| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally recurrent (not amenable to resection with curative intent) or metastatic disease scheduled for a first or any subsequent metastatic treatment line |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients whose primary tumor/ metastasis overexpresses HER2 (Human epidermal growth factor receptor 2) and who progresses locally with no possibility of resection with curative intent or distantly. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is to show, on a lesion-based analysis, 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).
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| E.2.2 | Secondary objectives of the trial |
1: 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.
2: 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
3: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.
4: Other secondary endpoints are exploratory. (Cf protocol section 3.3)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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 (see Section 5, figure 1 and Section 10, figure 4 for the schedule of assessments).
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| E.4 | Principal 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 (see Section 7.1.7 concomitant therapy)
17. Patients with a peripheral neuropathy Grade 3 or higher
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for this study is the negative predictive value (NPV) of the 89Zr-trastuzumab PET/CT, defined as the proportion of lesions with a negative imaging test result which will be classified as non responding lesions (stable or progressive) after 3 cycles of T-DM1.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
1/Negative predictive value of the early FDG PET/CT, defined as the proportion of lesions without an early metabolic response that will be classified as non responding lesions after 3 cycles of T-DM1 according to anatomic and metabolic criteria.
2/Negative predictive value of the 89Zr-trastuzumab PET/CT, defined as the proportion of lesions with a negative HER2 imaging test result that will be classified as non responding lesions after 3 cycles of T-DM1 according to metabolic criteria.
3/Negative predictive value of the combined 89Zr-trastuzumab PET/CT and early PET/CT. The NPV is defined as the proportion of lesions with a negative HER2 imaging test result and a non responding classification on the early FDG-PET/CT that will be classified as non responding lesions after 3 cycles of T-DM1 according to metabolic and morphological criteria.
Other secondary endpoints are exploratory. (Cf protocol section 3.3) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study will be declared when all the following criteria will be met:
- After the last visit of the last patient in the study
- Safety reporting has been done for all patient
- The trial is mature for the analysis of the endpoints as defined in the protocol
- The database has been fully cleaned and frozen for analyses
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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