV mean of blood pool measured in a 1-cm-diameter VOI within the descending thoracic aorta; non confluent with adjacent lesion; target lesion should not have been previously irradiated.
  3. A biopsy of a metastatic site is required if not done previously
  4. Primary tumor blocks (or 11 unstained slides) available for confirmatory central laboratory HER2 testing.
  5. Age≥18 y
  6. 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, Hb> 9 g/dL , Total Bilirubin ≤ 1.5 x ULN unless the patient has documented Gilbert's syndrome, AST(SGOT) and ALT (SGPT) < 2.5 x ULN, 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)<1.5x ULN (unless on therapeutic anti-coagulation)
  9. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule;
  10. For women of childbearing potential a pregnancy test will be done and an agreement to use a highly-effective form of contraception during all the study will be obtained.
  11. Signed written IC approved by Ethics Committee and obtained prior to any study 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, except if two of these bone lesions satisfy the RECIST 1.1 and metabolic criteria.
  2. Diffuse liver(≥ 75%)involvement on the FDG-PET/CT
  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.
  4. Current uncontrolled hypertension (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
  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. Current known uncontrolled infection with HIV, HBV, or HCV
  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 (Cf protocol)
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01565200

Locations
Belgium
Universitair Ziekenhuis Antwerpen (UZA)
Antwerpen, Edegem, Belgium, 2650
Institut Jules Bordet
Brussels, Belgium, 1180
Netherlands
Vrije Universiteit Amsterdam (VUMC)
Amsterdam, Netherlands, 1081HV
University Medical Center Groningen (UMCG)
Groningen, Netherlands, 9700RB
Radboud University Medical Centre Nijmegen (UMCN)
Nijmegen, Netherlands, 6525 GA
Sponsors and Collaborators
Jules Bordet Institute
Roche Pharma AG
Investigators
Study Chair: Geraldine Gebhart, MD Jules Bordet Institute
  More Information

No publications provided

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: March 10, 2014
Health Authority: Belgium: Federal Agency for Medicinal Products and Health Products
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Jules Bordet Institute:
HER2
Metastatic Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Trastuzumab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 15, 2014