A Phase I/II Study of Sunitinib Malate (SU011248) In Patients With Gastrointestinal Stromal Tumor (GIST)

This study has been completed.

Sponsor:

Information provided by:

Pfizer

ClinicalTrials.gov Identifier:

NCT00457743

First received: April 4, 2007

Last updated: October 2, 2009

Last verified: October 2009

History of Changes

Results First Received: July 16, 2009

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Single Group Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Gastrointestinal Stromal Tumors
Intervention:	Drug: Sunitinib malate (SU011248)

Participant Flow

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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
Phase 1 only included Cycle 1 for subjects enrolled in Phase 1. Phase 2 was comprised of either Cycle 2 and beyond for subjects who were enrolled in Phase 1, or all cycles for newly enrolled subjects. Additional subjects were enrolled to make a total of 30 in the recommended dose level (50-mg).

Reporting Groups

Description

SU-011248 25-mg

Subjects received sunitinib malate (SU-011248) at starting dose of 25-mg once daily. Treatment cycles were 6 weeks in duration, consisting of 4 weeks daily SU-011248 administration followed by 2 weeks off treatment.

Phase 1: If Dose Limiting Toxicity (DLT) was observed, the patients were withdrawn from the study treatment. Neither temporary discontinuation nor reduction was permitted.

Phase 2: The initial dose could be increased to the recommended dose. Treatment cycles were repeated until a study treatment withdrawal criterion was met. If drug-related adverse event (grade>=3) was observed, temporary discontinuation or dose reduction were taken according to the criteria.

SU-011248 50-mg

Subjects received sunitinib malate (SU-011248) at starting dose of 50-mg once daily. Treatment cycles were 6 weeks in duration, consisting of 4 weeks daily SU-011248 administration followed by 2 weeks off treatment.

Phase 1: If Dose Limiting Toxicity (DLT) was observed, the patients were withdrawn from the study treatment. Neither temporary discontinuation nor reduction was permitted.

Phase 2: Treatment cycles were repeated until a study treatment withdrawal criterion was met. If drug-related adverse event (grade>=3) was observed, temporary discontinuation or dose reduction were taken according to the criteria.

From Phase 1 part of this study, 50-mg was determined as the maximum tolerated dose and the recommended dose.

SU-011248 75-mg

Subjects received sunitinib malate (SU-011248) at starting dose of 75-mg once daily. Treatment cycles were 6 weeks in duration, consisting of 4 weeks daily SU-011248 administration followed by 2 weeks off treatment.

Phase 1: If Dose Limiting Toxicity (DLT) was observed, the patients were withdrawn from the study treatment. Neither temporary discontinuation nor reduction was permitted.

Phase 2: The initial dose could be reduced to the recommended dose. Treatment cycles were repeated until a study treatment withdrawal criterion was met. If drug-related adverse event (grade>=3) was observed, temporary discontinuation or dose reduction were taken according to the criteria.

Participant Flow: Overall Study

	SU-011248 25-mg	SU-011248 50-mg	SU-011248 75-mg
STARTED	3 ^[1]	30 ^[1]	3 ^[1]
Enrolled in Phase 1	3	6	3
Completed Phase 1	3	6	3
Enrolled in Phase 2	3 ^[2]	30 ^[3]	3 ^[2]
COMPLETED	0 ^[4]	3 ^[5]	0 ^[6]
NOT COMPLETED	3	27	3
Adverse Event	0	4	0
Lack of Efficacy	3	23	3

[1]	Overall study
[2]	Three subjects who completed Phase 1 entered Phase 2.
[3]	Six subjects who completed Phase 1 entered Phase 2, and 24 subjects were newly enrolled.
[4]	However, all 3 subjects enrolled were included in analysis (Intent-to treat population).
[5]	However, all 30 subjects enrolled were included in analysis(Intent-to treat population).
[6]	However, all 3 subjects enrolled were included in analysis(Intent-to treat population).

Baseline Characteristics

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Reporting Groups

	Description
SU-011248 25-mg	Subjects received sunitinib malate (SU-011248) at starting dose of 25-mg once daily. Treatment cycles were 6 weeks in duration, consisting of 4 weeks daily SU-011248 administration followed by 2 weeks off treatment. Phase 1: If Dose Limiting Toxicity (DLT) was observed, the patients were withdrawn from the study treatment. Neither temporary discontinuation nor reduction was permitted. Phase 2: The initial dose could be increased to the recommended dose. Treatment cycles were repeated until a study treatment withdrawal criterion was met. If drug-related adverse event (grade>=3) was observed, temporary discontinuation or dose reduction were taken according to the criteria.
SU-011248 50-mg	Subjects received sunitinib malate (SU-011248) at starting dose of 50-mg once daily. Treatment cycles were 6 weeks in duration, consisting of 4 weeks daily SU-011248 administration followed by 2 weeks off treatment. Phase 1: If Dose Limiting Toxicity (DLT) was observed, the patients were withdrawn from the study treatment. Neither temporary discontinuation nor reduction was permitted. Phase 2: Treatment cycles were repeated until a study treatment withdrawal criterion was met. If drug-related adverse event (grade>=3) was observed, temporary discontinuation or dose reduction were taken according to the criteria. From Phase 1 part of this study, 50-mg was determined as the maximum tolerated dose and the recommended dose.
SU-011248 75-mg	Subjects received sunitinib malate (SU-011248) at starting dose of 75-mg once daily. Treatment cycles were 6 weeks in duration, consisting of 4 weeks daily SU-011248 administration followed by 2 weeks off treatment. Phase 1: If Dose Limiting Toxicity (DLT) was observed, the patients were withdrawn from the study treatment. Neither temporary discontinuation nor reduction was permitted. Phase 2: The initial dose could be reduced to the recommended dose. Treatment cycles were repeated until a study treatment withdrawal criterion was met. If drug-related adverse event (grade>=3) was observed, temporary discontinuation or dose reduction were taken according to the criteria.
Total	Total of all reporting groups

Baseline Measures

	SU-011248 25-mg	SU-011248 50-mg	SU-011248 75-mg	Total
Number of Participants [units: participants]	3	30	3	36
Age, Customized [units: participants]
18-44 years	2	2	0	4
45-64 years	1	24	1	26
>=65 years	0	4	2	6
Gender [units: participants]
Female	1	11	0	12
Male	2	19	3	24
Region of Enrollment [units: participants]
Japan	3	30	3	36
Eastern Cooperative Oncology Group (ECOG) Performance Status ^[1] [units: participants]
0	3	18	2	23
1	0	12	1	13

[1]	Grade 0: Fully active, able to carry on all pre-disease performance without restriction. Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work.

Outcome Measures

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1. Primary:

Number of Subjects With Dose Limiting Toxicities (DLT) [ Time Frame: Cycle 1 (Baseline to Week 6) ]

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2. Primary:

Maximum Plasma Concentration (Cmax) on Cycle 1 Day 1 [ Time Frame: Day 1 of Cycle 1 ]

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3. Primary:

Maximum Plasma Concentration (Cmax) on Cycle 1 Day 28 [ Time Frame: Day 28 of Cycle 1 ]

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Measure Type	Primary
Measure Title	Maximum Plasma Concentration (Cmax) on Cycle 1 Day 28
Measure Description	Maximum Plasma Concentration (Cmax) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) in the subjects enrolled in Phase 1. The Cmax for total drug (SU-011248+SU-012662) was calculated as the mean of the Cmax of total drug from each individual subject (it is not the simple sum of means of Cmax of SU-011248 and SU-012662).
Time Frame	Day 28 of Cycle 1
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All enrolled subjects who received at least 1 dose of study medication and who had at least 1 blood concentration data for Pharmacokinetic analysis. 3 subjects in 75mg dose group discontinued before Cycle 1 Day 28, therefore no data presented.

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

All enrolled subjects who received at least 1 dose of study medication and who had at least 1 blood concentration data for Pharmacokinetic analysis.

3 subjects in 75mg dose group discontinued before Cycle 1 Day 28, therefore no data presented.

Reporting Groups

Description

SU-011248 25-mg

Phase 1: If Dose Limiting Toxicity (DLT) was observed, the patients were withdrawn from the study treatment. Neither temporary discontinuation nor reduction was permitted.

SU-011248 50-mg

Phase 1: If Dose Limiting Toxicity (DLT) was observed, the patients were withdrawn from the study treatment. Neither temporary discontinuation nor reduction was permitted.

From Phase 1 part of this study, 50-mg was determined as the maximum tolerated dose and the recommended dose.

Measured Values

	SU-011248 25-mg	SU-011248 50-mg
Number of Participants Analyzed [units: participants]	3	6
Maximum Plasma Concentration (Cmax) on Cycle 1 Day 28 [units: ng/mL] Mean ± Standard Deviation
SU-011248	39.5 ± 25.0	69.3 ± 18.9
SU-012662	15.2 ± 10.2	38.8 ± 16.0
SU-011248+SU-012662	54.0 ± 32.2	105 ± 35

No statistical analysis provided for Maximum Plasma Concentration (Cmax) on Cycle 1 Day 28

4. Primary:

Area Under the Plasma Concentration Curve (AUC0-24) on Cycle 1 Day 1 [ Time Frame: Day 1 of Cycle 1 ]

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5. Primary:

Area Under the Plasma Concentration Curve (AUC0-24) on Cycle 1 Day 28 [ Time Frame: Day 28 of Cycle 1 ]

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6. Primary:

Time to First Occurrence of Cmax (Tmax) on Cycle 1 Day 1 [ Time Frame: Day 1 of Cycle 1 ]

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7. Primary:

Time to First Occurrence of Cmax (Tmax) on Cycle 1 Day 28 [ Time Frame: Day 28 of Cycle 1 ]

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8. Primary:

SU-011248 Clearance on Cycle 1 Day 28 [ Time Frame: Day 28 of Cycle 1 ]

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9. Primary:

Accumulation Ratio (Rac) on Cycle 1 Day 28 [ Time Frame: Day 28 of Cycle 1 ]

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10. Primary:

Number of Subjects With Clinical Benefit Response (CBR) Based on the Extramural Review Committee Assessment in Recommended Dose Group [ Time Frame: Day 28 of Cycles 1-4 ]

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11. Secondary:

Plasma Concentrations of Vascular Endothelial Growth Factor (VEGF) [ Time Frame: Day 1, 14, 28 of Cycles 1-4 ]

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12. Secondary:

Plasma Concentrations of Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2) [ Time Frame: Day 1, 14, 28 of Cycles 1-4 ]

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13. Secondary:

Plasma Concentrations of Soluble Stem Cell Factor Receptor (sKIT) [ Time Frame: Day 1, 14, 28 of Cycles 1-4 ]

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14. Secondary:

Trough Plasma Concentration (Ctrough) of SU-011248 [ Time Frame: Day 14, 28 of Cycle 1; Day 1, 14, 28 of Cycles 2-4 ]

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15. Secondary:

Trough Plasma Concentration (Ctrough) of SU-012262 [ Time Frame: Day 14, 28 of Cycle 1; Day 1, 14, 28 of Cycles 2-4 ]

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16. Secondary:

Trough Plasma Concentration (Ctrough) of SU-011248+SU-012662 [ Time Frame: Day 14, 28 of Cycle 1; Day 1, 14, 28 of Cycles 2-4 ]

Show Outcome Measure 16

17. Secondary:

Changes From Baseline of Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Questionnaires [ Time Frame: Day 7, 14, 28, 35 of Cycle 1; Day 1, 7, 14, 28, 35 of Cycles 2-4 ]

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18. Secondary:

Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires [ Time Frame: Day 28 of Cycle 1; Day 1, 28 of Cycles 2-4 ]

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19. Secondary:

Number of Subjects With Disease Controlled Based on the Extramural Review Committee Assessment in Recommended Dose Group [ Time Frame: Day 28 of Cycles 1-4 ]

Show Outcome Measure 19

20. Secondary:

Number of Subjects With Objective Response Based on the Extramural Review Committee Assessment in Recommended Dose Group [ Time Frame: Day 28 of Cycles 1-4 ]

Show Outcome Measure 20

21. Secondary:

Time To Tumor Progression (TTP) [ Time Frame: From the first dose to Progressive Disease ]

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22. Secondary:

Progression-Free Survival (PFS) [ Time Frame: From the first dose to Progressive Disease or Death ]

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23. Secondary:

Time To Failure (TTF) [ Time Frame: From the first dose to Progressive Disease, Treatment discontinuation except completion of treatment, or Death due to cancer. ]

Show Outcome Measure 23

24. Secondary:

Overall Survival Time [ Time Frame: From the first dose to death ]

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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 < 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), < 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential info 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
No text entered.

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

Responsible Party:	Director, Clinical Trial Disclosure Group, Pfizer Inc
ClinicalTrials.gov Identifier:	NCT00457743 History of Changes
Other Study ID Numbers:	A6181045, JapicCTI-070386
Study First Received:	April 4, 2007
Results First Received:	July 16, 2009
Last Updated:	October 2, 2009
Health Authority:	Japan: Ministry of Health, Labor and Welfare

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