Ketoconazole, Hydrocortisone, Dutasteride and Lapatinib (KHAD-L) in Prostate Cancer

The current study builds on investigators' KHAD experience by further targeting pathways that
may still be enhancing AR activity despite reduced testosterone and DHT. Importantly, studies
from several groups have shown that EGFR and Her2/Neu activation can enhance AR signaling and
increase AR transcriptional activity in response to low levels of androgens. Evaluation in
the clinic and lab has shown that there is increased expression of EGFR or Her2/Neu in CRPC.
In addition to upregulation in EGFR and Her2/Neu protein expression, signaling through these
receptors may be enhanced in some tumors by increases in growth factor levels or other
mechanisms. Based on these results, the investigators suggest that EGFR and Her2/Neu
contribute to enhancing AR transcriptional activity especially at low androgen levels. If
this hypothesis is correct, then dual blockade of EGFR and Her2/Neu in CRPC should enhance
the ability of KHAD to abrogate AR activity. Moreover, as androgens can protect PCa cells
from cell death in response to EGFR/Her2/Neu/PI3 kinase pathway inhibition, we propose that
KHAD plus lapatinib may be a particularly active combination therapy for CRPC.

Inclusion Criteria:

- Patients with CRPC with metastatic bone disease. At least one site of metastatic
disease must be amenable to a needle biopsy. Bone sites include lumbar vertebrae,
pelvic bones and long bones. Excluded sites are thoracic, cervical vertebrae, skull
and rib lesions

- Patients may have had a number of previous hormonal therapies including ketoconazole
and abiraterone, provided these were discontinued >3 months before starting the trial

- Patients may have had any number of previous cytotoxic therapies

- Castrate resistant disease as defined by PSA working group. Patients must have a rise
in PSA on two successive determinations at least one week apart and PSA levels 5ng/ml
or greater and testosterone levels <50

- Adequate renal, hepatic and bone marrow function as outlined in protocol

- PTT< 60, INR <1.5NL unless on warfarin therapy

- > 6 month life expectancy

- At least a 4 week interval from previous treatment other than LHRH analog and
bisphosphonates. Patients on bicalutamide must have discontinued this medication for
at least 6 weeks to be eligible

- Patients receiving bisphosphonate can be maintained on this therapy

- No major surgery or radiation therapy within 4 weeks

- No strontium-89 or samarium-153 therapy within 4 weeks

- ECG showing normal QT interval

- No thromboembolism in past 6 months

- Age > 18 years

- Investigator must check current patient medications against the list of CYP3A4
inhibitors and inducers prior to registration

- Echocardiogram or MUGA demonstrating ejection fraction within institutional normal
limits

Exclusion Criteria:

- No previous therapy with lapatinib

- No previous therapy with ketoconazole within 3 months of starting trial

- The use of complementary therapy directed at prostate cancer treatment excluding the
following: green tea, commercial multivitamin preparations. Vitamin B complex, C, D, E
and multivitamins are permitted if these are being taken at less than 3 times the RDA

- The concomitant use of drugs known to be narrow therapeutic index CYP3A4 substrates
are excluded

- Drugs that are sensitive to CYP3A4 substrates are excluded

- Patients taking drugs that may further prolong QT intervals and present a known risk
for Torsades de Pointes are excluded.

- Patients who have alcohol or drug dependence currently or in the last 6 months are
excluded from this study

- Any other events, other than those defined above, in the opinion of the investigator,
may make the patient ineligible for this trial

- No contraindication to biopsy such as bleeding disorders. Patients on anticoagulants
such as warfarin must be able to safely stop the drug for a three-day period. Patients
may not go on heparin during this time

- No active malignancy other than skin cancer or superficial bladder cancer

- Cardiac disease: congestive heart failure > class II NYHA. Patients must no have
unstable angina or new onset angina or myocardial infarction within the past 6 months.
Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Patients must have
an ejection fraction within normal limits at the enrolling institution based on an
echocardiogram

- Uncontrolled hypertension defined as sustained BP > 160 and diastolic > 100 despite
optimal medical management

- Known HIV or chronic Hep B or C

- Thrombolic or embolic events such as CVA within the last 6 months

- Pulmonary hemorrhage or any bleeding event CTCAE Grade 2 or greater within 6 months of
first dose of study drug of KHAD

- Serious non-healing wound, ulcer, or bone fracture

- Evidence of history of bleeding diathesis or coagulopathy

- Major surgery or significant traumatic injury within 4 weeks of first study drug of
KHAD