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