The goal of this clinical trial is to test a new PET tracer in patients with HER2-positive breast or gastric cancer. This tracer is made of radioactively labeled trastuzumab, and can show where HER2 is present in the body using a PET-scan. For this research, the investigators make PET-scans in people with HER2-positive, metastasized breast- or gastric cancer. The investigators will investigate if the new HER2-tracer correctly shows all tumor lesions. In the future, this method may be useful to help predict who will benefit from certain HER2-directed therapies. Participants will be injected with the radioactive tracer once. After injection, participants will undergo 3 PET-scans. Each PET-scan will take a maximum of 60 minutes. The PET-scans are on separate days within a week after injection of the tracer (e.g. 1 day, 2 days and 4 days after injection). Furthermore, the investigators will take 7 blood samples (5 mL each). Participants are not required to stay at the hospital. The first 3 participants will undergo an extra PET-scan 1 - 2 hours after injection. The amount of radioactivity injected will be 37 MBq (± 10%).
Positron emission tomography (PET) imaging with 89Zr-labeled trastuzumab can potentially discriminate between human epidermal growth factor 2 (HER2) positive and HER2-negative lesions in cancer patients. The obvious advantage over tumor biopsies is that PET imaging provides an overview regarding the heterogeneity of HER2-positivity of all lesions in the patient noninvasively at any given time. The use of a tracer with high specificity and low background signal is critical for accurately identifying positive lesions in patients. Earlier studies in patients with HER2-positive (HER2+) breast cancer and gastric cancer using 89Zr-trastuzumab led to the identification of HER2-positive tumor lesions. However, also lesions were missed and false-positive lesions were seen. Previous work has shown that organs like liver and spleen have significant uptake of 89Zr-trastuzumab. In addition, HER2-directed therapy is most effective in HER2-positive tumors, which are defined as immunohistochemistry (IHC) HER2 expression 3+ or HER2 2+ with gene amplification. Tumors with IHC 0, 1+ or 2+ without amplification are considered HER2-negative. To be able to discriminate between these expression levels with PET imaging, an excellent signal to background ratio is required. Recently, an improved 89Zr-labeled trastuzumab tracer has been developed using a different chelator for 89Zr binding, DFO\*, which further improves stability of the 89Zr-labeled trastuzumab tracer. 89Zr-DFO\*-trastuzumab preclinically shows improved specificity in uptake of tumor lesions while non-tumor related uptake in bone, liver and spleen is reduced, potentially improving the discrimination of HER2-positive tumor lesions in patients. The investigators hypothesize that the improved 89Zr-DFO\*-trastuzumab tracer will lead to a reduced background uptake and thus a better discrimination of HER2-positive tumor lesions.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
DIAGNOSTIC
Masking
NONE
Enrollment
6
Patients will be administered 37 MBq 89Zr-DFO\*-trastuzumab and undergo 3 PET scans on the total body PET scanner at day 1, day 2 and day 4 post-injection (p.i.). The first 3 patients will undergo an additional PET 1-2 h p.i. for dosimetry purposes. Three scans are needed for PK modelling and day 4 p.i. is chosen because it is the same time point as in historical controls. Blood samples for (radioactive) PK analysis will be taken at 10 min, 30 min, 1 h and 2 h p.i., and at every PET scan.
AmsterdamUMC
Amsterdam, North Holland, Netherlands
89Zr-DFO*-trastuzumab uptake (standard uptake values (SUVmean, %ID/kg) in normal organs/tissues and bloodpool.
Time frame: SUVmean on day 4 post injection.
89Zr-trastuzumab uptake (standard uptake values (SUVmean, %ID/kg) in normal organs/tissues and bloodpool in historical controls with HER2+ breast cancer (n = 20) who underwent 89Zr-trastuzumab PET imaging.
Time frame: SUVmean on day 4 post injection.
Tumor uptake: 89Zr-DFO*-trastuzumab uptake (SUV, %ID/kg) in tumor lesions
Time frame: SUV on day 4 post injection.
Tumor uptake: 89Zr-trastuzumab uptake (SUV, %ID/kg) in tumor lesions in historical controls with HER2+ breast cancer (n = 20) who underwent 89Zr-trastuzumab PET imaging.
Time frame: SUV on day 4 post injection.
Whole blood pharmacokinetics (PK) of 89Zr-DFO*-trastuzumab (Maximum Plasma Concentration (Cmax) µg/mL)
Time frame: PK samples are taken at 10, 30, 60 and 120 min post injection, and at 1, 2 and 4 days post injection (at the day of each scan).
Whole blood PK of 89Zr-DFO*-trastuzumab (AUC µg/mL × h)
Time frame: PK samples are taken at 10, 30, 60 and 120 min post injection, and at 1, 2 and 4 days post injection (at the day of each scan).
Plasma PK of 89Zr-DFO*-trastuzumab (Cmax in µg/mL)
Time frame: PK samples are taken at 10, 30, 60 and 120 min post injection, and at 1, 2 and 4 days post injection (at the day of each scan).
Plasma PK of 89Zr-DFO*-trastuzumab (AUC µg/mL × h)
Time frame: PK samples are taken at 10, 30, 60 and 120 min post injection, and at 1, 2 and 4 days post injection (at the day of each scan).
Image-derived PK for 89Zr-DFO*-trastuzumab (µg/mL)
For each timepoint, volumes of interest (VOIs) will be delineated in the aorta ascendens, and the activity of the VOI will be calculated afterwards for each timepoint. This calculated activity (in Bq/mL) will then be recalculated to the actual amount of tracer (in µg/mL), which is the image-derived PK.
Time frame: Day 1, 2 and 4 post injection (at each scan)
Literature-derived PK for unlabelled trastuzumab (Cmax in µg/mL)
Time frame: Day of injection till 7 days post injection.
Literature-derived PK for unlabelled trastuzumab (AUC in µg/mL × day)
Time frame: Day of injection till 7 days post injection.
Visual PET imaging analysis of tumor uptake of 89Zr-DFO*-trastuzumab and 89Zr-trastuzumab
Time frame: Day 1, 2 and 4 post injection.
Tumor-to-blood ratio of 89Zr-DFO*-trastuzumab (whole blood and plasma as well as image derived)
Time frame: Day 1, 2 and 4 post injection.
Tumor-to-image derived blood uptake ratio of 89Zr-trastuzumab
Time frame: Day 1, 2 and 4 post injection.
HER2 expression measured by IHC on tumor biopsies
Time frame: The biopsies are at most 8 weeks old at the day of injection, and will be compared with the data of the scans from day 1, 2 and 4 post injection.
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