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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

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Prostate Cancer
Interventions Drug: ketoconazole
Drug: hydrocortisone
Drug: dutasteride
Drug: lapatinib
Enrollment 11
Recruitment Details Participants enrolled from September 2009 until December 2011.
Pre-assignment Details  
Arm/Group Title Phase I Dose Level 1: KHAD+L (250 mg) Phase I Dose Level 2: KHAD+L (500 mg)
Hide Arm/Group Description

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.

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

Participants are treated until unacceptable toxicity, disease progression or withdrawal.

Period Title: Overall Study
Started 6 5
DLT Evaluable [1] 3 5
Treated 4 5
Pharmacokinetic (PK) Evaluable [2] 4 3
Completed 4 [3] 4
Not Completed 2 1
Reason Not Completed
Adverse Event             0             1
Ineligible after Consent             2             0
[1]
Participants were DLT evaluable if they received 1 cycle of KHLAD and full dose ketoconazole (KHAD).
[2]
Participants with pre- and post KHLAD day 28 samples.
[3]
One participant enrolled on dose level 1 did not receive full dose ketoconazole and was replaced.
Arm/Group Title Phase I Dose Level 1: KHAD+L (250 mg) Phase I Dose Level 2: KHAD+L (500 mg) Total
Hide Arm/Group Description

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.

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

Participants are treated until unacceptable toxicity, disease progression or withdrawal.

Total of all reporting groups
Overall Number of Baseline Participants 6 5 11
Hide Baseline Analysis Population Description
The analysis dataset is comprised of all enrolled participants.
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 6 participants 5 participants 11 participants
66
(51 to 87)
67
(65 to 69)
67
(51 to 87)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 5 participants 11 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
6
 100.0%
5
 100.0%
11
 100.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 6 participants 5 participants 11 participants
6
 100.0%
5
 100.0%
11
 100.0%
1.Primary Outcome
Title Lapatinib Maximum Tolerated Dose (MTD) [Phase I]
Hide Description 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.
Time Frame The evaluation for MTD occurred continuously through one cycle of KHLAD treatment (28 days).
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all DLT evaluable participants.
Arm/Group Title All Phase I Participants KHAD+L
Hide Arm/Group Description:

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: orally 1x day according to the established dose escalation schedule

Participants are treated until unacceptable toxicity, disease progression or withdrawal.

Overall Number of Participants Analyzed 8
Measure Type: Number
Unit of Measure: mg 1x daily
NA [1] 
[1]
While 2 DLTs occurred at DL2, the MTD was not established as DL1 because based on PK analysis, the observed level of lapatinib was well above therapeutic levels which raised sufficient concern to terminate the study.
2.Primary Outcome
Title Lapatinib Dose Limiting Toxicity (DLT) [Phase I]
Hide Description

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.
Time Frame The evaluation for DLT occurred continuously through one cycle of treatment (28 days).
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all DLT evaluable participants.
Arm/Group Title Phase I Dose Level 1: KHAD+L (250 mg) Phase I Dose Level 2: KHAD+L (500 mg)
Hide Arm/Group Description:

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.

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

Participants are treated until unacceptable toxicity, disease progression or withdrawal.

Overall Number of Participants Analyzed 3 5
Measure Type: Number
Unit of Measure: participants with DLT
0 2
3.Primary Outcome
Title Plasma Lapatinib Levels [Phase I]
Hide Description Plasma lapatinib levels were measured after day 28 of KHLAD treatment. Participants were instructed to fast prior to samples being taken.
Time Frame After first 28 days of KHLAD treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of participants who received KHLAD and had an evaluable plasma sample after the first cycle (day 28).
Arm/Group Title Phase I Dose Level 1: KHAD+L (250 mg) Phase I Dose Level 2: KHAD+L (500 mg)
Hide Arm/Group Description:

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.

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

Participants are treated until unacceptable toxicity, disease progression or withdrawal.

Overall Number of Participants Analyzed 4 3
Mean (Full Range)
Unit of Measure: ng/mL
731
(416 to 1424)
1506
(680 to 2186)
4.Secondary Outcome
Title Grade 3-4 Treatment-Related Adverse Events Rate
Hide Description 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.
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.
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis dataset is comprised of all participants who ever started treatment.
Arm/Group Title Phase I Dose Level 1: KHAD+L (250 mg) Phase I Dose Level 2: KHAD+L (500 mg)
Hide Arm/Group Description:

For the initial four weeks (1 cycle=28 days), participants receive KHAD treatment.

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: 250 mg orally 1x day

Participants are treated until unacceptable toxicity, disease progression or withdrawal.

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

Overall Number of Participants Analyzed 4 5
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: proportion of participants
0
(0.0 to 0.451)
0.40
(0.076 to 0.811)
Time Frame Assessed each cycle throughout treatment. Median (range) treatment duration (months) for dose level 1: 5.5 (1.8-8.3) and dose level 2: 5.4 (0.2-17.9). Thus, AEs were followed up to 17.9 months.
Adverse Event Reporting Description The analysis dataset is comprised of all participants who ever started treatment. Maximum grade toxicity by type was first calculated. Serious AEs were defined as events with treatment attribution of possibly, probably or definitely and grade 3 or higher. All remaining events regardless of treatment attribution were classified as Other AEs. No further data is available to specify classification of other beyond the general term.
 
Arm/Group Title Phase I Dose Level 1: KHAD+L (250 mg) Phase I Dose Level 2: KHAD+L (500 mg)
Hide Arm/Group Description

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.

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

Participants are treated until unacceptable toxicity, disease progression or withdrawal.

All-Cause Mortality
Phase I Dose Level 1: KHAD+L (250 mg) Phase I Dose Level 2: KHAD+L (500 mg)
Affected / at Risk (%) Affected / at Risk (%)
Total   0/4 (0.00%)   0/5 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Phase I Dose Level 1: KHAD+L (250 mg) Phase I Dose Level 2: KHAD+L (500 mg)
Affected / at Risk (%) Affected / at Risk (%)
Total   0/4 (0.00%)   2/5 (40.00%) 
Cardiac disorders     
Cardiac-other  1 [1]  0/4 (0.00%)  1/5 (20.00%) 
Metabolism and nutrition disorders     
Hypophosphatemia  1  0/4 (0.00%)  1/5 (20.00%) 
1
Term from vocabulary, CTCAE (3.0)
Indicates events were collected by systematic assessment
[1]
AE connected with grade 3 or higher EKG changes
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Phase I Dose Level 1: KHAD+L (250 mg) Phase I Dose Level 2: KHAD+L (500 mg)
Affected / at Risk (%) Affected / at Risk (%)
Total   4/4 (100.00%)   5/5 (100.00%) 
Blood and lymphatic system disorders     
Hemoglobin  1  1/4 (25.00%)  0/5 (0.00%) 
Lymphatics-other  1  0/4 (0.00%)  1/5 (20.00%) 
Cardiac disorders     
Cardiac-other  1  2/4 (50.00%)  2/5 (40.00%) 
Sinus bradycardia  1  0/4 (0.00%)  1/5 (20.00%) 
Endocrine disorders     
Endocrine-other  1  0/4 (0.00%)  1/5 (20.00%) 
Gastrointestinal disorders     
Constipation  1  1/4 (25.00%)  0/5 (0.00%) 
Diarrhea w/o prior colostomy  1  0/4 (0.00%)  2/5 (40.00%) 
Dry mouth  1  0/4 (0.00%)  1/5 (20.00%) 
Dyspepsia  1  0/4 (0.00%)  1/5 (20.00%) 
Flatulence  1  1/4 (25.00%)  0/5 (0.00%) 
GI-other  1  1/4 (25.00%)  0/5 (0.00%) 
Incontinence, anal  1  0/4 (0.00%)  1/5 (20.00%) 
Lip, pain  1  1/4 (25.00%)  0/5 (0.00%) 
Nausea  1  1/4 (25.00%)  1/5 (20.00%) 
Rectum, hemorrhage  1  0/4 (0.00%)  1/5 (20.00%) 
Vomiting  1  1/4 (25.00%)  2/5 (40.00%) 
General disorders     
Edema limb  1  0/4 (0.00%)  2/5 (40.00%) 
Fatigue  1  3/4 (75.00%)  5/5 (100.00%) 
Fever w/o neutropenia  1  0/4 (0.00%)  1/5 (20.00%) 
Pain-other  1  0/4 (0.00%)  2/5 (40.00%) 
Rigors/chills  1  0/4 (0.00%)  1/5 (20.00%) 
Infections and infestations     
Infection Gr0-2 neut, urinary tract  1  1/4 (25.00%)  0/5 (0.00%) 
Infection w/ gr3-4 neut, urinary tract  1  0/4 (0.00%)  1/5 (20.00%) 
Infection w/ unk ANC ungual (nails)  1  0/4 (0.00%)  1/5 (20.00%) 
Injury, poisoning and procedural complications     
Stoma, GI hemorrhage  1  1/4 (25.00%)  0/5 (0.00%) 
Investigations     
ALT, SGPT  1  0/4 (0.00%)  1/5 (20.00%) 
Amylase  1  1/4 (25.00%)  0/5 (0.00%) 
AST, SGOT  1  1/4 (25.00%)  2/5 (40.00%) 
Creatinine  1  1/4 (25.00%)  1/5 (20.00%) 
Lipase  1  1/4 (25.00%)  0/5 (0.00%) 
QTc interval  1  0/4 (0.00%)  1/5 (20.00%) 
Weight gain  1  0/4 (0.00%)  1/5 (20.00%) 
Metabolism and nutrition disorders     
Anorexia  1  1/4 (25.00%)  0/5 (0.00%) 
Dehydration  1  0/4 (0.00%)  1/5 (20.00%) 
Hyperglycemia  1  0/4 (0.00%)  1/5 (20.00%) 
Hyperkalemia  1  1/4 (25.00%)  0/5 (0.00%) 
Musculoskeletal and connective tissue disorders     
Back, pain  1  3/4 (75.00%)  1/5 (20.00%) 
Chest wall, pain  1  0/4 (0.00%)  1/5 (20.00%) 
Extremity-limb, pain  1  0/4 (0.00%)  1/5 (20.00%) 
Joint, pain  1  2/4 (50.00%)  1/5 (20.00%) 
Nonneuropathic lower extr muscle weak  1  0/4 (0.00%)  1/5 (20.00%) 
Nervous system disorders     
Neuropathy-motor  1  1/4 (25.00%)  0/5 (0.00%) 
Syncope  1  0/4 (0.00%)  1/5 (20.00%) 
Psychiatric disorders     
Insomnia  1  1/4 (25.00%)  0/5 (0.00%) 
Renal and urinary disorders     
Renal failure  1  1/4 (25.00%)  0/5 (0.00%) 
Renal/GU-other  1  1/4 (25.00%)  1/5 (20.00%) 
Urinary frequency/urgency  1  1/4 (25.00%)  0/5 (0.00%) 
Urine color  1  0/4 (0.00%)  1/5 (20.00%) 
Reproductive system and breast disorders     
Testicle, pain  1  0/4 (0.00%)  1/5 (20.00%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  0/4 (0.00%)  2/5 (40.00%) 
Dyspnea  1  0/4 (0.00%)  1/5 (20.00%) 
Nasal cavity/paranasal sinus reaction  1  0/4 (0.00%)  1/5 (20.00%) 
Nose, hemorrhage  1  0/4 (0.00%)  1/5 (20.00%) 
Skin and subcutaneous tissue disorders     
Dry skin  1  0/4 (0.00%)  2/5 (40.00%) 
Erythema multiforme  1  0/4 (0.00%)  1/5 (20.00%) 
Nail changes  1  1/4 (25.00%)  0/5 (0.00%) 
Rash/desquamation  1  1/4 (25.00%)  1/5 (20.00%) 
Rash: acne/acneiform  1  1/4 (25.00%)  1/5 (20.00%) 
Skin-other  1  2/4 (50.00%)  1/5 (20.00%) 
Vascular disorders     
Hot flashes  1  0/4 (0.00%)  1/5 (20.00%) 
Hypertension  1  0/4 (0.00%)  2/5 (40.00%) 
1
Term from vocabulary, CTCAE (3.0)
Indicates events were collected by systematic assessment
This study was terminated early due to concern of exposure levels observed in PK analyses for the drug under investigation.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Glenn Bubley, MD
Organization: Beth Israel Deaconess Medical Center
EMail: gbubley@bidmc.harvard.edu
Layout table for additonal information
Responsible Party: Glenn Bubley, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT00953576     History of Changes
Other Study ID Numbers: 08-374
First Submitted: August 4, 2009
First Posted: August 6, 2009
Results First Submitted: May 21, 2018
Results First Posted: September 3, 2018
Last Update Posted: September 3, 2018