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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00953576
Recruitment Status : Terminated (drug toxicity)
First Posted : August 6, 2009
Last Update Posted : January 26, 2017
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Massachusetts General Hospital
Prostate Cancer Foundation Clinical Research Consortium
Information provided by (Responsible Party):
Glenn Bubley, MD, Dana-Farber Cancer Institute

Brief Summary:
The purpose of this research study is to determine the safety of giving ketoconazole, hydrocortisone and dutasteride (KHAD) with lapatinib. 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 lapatinib. By adding lapatinib 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.

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: ketoconazole Drug: hydrocortisone Drug: dutasteride Drug: lapatinib Phase 1 Phase 2

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 participants will undergo a CT-guided bone biopsy.
  • After completion of 4 weeks on KHAD treatment, participants will start taking lapatinib along with KHAD starting from week 5. Lapatinib is taken orally once a day.
  • During the 3rd or 4th week of KHAD and Lapatinib (KHLAD) treatment, participants will undergo a CT-guided bone biopsy.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : August 2009
Estimated Primary Completion Date : April 2017

Arm Intervention/treatment
Experimental: KHAD+L
Ketoconazole, Hydrocortisone, Dutasteride and Lapatinib
Drug: ketoconazole
Taken orally three times daily

Drug: hydrocortisone
Taken orally twice daily

Drug: dutasteride
Taken orally once a day

Drug: lapatinib
Starting week 5, taken orally once daily

Primary Outcome Measures :
  1. Assess the safety of combination therapy of ketoconazole, hydrocortisone, dutasteride and lapatinib [ Time Frame: 2 years ]
  2. Establish the MTD of KHAD plus lapatinib [ Time Frame: 2 years ]
    The goal of the study was to determine what dose of lapatinib was safe and tolerable in combination with ketoconazole

  3. Determine the pharmacokinetics of lapatinib when used in combination with KHAD [ Time Frame: 2 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00953576

United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02115
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
Dana-Farber Cancer Institute
Brigham and Women's Hospital
Massachusetts General Hospital
Prostate Cancer Foundation Clinical Research Consortium
Principal Investigator: Glenn Bubley, MD Beth Israel Deaconess Medical Center

Responsible Party: Glenn Bubley, MD, Principal Investigator, Dana-Farber Cancer Institute Identifier: NCT00953576     History of Changes
Other Study ID Numbers: 08-374
First Posted: August 6, 2009    Key Record Dates
Last Update Posted: January 26, 2017
Last Verified: January 2017

Keywords provided by Glenn Bubley, MD, Dana-Farber Cancer Institute:
castration resistant prostate cancer

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Cortisol succinate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors
5-alpha Reductase Inhibitors