PET Imaging of PARP Activity in Cancer

Poly(ADP-ribose) polymerase 1 (PARP1) is a deoxyribonucleic acid (DNA) repair enzyme that
enables normal cell survival as well as certain cancers. Pharmaceutical companies have
invested heavily in PARP1 inhibitor development because these agents can effectively treat
certain cancers as single agents, thus sparing those patients from chemotherapy toxicities.
However, clinical trials testing PARP1 inhibitors have demonstrated mixed results due to the
inability to measure the degree of PARP1 inhibition in tumors reliably. Accurately measuring
tumoral PARP1 activity levels before and after PARP1 inhibitor treatment will: (1) enable
identification of patients whose tumors exhibit PARP activity and are therefore good
candidates for PARP inhibitor therapy, and (2) confirm that adequate doses of PARP1
inhibitors are being administered to patients, thus improving dose selection for further
study in clinical trials. Thus, noninvasive approaches for measuring tumoral PARP1 activity
would have commercialization potential in not only supporting development of PARP1 inhibitors
but also after Food and Drug Administration (FDA) approval to assess clinical PARP1 inhibitor
treatment responses.

Inflammation also contributes to a number of diseases involving the lungs and other organs.
Increasing evidence suggests that PARP1 may also play a central role in modulating immune
inflammatory responses. Thus, the data from this trial will also be used to develop this
approach for studying lung inflammatory responses.

A new radiolabeled compound, [18F]FluorThanatrace ([18F]FTT), has been generated which can be
used to measure PARP1 activity noninvasively and quantitatively using positron emission
tomography (PET). Our data in cancer models show that the uptake of our compound is specific
for PARP1 activity and correlates with biochemically determined PARP1 activity. Additional
preliminary data also suggests that decreased [18F]FTT uptake predicts tumor response to PARP
inhibition with olaparib, a PARP1 inhibitor currently being evaluated in clinical trials.
Therefore, the investigators are conducting this Phase 0 trial to develop [18F]FTT for
clinical use in cancer patients.

To date, no biomarkers have been developed beyond genetic testing for breast cancer 1 and 2
(BRCA1/2) mutations that can aid in patient selection for treatment with PARP inhibition.
Moreover, no technologies are available to monitor the efficacy of PARP inhibition. Our
technology provides both a biomarker for patient selection as well as a means of monitoring
PARP activity during treatment.

Inclusion Criteria:

- Men or women 18 years of age or older.

- Healthy volunteers without history of cardiopulmonary conditions requiring any
treatment or medical intervention and who are not current smokers (Dosimetry Studies
Arm only).

- Patients with biopsy-proven diagnosis of head and neck squamous cell cancer (HNSCC) or
any histopathologic type of lung cancer or any other type of cancer that can be
treated with platinum-based chemotherapy as first-line therapy (which includes but is
not limited to ovarian, gastric, and pancreatic cancers).

- At least one tumor site that is at least 1 cm in the shortest transaxial diameter by
computed tomography (CT) (Kinetic Studies Arm only; disease-free participants can be
enrolled in the Dosimetry Studies Arm).

Exclusion Criteria:

- History of claustrophobia or other preventing condition that has previously or would
interfere with completion of protocol specified imaging sessions.

- Inability to comprehend or unwillingness to follow instructions for the study
procedures as called for by the protocol.

- Presence of an implanted device that is incompatible with CT scanning.

- Non-measurable disease (< 1 cm) by CT (Kinetic Studies Arm only; disease-free
participants can be enrolled in the Dosimetry Studies Arm).

- Unable to lie in the PET/CT scanner for the time required for scanning, up to 1 hour
and 15 min at a time and possibly with arms raised above the head for lung imaging.