Prostate Cancer Clinical Trial

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

Summary

The purpose of this research study is to determine the safety of giving ketoconazole, hydrocortisone and dutasteride (KHAD) with lapatinib. Safety is primarily based on dose limiting toxicity (DLT) evaluation at various dose levels (DL). The investigators believe that there is evidence in castrate resistant prostate cancer (CRPC) that two growth factor receptors (EGFR and Her 2/Neu) are increased in prostate cancer (PCa) cells. Both these receptors are turned off by the drug lapatinib. By adding lapatinib, the investigators hope that signaling from the receptors will be turned off and therefore make the participant's cancer more responsive to KHAD treatment.

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Full Description

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.

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Eligibility 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 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

Study is for people with:

Prostate Cancer

Phase:

Phase 1

Estimated Enrollment:

11

Study ID:

NCT00953576

Recruitment Status:

Terminated

Sponsor:

Dana-Farber Cancer Institute

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There is 1 Location for this study

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Beth Israel Deaconess Medical Center
Boston Massachusetts, 02115, United States
Dana-Farber Cancer Institute
Boston Massachusetts, 02115, United States

How clear is this clinincal trial information?

Study is for people with:

Prostate Cancer

Phase:

Phase 1

Estimated Enrollment:

11

Study ID:

NCT00953576

Recruitment Status:

Terminated

Sponsor:


Dana-Farber Cancer Institute

How clear is this clinincal trial information?

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