Phase 1 Study Of Aurora Kinase Inhibitor PF-03814735 In Patients With Advanced Solid Tumors - Study Results

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized; Endpoint Classification: Safety Study; Intervention Model: Single Group Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Solid Tumors
Intervention:	Drug: PF-03814735

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
59 participants enrolled and 57 sequentially assigned to treatment in Schedule A or B of study treatment. Schedule A: starting dose was 5 milligrams per day (mg/day) and dose was escalated up to 100 mg/day. Schedule B: starting dose determined based on occurrence of dose limiting toxicities and maximum tolerated dose in Schedule A.

Reporting Groups

	Description
PF-03814735 5 mg (Schedule A)	Participants received daily dosing of PF-03814735 of 5 milligrams (mg) administered orally (PO) every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.
PF-03814735 10 mg (Schedule A)	Participants received daily dosing of PF-03814735 of 10 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.
PF-03814735 20 mg (Schedule A)	Participants received daily dosing of PF-03814735 of 20 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.
PF-03814735 40 mg (Schedule A)	Participants received daily dosing of PF-03814735 of 40 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.
PF-03814735 60 mg (Schedule A)	Participants received daily dosing of PF-03814735 of 60 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.
PF-03814735 80 mg (Schedule A)	Participants received daily dosing of PF-03814735 of 80 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.
PF-03814735 100 mg (Schedule A)	Participants received daily dosing of PF-03814735 of 100 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.
PF-03814735 40 mg (Schedule B)	Participants received daily dosing of PF-03814735 of 40 mg administered PO every morning on an empty stomach for 10 consecutive days out of 21-day cycles on an outpatient basis.
PF-03814735 50 mg (Schedule B)	Participants received daily dosing of PF-03814735 of 50 mg administered PO every morning on an empty stomach for 10 consecutive days out of 21-day cycles on an outpatient basis.
PF-03814735 60 mg (Schedule B)	Participants received daily dosing of PF-03814735 of 60 mg administered PO every morning on an empty stomach for 10 consecutive days out of 21-day cycles on an outpatient basis.

Participant Flow: Overall Study

	PF-03814735 5 mg (Schedule A)	PF-03814735 10 mg (Schedule A)	PF-03814735 20 mg (Schedule A)	PF-03814735 40 mg (Schedule A)	PF-03814735 60 mg (Schedule A)	PF-03814735 80 mg (Schedule A)	PF-03814735 100 mg (Schedule A)	PF-03814735 40 mg (Schedule B)	PF-03814735 50 mg (Schedule B)	PF-03814735 60 mg (Schedule B)
STARTED	1	1	1	4	3	15	7	3	16	6
COMPLETED	0	0	0	0	0	0	0	0	0	0
NOT COMPLETED	1	1	1	4	3	15	7	3	16	6
Death	0	0	0	0	0	2	0	0	0	0
Adverse Event	0	0	0	0	0	0	0	0	3	2
Global deterioration of health status	0	0	0	1	1	0	0	0	0	0
Objective progression or relapse	1	1	1	2	2	13	7	3	12	4
Unspecified	0	0	0	1	0	0	0	0	1	0

Baseline Characteristics

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Reporting Groups

	Description
PF-03814735 (Schedule A)	Participants received daily dosing of PF-03814735 of 5, 10, 20, 40, 60, 80, or 100 mg administered PO every morning on an empty stomach for 5 consecutive days out of 21-day cycles on an outpatient basis.
PF-03814735 (Schedule B)	Participants received daily dosing of PF-03814735 of 40, 50, or 60 mg administered PO every morning on an empty stomach for 10 consecutive days out of 21-day cycles on an outpatient basis.
Total	Total of all reporting groups

Baseline Measures

	PF-03814735 (Schedule A)	PF-03814735 (Schedule B)	Total
Number of Participants [units: participants]	32	25	57
Age [units: years] Mean ± Standard Deviation	63.6 ± 9.0	58.2 ± 10.2	61.2 ± 9.8
Gender [units: participants]
Female	18	13	31
Male	14	12	26

Outcome Measures

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1. Primary:

Number of Participants With First Cycle Dose Limiting Toxicities (DLTs) Graded According to Common Terminology Criteria Adverse Events (CTCAE), Version 3 [ Time Frame: Day 1 up to Day 21 of first cycle ]

Show Outcome Measure 1

2. Secondary:

Maximum Observed Serum Concentration (Cmax) [ Time Frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose ]

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3. Secondary:

Time for Maximum Observed Serum Concentration (Tmax) [ Time Frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose ]

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4. Secondary:

Area Under the Serum Concentration Time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) [ Time Frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose ]

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5. Secondary:

Area Under the Serum Concentration Time Profile From Time 0 to Time Tau (τ), the Dosing Interval, Where τ = 24 Hours (AUCτ). [ Time Frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose ]

Show Outcome Measure 5

6. Secondary:

Minimum Observed Serum Trough Concentration (Cmin) [ Time Frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose ]

Show Outcome Measure 6

7. Secondary:

Observed Serum Accumulation Ratio (Rac) [ Time Frame: Schedule B Day-5: pre-dose, 0.5, 1, 2, 4, 6, 10, 24, 32, 48, and 72 hours post-dose, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose ]

Show Outcome Measure 7

8. Secondary:

Terminal Half-life (t 1/2) [ Time Frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose ]

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9. Secondary:

Urine Pharmacokinetics [ Time Frame: Schedule A Cycle 1/Day 4, Schedule B Cycle 1/Day 9: pre-dose, 0.5, 1, 2, 4, 6, 10, and 24 hours post-dose ]

Show Outcome Measure 9

10. Secondary:

Summary of Tumor Metabolism Assessed by Positron Emission Tomography With F-18-fluorodeoxyglucose (FDG-PET) [ Time Frame: Baseline (Schedule A or Schedule B Day -7) and Schedule A Cycle 1/Day 3 or Day 4, Schedule B Cycle 1/Day 8 or 9 ]

Show Outcome Measure 10

11. Secondary:

Target Modulation by Phosphohistone H3 (pH3) Expression in Tumor Tissue (IHC) [ Time Frame: Schedule A Cycle 1 or Cycle 2 /Day 4 or Day 5, Schedule B Cycle 1/Day 9 or Day 10 ]

Show Outcome Measure 11

12. Secondary:

Number of Participants With Objective Tumor Response [ Time Frame: Every 2 cycles (each cycle=21 days) until disease progression or participant discontinuation; maximum follow-up was from baseline up to 12 cycles ]

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13. Secondary:

Time to Progression [ Time Frame: Baseline, every 2 cycles (each cycle=21 days) until disease progression or participant discontinuation; maximum follow-up was from baseline up to 12 cycles ]

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14. Secondary:

Duration of Response [ Time Frame: Every 2 cycles (each cycle=21 days) until disease progression or participant discontinuation; maximum follow-up was from baseline up to 12 cycles ]

Show Outcome Measure 14

15. Secondary:

Germ Line Polymorphism of Candidate Genes Targeted by PF-03814735 [ Time Frame: Schedule A Cycle 1 or Cycle 2 /Day 4 or Day 5, Schedule B Cycle 1/Day 9 or Day 10 (each cycle=21 days) ]

Show Outcome Measure 15

16. Secondary:

Aurora Gene Somatic Mutations/Amplification and Pathway Genes in Tumor Tissue [ Time Frame: Schedule A Cycle 1 or Cycle 2 /Day 4 or Day 5, Schedule B Cycle 1/Day 9 or Day 10 (each cycle=21 days) ]

Show Outcome Measure 16

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS 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.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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Results Point of Contact:

Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
phone: 1-800-718-1021
e-mail: ClinicalTrials.govCallCenter@pfizer.com

No publications provided by Pfizer

Publications automatically indexed to this study:

Schöffski P, Jones SF, Dumez H, Infante JR, Van Mieghem E, Fowst C, Gerletti P, Xu H, Jakubczak JL, English PA, Pierce KJ, Burris HA. Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours. Eur J Cancer. 2011 Oct;47(15):2256-64. Epub 2011 Aug 16.

Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT00424632 History of Changes
Other Study ID Numbers:	A9491001
Study First Received:	January 18, 2007
Results First Received:	March 21, 2012
Last Updated:	June 14, 2012
Health Authority:	United States: Food and Drug Administration