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

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ClinicalTrials.gov Identifier: NCT00953576
Recruitment Status : Terminated (The study terminated early due to concerns about drug toxicity.)
First Posted : August 6, 2009
Results First Posted : September 3, 2018
Last Update Posted : September 3, 2018
Sponsor:
Collaborators:
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Massachusetts General Hospital
Prostate Cancer Foundation Clinical Research Consortium
GlaxoSmithKline
Information provided by (Responsible Party):
Glenn Bubley, MD, Dana-Farber Cancer Institute

August 4, 2009
August 6, 2009
May 21, 2018
September 3, 2018
September 3, 2018
September 29, 2009
April 11, 2013   (Final data collection date for primary outcome measure)
  • Lapatinib Maximum Tolerated Dose (MTD) [Phase I] [ Time Frame: The evaluation for MTD occurred continuously through one cycle of KHLAD treatment (28 days). ]
    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.
  • Lapatinib Dose Limiting Toxicity (DLT) [Phase I] [ Time Frame: The evaluation for DLT occurred continuously through one cycle of treatment (28 days). ]

    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:

    1. Any Grade 3 or greater non-hematological treatment related (possible, probable, or definite attribution) including diarrhea
    2. Grade 4 or greater for hematological toxicities, regardless of attribution.
    3. Grade 3 skin reactions, pulmonary reactions, regardless of attribution.
  • Plasma Lapatinib Levels [Phase I] [ Time Frame: After first 28 days of KHLAD treatment ]
    Plasma lapatinib levels were measured after day 28 of KHLAD treatment. Participants were instructed to fast prior to samples being taken.
  • Assess the safety of combination therapy of ketoconazole, hydrocortisone, dutasteride and lapatanib [ Time Frame: 2 years ]
  • Establish the MTD of KHAD plus lapatanib [ Time Frame: 2 years ]
  • Determine the pharmacokinetics of lapatanib when used in combination with KHAD [ Time Frame: 2 years ]
Complete list of historical versions of study NCT00953576 on ClinicalTrials.gov Archive Site
Grade 3-4 Treatment-Related Adverse Events Rate [ Time Frame: 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. ]
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.
Not Provided
Not Provided
Not Provided
 
Ketoconazole, Hydrocortisone, Dutasteride and Lapatinib (KHAD-L) in Prostate Cancer
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
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.
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.
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
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.
Masking: None (Open Label)
Primary Purpose: Treatment
Prostate Cancer
  • Drug: ketoconazole
    Other Name: Nizoral
  • Drug: hydrocortisone
    Other Names:
    • Cortef
    • Hydrocortone
  • Drug: dutasteride
    Other Name: Avodart
  • Drug: lapatinib
    Other Names:
    • lapatinib ditosylate
    • Tyverb
  • Experimental: Phase I Dose Level 1 (DL1): KHAD+L (250 mg)

    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.

    Interventions:
    • Drug: ketoconazole
    • Drug: hydrocortisone
    • Drug: dutasteride
    • Drug: lapatinib
  • Experimental: Phase I Dose Level 2 (DL2): KHAD+L (500 mg)

    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

    Interventions:
    • Drug: ketoconazole
    • Drug: hydrocortisone
    • Drug: dutasteride
    • Drug: lapatinib
  • Experimental: All Phase I Participants

    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.

    Interventions:
    • Drug: ketoconazole
    • Drug: hydrocortisone
    • Drug: dutasteride
    • Drug: lapatinib
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
11
24
April 11, 2013
April 11, 2013   (Final data collection date for primary outcome measure)

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
Sexes Eligible for Study: Male
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00953576
08-374
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
Glenn Bubley, MD, Dana-Farber Cancer Institute
Dana-Farber Cancer Institute
  • Beth Israel Deaconess Medical Center
  • Brigham and Women's Hospital
  • Massachusetts General Hospital
  • Prostate Cancer Foundation Clinical Research Consortium
  • GlaxoSmithKline
Principal Investigator: Glenn Bubley, MD Beth Israel Deaconess Medical Center
Dana-Farber Cancer Institute
July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP