Study Evaluating the Biologic Activity of Guanabenz in Bone Metastasis

OBJECTIVES Primary Objective: Evaluate the biologic effect of guanabenz on markers of bone
formation and bone resorption in patients with solid tumors and bone metastasis.

Secondary Objectives: (1) Compare guanabenz exposure in patients based on limited PK sampling
to activity observed in previous pre-clinical studies; (2) Assess the safety/tolerability of
guanabenz; and (3) Evaluate the biologic effect of guanabenz on bone metabolism markers.

Tertiary Objective: Compare change in bone turn over markers (formation, resorption and
metabolism) achieved with guanabenz to change in bone turn over markers with standard of care
(bisphosphonate/denosumab).

STUDY DESIGN This is an exploratory pilot study evaluating the biologic effect of guanabenz
bone formation and bone resorption markers in patients with solid tumors and bone metastasis.

PROCEDURES All registered patients will receive oral guanabenz the first two months prior to
the start of any standard of care skeletal protective therapy. All patients on study will
receive standard of care systemic treatment for their underlying solid malignancy as deemed
necessary by their treating physician. Guanabenz will be administered concurrently with any
primary cancer systemic treatment. However patients will withhold standard of care bone
directed therapy for 8 weeks. The study will exclude patients in immediate need of such
treatment. Patients experiencing skeletal related events while on study will be withdrawn.
Delaying standard of care skeletal therapy for 2 months will not be considered a major
deviation as long as such therapy is delayed for a necessary purpose as deemed by the
treating physician.

Patients with known hypertension and on antihypertensive medications at study enrollment will
be eligible to participate. Antihypertensive medications will not be changed as a result of
study enrollment unless deemed necessary by the treating physician; only the dose of
guanabenz will be adjusted.

TREATMENT Patients will begin taking 8 mg by mouth (PO) at bed time (HS) starting day 1 for
one week. The dose will be increased to 8 mg PO twice a day (BID) (8 mg daily morning (QAM)
and 8 mg daily evening (QPM) for a total of 16 mg) on day 8 (+/-3 days), then increased to 8
mg PO QAM 16 mg PO QPM (total of 24 mg) on day 15 (+/- 3 days), then increased to 16 mg PO
BID (16 mg QAM and 16 mg QPM for a total of 32 mg) on day 22. Patients will continue on their
maximum tolerated dose (MTD) until day 56 (+/- 3 days). The dose will be weaned for patients
receiving more than 8 mg daily after completing week 8 when the standard of care skeletal
protective therapy begins. Guanabenz will be weaned off by week 11, and patients will
continue standard of care skeletal protective therapy as deemed necessary by the treating
physician.

To ensure patient safety during dose escalation and throughout the study, patients will be
provided and taught the use of home blood pressure (BP) monitoring. We will instruct patients
to check their BP 2 hours after each guanabenz dose escalation and at least three times
weekly. Patients will maintain a diary of BP results during the dose escalation phase.
Patients will report any hypotensive measurement to their research nurse defined as at least
two readings less than < 100/60 mm Hg in sitting position taken more than 30 min apart.

At each visit, blood pressure and adverse events will be assessed. Dose escalation will
continue with guanabenz if BP >= 110/70 mm Hg and/or until unacceptable toxicity.

Guanabenz should be taken as instructed on an empty stomach. If the patient misses a dose of
guanabenz, he/she can take the missing dose no later than 3 hours after instructed time and
then continue as scheduled.

On day 57 (+/- 3 days), all study patients start the guanabenz wean. All patients will
receive ongoing standard of care skeletal protective therapy (denosumab/zometa) as determined
by the treating physician at the beginning of the weaning phase.

Inclusion Criteria:

1. ≥ 18 years old at the time of informed consent

2. Ability to provide written informed consent and HIPAA authorization

3. Solid organ malignancy with documented bone metastasis by imaging

4. Adequate liver function (serum total bilirubin <= 3 and AST/ALT <= 3 times the upper
normal limit)

5. Adequate renal function (serum creatinine <= 2mg/dL)

6. Ability to swallow oral tablets

7. Females of childbearing potential must have a negative pregnancy test <= 28 days prior
to registration. All females of childbearing potential who are sexually active, must
agree to use a highly reliable method of contraception to prevent pregnancy. These
include abstinence, partner with previous vasectomy, placement of an intrauterine
device (IUD), condom with spermicidal foam/gel/film/cream/suppository, diaphragm or
cervical vault cap, or hormonal birth control (pills or injections).

NOTE: Females are considered of childbearing potential unless they are surgically
sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral
oophorectomy) or they are postmenopausal (> 12 months since last menses).

8. Patients are permitted to participate in other clinical trials while participating in
this trial.

9. Patients will receive standard of care systemic treatment for underlying solid
malignancy as deemed necessary by treating physician.

Exclusion Criteria:

1. No prior history of bisphosphonate ordenosumab use in the past 12 months

2. No history of SRE within past 3 months

1. Excruciating bone pain requiring RT

2. Cord compression

3. Hypercalcemia [serum calcium >10.5]

4. Pathologic fracture

3. No history of Paget's disease

4. No history of epilepsy/seizures

5. No history of hypotension (defined as resting systolic blood pressure of < 110 mm Hg
or diastolic blood pressure of < 70 mm Hg) or orthostasis (defined as drop in systolic
blood pressure of >20 mm Hg or increase in HR of > 20 from supine to standing
position).