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

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00953576
• Collaborator: Beth Israel Deaconess Medical Center (Other), Brigham and Women's Hospital (Other), Massachusetts General Hospital (Other), Prostate Cancer Foundation Clinical Research Consortium (Other), GlaxoSmithKline (Industry)
• Enrollment: 11
• Locations: 2
• Arms: 3
• Actual Duration (Months): 42.4
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: ketoconazole; Drug: hydrocortisone; Drug: dutasteride; Drug: lapatinib	Phase 1/Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• 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.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
• 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
• Actual Study Start Date: Sep 29, 2009
• Actual Primary Completion Date: Apr 11, 2013
• Actual Study Completion Date: Apr 11, 2013

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: ketoconazole; Other Names: Nizoral ; Drug: hydrocortisone; Other Names: Cortef Hydrocortone ; Drug: dutasteride; Other Names: Avodart ; Drug: lapatinib; Other Names: lapatinib ditosylate Tyverb
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	Drug: ketoconazole; Other Names: Nizoral ; Drug: hydrocortisone; Other Names: Cortef Hydrocortone ; Drug: dutasteride; Other Names: Avodart ; Drug: lapatinib; Other Names: lapatinib ditosylate Tyverb
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.	Drug: ketoconazole; Other Names: Nizoral ; Drug: hydrocortisone; Other Names: Cortef Hydrocortone ; Drug: dutasteride; Other Names: Avodart ; Drug: lapatinib; Other Names: lapatinib ditosylate Tyverb

Outcome Measures

Primary Outcome Measures

1. Lapatinib Maximum Tolerated Dose (MTD) [Phase I] [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.

2. Lapatinib Dose Limiting Toxicity (DLT) [Phase I] [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: 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.

3. Plasma Lapatinib Levels [Phase I] [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.

Secondary Outcome Measures

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.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Glenn Bubley, MD, Beth Israel Deaconess Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Glenn Bubley, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00953576
• Other Study ID Numbers: 08-374
• First Posted: Aug 6, 2009
• Last Update Posted: Sep 4, 2018
• Last Verified: Jul 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Glenn Bubley, MD, Principal Investigator, Dana-Farber Cancer Institute: castration resistant prostate cancer; KHAD
• Additional relevant MeSH terms: Prostatic Neoplasms; Ketoconazole; Hydrocortisone; Lapatinib; Dutasteride

Study Results

Participant Flow

Recruitment Details	Participants enrolled from September 2009 until December 2011.

Arm/Group Title	Phase I Dose Level 1: KHAD+L (250 mg)	Phase I Dose Level 2: KHAD+L (500 mg)
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	3	5
Treated	4	5
Pharmacokinetic (PK) Evaluable	4	3
COMPLETED	4	4
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Phase I Dose Level 1: KHAD+L (250 mg)	Phase I Dose Level 2: KHAD+L (500 mg)	Total
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 Participants	6	5	11
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	66	67	67
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	6 100%	5 100%	11 100%
Region of Enrollment (Count of Participants)
United States	6 100%	5 100%	11 100%

Outcome Measures

1. Primary Outcome

Title	Lapatinib Maximum Tolerated Dose (MTD) [Phase I]
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).

Outcome Measure Data

Analysis Population Description

The analysis dataset is comprised of all DLT evaluable participants.

Arm/Group Title	All Phase I Participants KHAD+L
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.
Measure Participants	8
Number [mg 1x daily]	NA

2. Primary Outcome

Title	Lapatinib Dose Limiting Toxicity (DLT) [Phase I]
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: 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.
Time Frame	The evaluation for DLT occurred continuously through one cycle of treatment (28 days).

Outcome Measure Data

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)
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.
Measure Participants	3	5
Number [participants with DLT]	0 0%	2 40%

3. Primary Outcome

Title	Plasma Lapatinib Levels [Phase I]
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

Outcome Measure Data

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)
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.
Measure Participants	4	3
Mean (Full Range) [ng/mL]	731	1506

4. Secondary Outcome

Title	Grade 3-4 Treatment-Related Adverse Events Rate
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.

Outcome Measure Data

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)
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
Measure Participants	4	5
Number (90% Confidence Interval) [proportion of participants]	0 0%	0.40 8%

Adverse Events

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)
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/5 (0%)
Serious Adverse Events
	Phase I Dose Level 1: KHAD+L (250 mg)		Phase I Dose Level 2: KHAD+L (500 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		2/5 (40%)
Cardiac disorders
Cardiac-other	0/4 (0%)		1/5 (20%)
Metabolism and nutrition disorders
Hypophosphatemia	0/4 (0%)		1/5 (20%)
Other (Not Including Serious) Adverse Events
	Phase I Dose Level 1: KHAD+L (250 mg)		Phase I Dose Level 2: KHAD+L (500 mg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		5/5 (100%)
Blood and lymphatic system disorders
Hemoglobin	1/4 (25%)		0/5 (0%)
Lymphatics-other	0/4 (0%)		1/5 (20%)
Cardiac disorders
Cardiac-other	2/4 (50%)		2/5 (40%)
Sinus bradycardia	0/4 (0%)		1/5 (20%)
Endocrine disorders
Endocrine-other	0/4 (0%)		1/5 (20%)
Gastrointestinal disorders
Constipation	1/4 (25%)		0/5 (0%)
Diarrhea w/o prior colostomy	0/4 (0%)		2/5 (40%)
Dry mouth	0/4 (0%)		1/5 (20%)
Dyspepsia	0/4 (0%)		1/5 (20%)
Flatulence	1/4 (25%)		0/5 (0%)
GI-other	1/4 (25%)		0/5 (0%)
Incontinence, anal	0/4 (0%)		1/5 (20%)
Lip, pain	1/4 (25%)		0/5 (0%)
Nausea	1/4 (25%)		1/5 (20%)
Rectum, hemorrhage	0/4 (0%)		1/5 (20%)
Vomiting	1/4 (25%)		2/5 (40%)
General disorders
Edema limb	0/4 (0%)		2/5 (40%)
Fatigue	3/4 (75%)		5/5 (100%)
Fever w/o neutropenia	0/4 (0%)		1/5 (20%)
Pain-other	0/4 (0%)		2/5 (40%)
Rigors/chills	0/4 (0%)		1/5 (20%)
Infections and infestations
Infection Gr0-2 neut, urinary tract	1/4 (25%)		0/5 (0%)
Infection w/ gr3-4 neut, urinary tract	0/4 (0%)		1/5 (20%)
Infection w/ unk ANC ungual (nails)	0/4 (0%)		1/5 (20%)
Injury, poisoning and procedural complications
Stoma, GI hemorrhage	1/4 (25%)		0/5 (0%)
Investigations
ALT, SGPT	0/4 (0%)		1/5 (20%)
Amylase	1/4 (25%)		0/5 (0%)
AST, SGOT	1/4 (25%)		2/5 (40%)
Creatinine	1/4 (25%)		1/5 (20%)
Lipase	1/4 (25%)		0/5 (0%)
QTc interval	0/4 (0%)		1/5 (20%)
Weight gain	0/4 (0%)		1/5 (20%)
Metabolism and nutrition disorders
Anorexia	1/4 (25%)		0/5 (0%)
Dehydration	0/4 (0%)		1/5 (20%)
Hyperglycemia	0/4 (0%)		1/5 (20%)
Hyperkalemia	1/4 (25%)		0/5 (0%)
Musculoskeletal and connective tissue disorders
Back, pain	3/4 (75%)		1/5 (20%)
Chest wall, pain	0/4 (0%)		1/5 (20%)
Extremity-limb, pain	0/4 (0%)		1/5 (20%)
Joint, pain	2/4 (50%)		1/5 (20%)
Nonneuropathic lower extr muscle weak	0/4 (0%)		1/5 (20%)
Nervous system disorders
Neuropathy-motor	1/4 (25%)		0/5 (0%)
Syncope	0/4 (0%)		1/5 (20%)
Psychiatric disorders
Insomnia	1/4 (25%)		0/5 (0%)
Renal and urinary disorders
Renal failure	1/4 (25%)		0/5 (0%)
Renal/GU-other	1/4 (25%)		1/5 (20%)
Urinary frequency/urgency	1/4 (25%)		0/5 (0%)
Urine color	0/4 (0%)		1/5 (20%)
Reproductive system and breast disorders
Testicle, pain	0/4 (0%)		1/5 (20%)
Respiratory, thoracic and mediastinal disorders
Cough	0/4 (0%)		2/5 (40%)
Dyspnea	0/4 (0%)		1/5 (20%)
Nasal cavity/paranasal sinus reaction	0/4 (0%)		1/5 (20%)
Nose, hemorrhage	0/4 (0%)		1/5 (20%)
Skin and subcutaneous tissue disorders
Dry skin	0/4 (0%)		2/5 (40%)
Erythema multiforme	0/4 (0%)		1/5 (20%)
Nail changes	1/4 (25%)		0/5 (0%)
Rash/desquamation	1/4 (25%)		1/5 (20%)
Rash: acne/acneiform	1/4 (25%)		1/5 (20%)
Skin-other	2/4 (50%)		1/5 (20%)
Vascular disorders
Hot flashes	0/4 (0%)		1/5 (20%)
Hypertension	0/4 (0%)		2/5 (40%)

Limitations/Caveats

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

More Information

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.