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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: ketoconazole
* Drug: hydrocortisone
* Drug: dutasteride
* Drug: lapatinib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Dose Level 1 (DL1): KHAD+L (250 mg)<br>For the initial four weeks (1 cycle=28 days), participants receive KHAD treatment. Ketoconazole: 400 mg orally 3x day Hydrocortisone: 30 mg (a.m.) and 10 mg (p.m.) orally 2x day Dutasteride: 0.5 mg orally 1x day Participants start KHLAD on day 29 or d1 of cycle 2/ week 5. Lapatinib: 250 mg orally 1x day Participants are treated until unacceptable toxicity, disease progression or withdrawal. | Drug: ketoconazole<br> <br> * Other names: Nizoral;Drug: hydrocortisone<br> <br> * Other names: Hydrocortone;Drug: dutasteride<br> <br> * Other names: Avodart;Drug: lapatinib<br> <br> * Other names: Tyverb;|
| Experimental: Phase I Dose Level 2 (DL2): KHAD+L (500 mg)<br>For the initial four weeks (1 cycle=28 days), participants will receive KHAD treatment. Ketoconazole: 400 mg orally 3x day Hydrocortisone: 30 mg (a.m.) and 10 mg (p.m.) orally 2x day Dutasteride: 0.5 mg orally 1x day Participants will start KHLAD on day 29 or d1 of cycle 2/ week 5. Lapatinib: 500 mg orally 1x day | Drug: ketoconazole<br> <br> * Other names: Nizoral;Drug: hydrocortisone<br> <br> * Other names: Hydrocortone;Drug: dutasteride<br> <br> * Other names: Avodart;Drug: lapatinib<br> <br> * Other names: Tyverb;|
| Experimental: All Phase I Participants<br>For the initial four weeks (1 cycle=28 days), participants receive KHAD treatment. Ketoconazole: 400 mg orally 3x day Hydrocortisone: 30 mg (a.m.) and 10 mg (p.m.) orally 2x day Dutasteride: 0.5 mg orally 1x day Participants start KHLAD on day 29 or d1 of cycle 2/ week 5. Lapatinib: according to the established dose escalation schedule Participants are treated until unacceptable toxicity, disease progression or withdrawal. | Drug: ketoconazole<br> <br> * Other names: Nizoral;Drug: hydrocortisone<br> <br> * Other names: Hydrocortone;Drug: dutasteride<br> <br> * Other names: Avodart;Drug: lapatinib<br> <br> * Other names: Tyverb;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lapatinib Maximum Tolerated Dose (MTD) [Phase I] | The MTD of lapatinib in combination with KHAD is determined by the number of participants who experience a dose limiting toxicity (DLT) at the various dose levels of lapatinib under evaluation. See subsequent primary outcome measure for the DLT definition. The MTD is defined as the lapatinib dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached and the Recommended Phase II Dose (RP2D) will be based on safety and pharmacokinetic results. | The evaluation for MTD occurred continuously through one cycle of KHLAD treatment (28 days). | 
| Lapatinib Dose Limiting Toxicity (DLT) [Phase I] | A DLT is defined as an adverse event (AE) occurring during the first cycle of KHLAD treatment that are determined to related to the Lapatinib or the combination as follows: Any Grade 3 or greater non-hematological treatment related (possible, probable, or definite attribution) including diarrhea Grade 4 or greater for hematological toxicities, regardless of attribution. Grade 3 skin reactions, pulmonary reactions, regardless of attribution. | The evaluation for DLT occurred continuously through one cycle of treatment (28 days). | 
| Plasma Lapatinib Levels [Phase I] | Plasma lapatinib levels were measured after day 28 of KHLAD treatment. Participants were instructed to fast prior to samples being taken. | After first 28 days of KHLAD treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3-4 Treatment-Related Adverse Events Rate | All grade 3-4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted to calculate the proportion of participants experiencing at least one treatment-related grade 3 or 4 AE of any type on treatment. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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castration resistant prostate cancer, KHAD