A Study of HS-196, an HSP90 Inhibitor-linked NIR Probe for Solid Malignancies

The product to be tested under this IND, HS-196, is a tumor imaging agent.

Hsp90 (heat shock protein 90) is a chaperone protein that aids in the folding, stabilization,
and degradation of cellular proteins and is found in virtually all living organisms. Cancer
cells in particular have high expression of Hsp90. Hsp90 has three structural domains
including an N-terminal domain that contains an ATP binding site. Small molecule inhibitors
of HSP90 (Hsp90i) can selectively and competitively to the Hsp90 ATP binding domain. HS-196
consists of a HSP90 inhibitor that binds competitively to the Hsp90 ATP binding domain
connected by a linker to a contrast agent (near infrared (NIR) dye) that can be used for
imaging. HS-196 can freely enter tumor cells to selectively bind Hsp90. Due to the the NIR
dye, HS-196 accumulation in the malignant cells allows for specific visualization of tumors
within the body.

HS-196 will be used in this investigation for the imaging of solid tumors The objectives of
the study are to determine the dose of HS-196 that achieves the greatest ratio of tumor to
normal tissue fluorescence in patients with malignancy, the safety of HS-196 administration
in patients with malignancy, the average radiant efficiency in resected tumors following
HS-196 administration, the localization of the HS-196 by microscopy of tumor slices, and the
PK metrics of HS-196 when administered to patients.

Inclusion Criteria:

For Dose escalation and recommended dose phases:

- Diagnosis of a solid malignancy, stage I-IV, with planned surgical resection or
biopsy.

For Expansion phase:

- Patients with mammographically detected breast nodules with planned surgical resection
or biopsy.

For All phases:

- ECOG 0 or 1

- Estimated life expectancy > 3 months

- Age ≥ 18 years

- Adequate hematologic function, with WBC ≥ 3000/microliter, hemoglobin ≥ 9 g/dL (it is
acceptable to have had prior transfusion), platelets ≥ 75,000/microliter; PT-INR <1.5,
PTT <1.5X ULN

- Adequate renal and hepatic function, with serum creatinine < 1.5 mg/dL, bilirubin <
1.5 mg/dL (except for Gilbert's syndrome which will allow bilirubin ≤ 2.0 mg/dL), ALT
and AST ≤ 2.5 x upper limit of normal or if liver metastases are present < 5 x upper
limit of normal.

- Female patients must be of non-child-bearing potential or use effective contraception,
e.g., use of oral contraceptives with an additional barrier method (since the study
drug may impair the effectiveness of oral contraceptives), double barrier methods
(diaphragm with spermicidal gel or condoms with contraceptive foam), Depo-Provera,
partner vasectomy, total abstinence, and willing to continue the effective
contraception method for 30 days after the last dose of study drug;

- Ability to understand and provide signed informed consent that fulfills Institutional
Review Board's guidelines.

- Ability to return to Duke University Medical Center for adequate follow-up, as
required by this protocol.

Exclusion Criteria:

- Serious chronic or acute illness considered by the P.I. to constitute an unwarranted
high risk for investigational drug treatment.

- Medical or psychological impediment to probable compliance with the protocol.

- Asthma under medical management

- Uncontrolled high blood pressure

- Presence of a known active acute or chronic infection including HIV or viral hepatitis
(Hepatitis B and C)).

- Pregnant or nursing women