Non invasive imaging of tumor hypoxia with [18F]HX4 Positron-Emission-Tomography (PET): A phase II trial

Regulation of tissue oxygen homeostasis is critical for cell function,
proliferation and survival. Evidence for this continues to accumulate along
with our understanding of the complex oxygen-sensing pathways present within
cells. Several pathophysiological disorders are associated with a loss in
oxygen homeostasis, including heart disease, stroke, and cancer. The
microenvironment of tumors in particular is very oxygen heterogeneous, with
hypoxic areas which may explain our difficulty treating cancer effectively.

Prostate carcinomas are known to be hypoxic. Increasing levels of hypoxia
within prostatic tissue is related to increasing clinical stage, patient age
and a more aggressive prostate cancer.
Several researches indicated that hypoxia might also play a role in esophageal
cancer.
In glial brain tumors, hypoxia is correlated with more rapid tumor recurrence
and the hypoxic burden in newly diagnosed glioblastomas is linked to the
biological aggressiveness.
In brain metastases CA-IX expression (a marker for hypoxia) is correlated to
the primary non-small cell lung carcinomas.
Hypoxia enhances proliferation, angiogenesis, metastasis, chemoresistance and
radioresistance of hepatocellular carcinoma.
The hypoxic markers HIF-1*, VEGF, CA-IX and GLUT-1 were all over expressed in
colorectal cancer and its liver metastases.

Based on literature, hypoxia in tumors originating or disseminated to prostate,
esophagus, brain and rectum cancer will be studied in this trial.

Hypoxia can be measured in several ways.
Radio-labelled nitroimidazoles offer significant potential to emerge as
clinically useful non-invasive hypoxia markers.
The 2-nitroimidazole nucleoside analogue, 3-[18F]fluoro-
2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1- yl)propan-1-ol
([18F]HX4) was developed to achieve better water solubility and faster
clearance than most known nitro-imidazoles and is therefore expected to have
better pharmacokinetic properties.

Primary Objective:
Visualization and quantification of tumor hypoxia with [18F] HX4 PET imaging

Secondary Objectives:
- Correlation of [18F] HX4 with local tumor recurrence and survival
- Correlation of hypoxia imaging with blood hypoxia markers
- Correlation of hypoxia imaging with tumor tissue biomarkers
- Evaluation of tumor hypoxia changes during treatment.
- Spatial correlation of [18F] HX4-PET with imaging pre-treatment (if present
from routine clinical practice)
- Spatial correlation of [18F] HX4-PET with imaging three months after
treatment (if present from routine clinical practice)

A non-randomized, open label trial.

Eligible patients with histologically/cytologically proven primary tumors of
the prostate, esophagus, brain or rectum or metastatic disease to the brain
(originating from breast, lung or colorectal).

Before treatment
A baseline [18F]HX4 PET scan will be performed, by administrating 444 MBq (12
mCi) [18F]HX4 via a bolus IV injection. The PET/CT scan is acquired at 4 hours
p.i.* A blood sample is drawn to measure hypoxia-related proteins in the blood.

Treatment
The cancer treatment will not be changed by this study and will be performed
according to local guidelines. Radiotherapy will consist of a fractionated
schedule (combined with , e.g., chemotherapy or hormonal therapy) or of
stereotactic ablative (body) radiotherapy.

During treatment
If patients are treated with radiotherapy and/or chemotherapy the [18F]HX4 scan
(4h p.i.) will be repeated after 2 weeks of radiotherapy, by administrating
444MBq (12mCi) [18F]HX4 via a bolus IV injection. For prostate patients treated
with HDR brachytherapy an alternative timepoint is chosen: the HX4 scan during
treatment will be performed 4 weeks after HDR treatment.

Follow up
In some patients treated with radiotherapy only or chemoradiotherapy [18F]FDG
PET scan three months after the end of treatment will be acquired if part of
routine clinical practice. Clinical follow-up will take place according to
routine clinical practice at the outpatient clinic.

This study will cause no delay in the anticancer treatment.

* After 3 patients (of each tumor type) a feasibility evaluation will be
performed.
*

Based on current information, there are no adverse events anticipated in
relationship to the administration of [18F]HX4. However, the possibility of
commonly experienced mild side effects related to other components of the
investigational product or the PET-CT imaging procedure, such as bruising at
the IV site, may be anticipated.

The radiation burden due to [18F]HX4 is similar to that encountered in many
routine nuclear medicine procedures e.g. 18FDG PET. Administration of [18F]HX4
presents no known risks. In previous studies (healthy volunteers, phase I,
phase II) no adverse effects were observed. Radiation dosimetry estimates for
[18F]HX4 indicate that the radiation dose is similar to other radiodiagnostic
agents and does not represent any undue risk. Moreover, no delay of anti-cancer
therapy is required.

There are no immediate potential benefits except the satisfaction to
participate to improve of knowledge. Early research indicates that [18F]HX4-PET
imaging may provide the benefit to, non-invasively, assist in measuring tumor
hypoxic fraction in human tumors. It provides a tool that could offer
sufficient potential to improve cancer therapy.