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

NCT00953576 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: 08-374
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 2

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.

Conditions

Prostate Cancer

Keywords

castration resistant prostate cancer; KHAD

Outcome Measures

Primary Outcomes (3)

• 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: 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.

  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 Outcomes (1)

• Grade 3-4 Treatment-Related Adverse Events Rate

  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.

Study Arms (3)

Phase I Dose Level 1 (DL1): KHAD+L (250 mg)

EXPERIMENTAL

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; Drug: hydrocortisone; Drug: dutasteride; Drug: lapatinib

Phase I Dose Level 2 (DL2): KHAD+L (500 mg)

EXPERIMENTAL

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; Drug: hydrocortisone; Drug: dutasteride; Drug: lapatinib

All Phase I Participants

EXPERIMENTAL

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; Drug: hydrocortisone; Drug: dutasteride; Drug: lapatinib

Interventions

ketoconazole DRUG

Also known as: Nizoral

All Phase I Participants; Phase I Dose Level 1 (DL1): KHAD+L (250 mg); Phase I Dose Level 2 (DL2): KHAD+L (500 mg)

hydrocortisone DRUG

Also known as: Cortef, Hydrocortone

All Phase I Participants; Phase I Dose Level 1 (DL1): KHAD+L (250 mg); Phase I Dose Level 2 (DL2): KHAD+L (500 mg)

dutasteride DRUG

Also known as: Avodart

All Phase I Participants; Phase I Dose Level 1 (DL1): KHAD+L (250 mg); Phase I Dose Level 2 (DL2): KHAD+L (500 mg)

lapatinib DRUG

Also known as: lapatinib ditosylate, Tyverb

All Phase I Participants; Phase I Dose Level 1 (DL1): KHAD+L (250 mg); Phase I Dose Level 2 (DL2): KHAD+L (500 mg)

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Beth Israel Deaconess Medical Center: collaborator
• Brigham and Women's Hospital: collaborator
• Massachusetts General Hospital: collaborator
• Prostate Cancer Foundation Clinical Research Consortium: collaborator
• GlaxoSmithKline: collaborator

Study Sites (2)

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

Ketoconazole; Hydrocortisone; Dutasteride; Lapatinib

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Azasteroids; Steroids, Heterocyclic; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

This study was terminated early due to concern of exposure levels observed in PK analyses for the drug under investigation.

Results Point of Contact

• Title: Glenn Bubley, MD
• Organization: Beth Israel Deaconess Medical Center

gbubley@bidmc.harvard.edu

Study Officials

• Glenn Bubley, MD

  Beth Israel Deaconess Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: 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.

Study Record Dates

• First Submitted: August 4, 2009
• First Posted: August 6, 2009
• Study Start: September 29, 2009
• Primary Completion: April 11, 2013
• Study Completion: April 11, 2013
• Last Updated: September 4, 2018
• Results First Posted: September 4, 2018

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)