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

Condition(s) targeted: Prostate Cancer

Intervention: ketoconazole (Drug); hydrocortisone (Drug); dutasteride (Drug); lapatanib (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: Beth Israel Deaconess Medical Center

Official(s) and/or principal investigator(s):
Glenn Bubley, MD, Principal Investigator, Affiliation: Beth Israel Deaconess Medical Center

Overall contact:
Glenn Bubley, MD, Phone: 617-735-2061

The purpose of this research study is to determine the safety of giving ketoconazole, hydrocortisone adn dutasteride (KHAD) with lapatanib. The investigators believe that there is evidence in castrate resistant prostate cancer that two growth factor receptors (EGFr and Her 2 /neu )are increased in prostate cancer cells. Both these receptors are turned off by the drug lapatanib. By adding lapatanib to this trial, the investigators hope that the investigators can turn off the signaling from the receptors and therefore make the participant's cancer more responsive to KHAD treatment.

Official title: A Phase I/II Trial of Ketoconazole, Hydrocortisone, Dutasteride and Lapatanib (KHAD-L) in Castration Resistant Prostate Cancer With Pre- and Post-therapy Tumor Biopsies

Study design: Treatment, Open Label, Single Group Assignment, Safety/Efficacy Study

Primary outcome:

Assess the safety of combination therapy of ketoconazole, hydrocortisone, dutasteride and lapatanib

Establish the MTD of KHAD plus lapatanib

Determine the pharmacokinetics of lapatanib when used in combination with KHAD

Detailed description:

- For the initial four weeks of the study, participants will receive the drugs

ketoconazole, dutasteride and hydrocortisone daily (KHAD treatment). Ketoconazole will be taken orally three times a day, hydrocortisone will be taken orally twice a day and dutasteride will be taken orally once a day.

- During the 3rd or 4th week of KHAD treatment participant's will undergo a CT-guided

bone biopsy.

- After completion of 4 weeks on KHAD treatment, participant's will start taking

lapatanib along with KHAD starting from week 5. Lapatanib is taken orally once a day.

- During the 3rd or 4th week of KHAD and Lapatanib (KHLAD) treatment, participant's will

undergo a CT-guided bone biopsy.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Male.

Criteria:

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 abitererone, 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 adn 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 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

Glenn Bubley, MD, Phone: 617-735-2061

Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, United States; Recruiting
Glenn Bubley, MD, Principal Investigator

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States; Recruiting
Mary Ellen Taplin, MD, Principal Investigator

Starting date: August 2009
Last updated: August 31, 2009