Neoplasms

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Skin and Connective Tissue Diseases

Rare Diseases

Gastrointestinal Stromal Tumors

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Neoplasms, Connective and Soft Tissue

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Antineoplastic Agents

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Sunitinib

Imatinib Mesylate

Angiogenesis Inhibitors

Growth Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Sunitinib malate (SU011248)

Pfizer CT.gov Call Center

Phase I;To investigate the clinically recommended dose of Sunitinib malate (SU011248) following multiple oral dosing in the first cycle (4 consecutive weeks and 2 weeks rest) by reviewing the safety and tolerability.

Phase II;To determine the objective tumor response and the safety of Sunitinib malate (SU011248) at the clinically recommended dose.

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

A Phase I/II Study of Sunitinib Malate (SU011248) In The Treatment of Patients With Malignant Gastrointestinal Stromal Tumor (GIST) Previously Treated by Imatinib Mesylate.

Dose Limiting Toxicities(DLT) in the subjects enrolled in Phase 1.

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).

Area Under the Plasma Concentration Curve (AUC0-24) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) in the subjects enrolled in Phase 1.

The AUC0-24 for total drug (SU-011248+SU-012662) was calculated as the mean of the AUC0-24 of total drug from each individual subject (it is not the simple sum of means of AUC0-24 of SU-011248 and SU-012662).

Time to First Occurrence of Cmax (Tmax) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) in the subjects enrolled in Phase 1.

The Tmax for total drug (SU-011248+SU-012662) was calculated as the median of the Tmax of total drug from each individual subject (it is not the simple sum of median of Tmax of SU-011248 and SU-012662).

Time to First Occurrence of Cmax (Tmax) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) in the subjects enrolled in Phase 1.

The Tmax for total drug (SU-011248+SU-012662) was calculated as the median of the Tmax of total drug from each individual subject (it is not the simple sum of medians of Tmax of SU-011248 and SU-012662).

SU-011248 Clearance in the subjects enrolled in Phase 1.

Clearance was calculated by dividing a SU-011248 dose(mg) by AUC0-24(ng•h/mL).

Accumulation Ratio (Rac) of SU-011248, its active metabolite SU-012662 and Total drug (SU-011248+SU-012662) on Cycle 1 Day 28 in the subjects enrolled in Phase 1.

Rac was the ratio of Day 28 to Day 1.

Clinical Benefit Response is defined as sum of subjects confirmed with complete response (CR), partial response (PR), or stable disease (SD)\>= 22 weeks on study according to Response Evaluation Criteria in Solid Tumors (RECIST).

Plasma concentrations of potential pharmacodynamic markers; Vascular Endothelial Growth Factor (VEGF)

Plasma concentrations of potential pharmacodynamic markers; Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)

Plasma concentrations of potential pharmacodynamic markers; Soluble Stem Cell Factor Receptor (sKIT)

Trough Plasma Concentration (Ctrough) means the concentration prior to study drug administration

Patient-reported outcome: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaires (version 4A).

The questionnaire consists of a 13-item subscale which covers specific fatigue questions. The subject rates the intensity of fatigue and its related symptoms on a five-point scale(0 to 4). High score is indicating low fatigue. The total score of the 13 items was evaluated.

Change from Baseline: Score at each observation minus score at baseline

The EQ-5D questionnaires evaluates 5 dimensions of health. The subjects rates the severity of impairment for each dimensions on a 3-point scale(1 to 3). The digits for five dimensions were combined in a five-digit number describing the respondent's health state. Health states were converted into a weighted health state index. High score is indicating high health.

Change from Baseline: weighted health state index at each observation minus weighted health state index at baseline

Number of subjects with Disease Controlled is defined as sum of the subjects confirmed with complete response (CR), partial response (PR), or stable disease (SD)\>= 10 weeks on study according to Response Evaluation Criteria in Solid Tumors (RECIST).

Number of subjects with Objective Response is defined as sum of the subjects confirmed with complete response (CR) and partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST).

Time To tumor Progression (TTP) is defined as the time from the date of first dose of study treatment to the date of the first documentation of Progressive Disease (PD).

Progression-Free Survival (PFS) is defined as the time from the date of first dose of study treatment to the date of the first documentation of Progressive Disease (PD) or death.

Time To Failure (TTF) is defined as the time from the date of first dose of study treatment to the date of the first documentation of Progressive Disease (PD), the date of treatment discontinuation except completion of treatment, or date of death due to cancer.

Overall Survival Time is defined as the time from the date of first dose of study treatment to the date of the death due to any cause. For subjects whose death had not been confirmed, Overall Survival Time was censored on the last date when the patient was known to be alive.

Survival was surveyed once a year from the registration day of the first subject, for all the subjects who received the study drug at least once.

Pfizer

Director, Clinical Trial Disclosure Group

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 25-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 50-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.

SU-011248 75-mg

Total

18-44 years

45-64 years

>=65 years

Age, Customized

Sex: Female, Male

Japan

Region of Enrollment

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.

Eastern Cooperative Oncology Group (ECOG) Performance Status

Pfizer ClinicalTrials.gov Call Center

DLT analysis population consists of subjects who developed DLT or received 85% of the planned dose. One subject in 75-mg dose group was excluded from DLT analysis population because the subject received less than 85% of the planned dose.

Number of Subjects With Dose Limiting Toxicities (DLT)

SU-011248

SU-012662

SU-011248+SU-012662

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

Maximum Plasma Concentration (Cmax) on Cycle 1 Day 1

Cycle 1 Day 1 (n=30)

Cycle 1 Day 14 (n=30)

Cycle 1 Day 28 (n=19)

Cycle 2 Day 1 (n=26)

Cycle 2 Day 14 (n=24)

Cycle 2 Day 28 (n=20)

Cycle 3 Day 1 (n=18)

Cycle 3 Day 14 (n=19)

Cycle 3 Day 28 (n=13)

Cycle 4 Day 1 (n=11)

Cycle 4 Day 14 (n=12)

Cycle 4 Day 28 (n=9)

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

n= Number of subjects with analyzable data.

Plasma Concentrations of Vascular Endothelial Growth Factor (VEGF)

Plasma Concentrations of Soluble Vascular Endothelial Growth Factor Type 2 Receptors (sVEGFR2)

Plasma Concentrations of Soluble Stem Cell Factor Receptor (sKIT)

Cycle 1 Day 14 (n=28)

Cycle 1 Day 28 (n=18)

Cycle 2 Day 1 (n=15)

Cycle 2 Day 14 (n=23)

Cycle 3 Day 1 (n=11)

Cycle 3 Day 14 (n=14)

Cycle 3 Day 28 (n=10)

Cycle 4 Day 1 (n=5)

Cycle 4 Day 14 (n=7)

Cycle 4 Day 28 (n=8)

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

n= Number of subjects with analyzable data.

Trough Plasma Concentration (Ctrough) of SU-011248

Trough Plasma Concentration (Ctrough) of SU-012262

Trough Plasma Concentration (Ctrough) of SU-011248+SU-012662

Cycle 1 Day 7 (n=30)

Cycle 1 Day 21 (n=30)

Cycle 1 Day 28 (n=30)

Cycle 1 Day 35 (n=30)

Cycle 2 Day 1 (n=30)

Cycle 2 Day 7 (n=30)

Cycle 2 Day 14 (n=30)

Cycle 2 Day 21 (n=30)

Cycle 2 Day 28 (n=29)

Cycle 2 Day 35 (n=29)

Cycle 3 Day 1 (n=25)

Cycle 3 Day 7 (n=24)

Cycle 3 Day 14 (n=25)

Cycle 3 Day 21 (n=24)

Cycle 3 Day 28 (n=25)

Cycle 3 Day 35 (n=25)

Cycle 4 Day 1 (n=21)

Cycle 4 Day 7 (n=20)

Cycle 4 Day 14 (n=21)

Cycle 4 Day 21 (n=20)

Cycle 4 Day 28 (n=19)

Cycle 4 Day 35 (n=20)

Intent-to-Treat (ITT) population defined as all subjects enrolled in study that receive at least 1 dose of study medication.

n= Number of subjects with analyzable data.

Changes From Baseline of Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Questionnaires

Cycle 2 Day 28 (n=30)

Cycle 4 Day 28 (n=18)

Change From Baseline of European Quality of Life Questionnaire- 5 Dimensions(EQ-5D) Questionnaires

Total number of Subjects with CR+PR+SD>=10weeks

Complete Response (CR)

Partial Response (PR)

Stable Disease (SD) >= 10 weeks

Intent-to-Treat (ITT) population defined as all subjects enrolled in study that receive at least 1 dose of study medication.

Number of Subjects With Disease Controlled Based on the Extramural Review Committee Assessment in Recommended Dose Group

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.

Maximum Plasma Concentration (Cmax) on Cycle 1 Day 28

Total Number of Subjects with CR+PR

ITT population defined as all subjects enrolled in study that receive at least 1 dose of study medication.

Number of Subjects With Objective Response Based on the Extramural Review Committee Assessment in Recommended Dose Group

Time To Tumor Progression (TTP)

Area Under the Plasma Concentration Curve (AUC0-24) on Cycle 1 Day 1

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 75-mg dose group discontinued the dose on Cycle1, therefore no data showed.

Area Under the Plasma Concentration Curve (AUC0-24) on Cycle 1 Day 28

Time to First Occurrence of Cmax (Tmax) on Cycle 1 Day 1

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

Spots Global Cancer Trial Database for A Phase I/II Study of Sunitinib Malate (SU011248) In Patients With Gastrointestinal Stromal Tumor (GIST)

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