Clinical trial NCT00953576: Ketoconazole, Hydrocortisone, Dutasteride and Lapatinib (KHAD-L) in Prostate Cancer
Official title: A Phase I/II Trial of Ketoconazole, Hydrocortisone, Dutasteride and Lapatinib (KHAD-L) in Castration Resistant Prostate Cancer With Pre- and Post-therapy Tumor Biopsies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Prostate Cancer
Keywords: castration resistant prostate cancer
KHAD
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Beth Israel Deaconess Medical Center
name: Brigham and Women's Hospital
name: Massachusetts General Hospital
name: Prostate Cancer Foundation Clinical Research Consortium
name: GlaxoSmithKline
First posted: 2009-08-06
Enrollment: 11
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: The Phase I dose escalation schedule was to evaluate up to 4 dose levels of lapatinib as well as one step down dose for ketoconazole (-1). This is not a 'parallel assignment' since this dose escalation design proceeds in sequence not in parallel.
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

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

Primary outcomes:
measure: Lapatinib Maximum Tolerated Dose (MTD) [Phase I]
timeFrame: The evaluation for MTD occurred continuously through one cycle of KHLAD treatment (28 days).
measure: Lapatinib Dose Limiting Toxicity (DLT) [Phase I]
timeFrame: The evaluation for DLT occurred continuously through one cycle of treatment (28 days).
measure: Plasma Lapatinib Levels [Phase I]
timeFrame: After first 28 days of KHLAD treatment
Secondary outcomes:
measure: Grade 3-4 Treatment-Related Adverse Events Rate
timeFrame: Assessed each cycle throughout treatment. Treatment duration in months was a median (range) of 5.4 months (range 1 day-8.3 months). Thus, AEs were evaluated up to 8.3 months.
Other outcomes:
Locations:
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Glenn Bubley, MD
role: PRINCIPAL_INVESTIGATOR
References: