Hyperpolarized C-13 Pyruvate as a Biomarker in Patients With Advanced Solid Tumor Malignancies

This is a single center prospective imaging study investigating the utility of hyperpolarized
C-13 pyruvate/metabolic MR imaging. The current protocol will serve as a companion imaging
biomarker study paired with therapeutic trials of PI3K/mTOR pathway inhibitors (e.g.
CUDC-907, BYL719), as well as a stand-alone protocol for patients treated with
standard-of-care therapies inhibiting the PI3K/mTOR signaling pathway (eg. everolimus).

In Part A (run-in feasibility phase), patients will undergo imaging at a single time point,
without paired tumor biopsy. There will be no follow up imaging or requirement for treatment
with PI3K/mTOR pathway inhibitor. Iterative adjustment of radiofrequency coil geometry and
imaging sequences will be undertaken to optimize intra-tumoral hyperpolarized
pyruvate/lactate signal-to-noise ratio with the goal of achieving signal-to-noise ratio of at
least 10 in a minimum of 3 patients in order to proceed to Part B of the study.

In part B, patients will undergo paired baseline hyperpolarized C-13 pyruvate imaging + tumor
biopsy,then initiate treatment with agent inhibiting the PI3K/mTOR pathway. After 21 days
(+/- 14 days), patients will undergo repeat hyperpolarized C-13 pyruvate MR imaging + tumor
biopsy. Patients will subsequently be treated with PI3K/mTOR pathway inhibitor until disease
progression, unacceptable toxicity, or patient/physician decision to discontinue therapy.

Inclusion Criteria:

- Presence of at least one target liver lesion detected by standard staging scans that,
in the judgment of Study Investigators, would be amenable to hyperpolarized C-13
pyruvate/metabolic MR imaging: Target lesion must measure 1.5 cm in long axis diameter
on CT or MRI

- The subject is able and willing to comply with study procedures and provide signed and
dated informed consent.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

- Adequate organ function, including creatinine < 1.5 x ULN or estimated creatinine
clearance 50 mL/min (by the Cockcroft Gault equation) and total bilirubin <3x ULN.

Part B only:

- Presence of at least one target lesion amenable to percutaneous tumor biopsy in the
judgment of Interventional Radiology

- No prior local therapy to target liver lesion.

- No history of bleeding diathesis.

- Patients on anti-coagulation they must be able to safely stop treatment for purposes
of tumor biopsy.

- Planned treatment with agent targeting PI3K/mTOR pathway (either standard of care or
investigational agent)

Exclusion Criteria:

- Patients who because of age, general medical or psychiatric condition, or physiologic
status cannot give valid informed consent.

- Patients unwilling or unable to undergo MR imaging, including patients with
contra-indications to MRI, such as cardiac pacemakers or non-compatible intracranial
vascular clips.

- Metallic implant or device that distorts local magnetic field and compromises the
quality of MR imaging.

- Poorly controlled hypertension, defined as systolic blood pressure at study entry
greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg. The
addition of anti-hypertensives to control blood pressure is allowed.

- Congestive heart failure or New York Heart Association (NYHA) status ≥ 2.

- A history of clinically significant EKG abnormalities, including QT prolongation (QTcF
> 500 ms), a family history of prolonged QT interval syndrome, or myocardial
infarction (MI) within 6 months of study entry. Patients with rate-controlled atrial
fibrillation/flutter will be allowed on study.

- Any condition that, in the opinion of the Principal Investigator, would impair the
patient's ability to comply with study procedures.