Imaging the effect of HSP90 inhibitor AUY922 on HER2 expression by means of 89Zr-trastuzumab PET. A side study to the phase I-II study with AUY922 in either HER2 or ER positive locally advanced or metastatic breast cancer: protocol CAUY922A2101.

Heat Shock Protein (HSP) 90 is a molecular chaperone, required for stability
and function of signalling proteins that promote cancer cell growth and
survival. It plays a central role in the basic power of cancer cells to adapt
to various forms of stress. Client proteins of HSP90 include the human
epidermal growth factor receptor 2 (HER2), the hormone receptors, angiogenesis
regulator hypoxia-inducible factor 1α (HIF-1α), AKT, mutant p53, and so forth.
HSP90 is constitutively expressed to 2- to 10-fold higher levels in cancer
cells compared to their normal counterparts. Unlike in normal cells, HSP90 in
tumor cells is present in active multi-chaperone complexes, conferring relative
sensitivity to treatment with HSP90 inhibitors. Targeting multiple survival
pathways by means of HSP90 inhibition may contribute to circumvention of
resistance in cancer cells, to chemotherapeutics but also to trastuzumab and
hormonal therapy. This has already been shown in a recent study, in which HSP90
inhibitor 17-allylamino-17-demethoxy-geldanamycin (17-AAG) was combined with
trastuzumab in trastuzumab refractory patients. Tumor regression was reported
in 4 of 25 of these patients. Biomarkers for the early prediction of response
are increasingly important, for allocation of the right treatment to individual
cancer patients and to support drug development. No biomarker is yet available
for the early prediction of response to HSP90 inhibitors. Measurement of client
proteins in peripheral blood mononuclear cells and tumor biopsies have so far
not yielded consistent results. In vivo imaging of the effect of HSP90
inhibition on the expression on client proteins, is of great interest in this
setting. It allows whole body imaging of multiple tumor lesions in a non
invasive way, and can be repeated serially. The effect of HSP90 inhibitor
17-AAG on client protein HER2 was previously visualized by means of HER2 PET
imaging in a xenograft mouse model. In line with these experiments, we could
demonstrate early response to treatment with the HSP90 inhibitor AUY922, using
89Zr-trastuzumab microPET/CT imaging in a HER2 overexpressing xenograft mouse
model. Imaging of patients with HER2 positive breast cancer has already been
performed in our institution, with the SPECT tracer 111Indium-trastuzumab. This
approach resulted in the detection of more lesions than conventional staging
techniques. Currently also HER2 imaging with 89Zr-trastuzumab is operational in
our institution. We developed the PET radiopharmaceutical because it is
particularly suitable for quantification of tracer uptake. Preclinical data
showed specific uptake of this PET tracer in the tumor (confirmed with
histology), with low background uptake. 89Zr-trastuzumab imaging in humans
showed excellent sensitivity for tumor lesions detected with conventional CT.
For HER2 positive metastatic breast cancer patients, HSP90 inhibition can
possibly form a targeted drug modality, in addition to HER2 based treatment
(with trastuzumab and lapatinib). Serial HER2 imaging with a PET tracer for
HER2 quantification might serve as an early predictive biomarker for the effect
of HSP90 inhibition. This is also the case in patients who are refractory to
HER2 based treatment, as the expression of HER2 in their tumors is preserved.
In the present study, we will evaluate whether 89Zr-trastuzumab PET imaging can
be used to evaluate early respondse to HSP90 inhibitor AUY922 (see for further
information on the treatment with AUY922: protocol CAUY922A2101).

To show the effect of the HSP90 inhibitor AUY922 on HER2 expression by means of
89Zr-trastuzumab PET scanning.
Primary endpoint: measurement of decreased HER2 expression compared to
baseline. A decline is defined as a decrease of at least 30% in mean
Standardized Uptake Value (SUV) in a maximum of three lesions.

This study is designed as a side study to the multicenter, international phase
I-II trial with the HSP90 inhibitor AUY922 (protocol CAUY922A2101), as part of
the biomarker assessment. In protocol CAUY922A2101, section 4, the design of
this phase I-II trial is described (p36, 37). Briefly, a dose-escalation study
is performed according to phase I design. This part is followed by a
dose-expansion study according to a phase II design. In the latter part, breast
cancer patients are enrolled that are either refractory to hormone- or
trastuzumab treatment (both treatment arms, n=40 patients). Patients with HER2
positive, trastuzumab (and lapatinib) refractory breast cancer, will receive a
89Zr-trastuzumab PET scan as part of the present side study protocol. To this
end, a 89Zr-trastuzumab PET scan will be performed before (baseline) and during
treatment with the HSP90 inhibitor AUY922. A minimum of six patients and a
maximum of 11 pattients is needed to evaluate whether the 89Zr-trastuzumab PET
scan can be used for the detection of a decrease of HER2 expression, induced by
HSP90 inhibition (see statistical paragraph, see page 7).

In the present study, radioactive trastuzumab is used for PET scanning. The use
of such a tracer means exposure to ionizing radiation. Twice, an infusion of
radio active trastuzumab is administered: once before start of treatment and
once during treatment with AUY922. The total additional radiation dose for the
patient is 18 mSv at baseline, and 18 mSv at cyclus 1 (ICRP62, category III;
comparable to 1,5 times a CT scan).
The tracer for this study is administered intravenously, which means an
intravenous puncture. This puncture will be combined as much as possible with
the punctures that are requested in the setting of the treatment with HSP90
inhibitor AUY922.