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A Study of Sunitinib In Young Patients With Advanced Gastrointestinal Stromal Tumor

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ClinicalTrials.gov Identifier: NCT01396148
Recruitment Status : Completed
First Posted : July 18, 2011
Results First Posted : March 12, 2018
Last Update Posted : March 12, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
Children and young adults with gastrointestinal stromal tumors (GIST) will be treated with sunitinib. The safety (including pharmacokinetics) and tolerability of sunitinib will be studied in these patients. In addition, tumor responses and overall survival will be assessed.

Condition or disease Intervention/treatment Phase
Gastrointestinal Stromal Tumors Drug: sunitinib malate dose escalation Drug: sunitinib malate Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: Non-Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/ii Study Of Sunitinib In Young Patients With Advanced Gastrointestinal Stromal Tumor
Actual Study Start Date : June 25, 2012
Actual Primary Completion Date : August 21, 2017
Actual Study Completion Date : August 21, 2017


Arm Intervention/treatment
Experimental: Children with GIST
children ages 6yrs-<18yrs
Drug: sunitinib malate dose escalation
sunitinib starting dose will be 15mg/m^2 daily on a 4 weeks on/2 weeks off schedule (Schedule 4/2).
Experimental: Young adults with GIST
young adults ages 18yrs-<21 yrs
Drug: sunitinib malate
sunitinib 50mg daily on Schedule 4/2



Primary Outcome Measures :
  1. Estimated Steady-state Maximum Plasma Concentration (Cmax) for Sunitinib and Its Active Metabolite SU012662 [ Time Frame: Weeks 1-18 ]
    Data for this endpoint will be estimated and reported separately as part of the Non-linear Mixed Effects Modeling analysis, and will be provided once available.

  2. Estimated Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours Post Dose (AUC24) for Sunitinib and Its Active Metabolite SU012662 [ Time Frame: Weeks 1-18 ]
    Data for this endpoint will be estimated and reported separately as part of the Non-linear Mixed Effects Modeling analysis, and will be provided once available.

  3. Estimated Oral Clearance (CL/F) for Sunitinib [ Time Frame: Weeks 1-18 ]
    Data for this endpoint will be estimated and reported separately as part of the Non-linear Mixed Effects Modeling analysis, and will be provided once available.

  4. Maximum Observed Plasma Concentration (Cmax) of Sunitinib and Its Metabolite [ Time Frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose ]
    SU012662 is the metabolite of Sunitinib.

  5. Time to Reach Maximum Observed Plasma Concentration (Tmax) for Sunitinib and Its Metabolite [ Time Frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose ]
    SU012662 is the metabolite of Sunitinib.

  6. Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours Post Dose AUC(0-8) for Sunitinib and Its Metabolite [ Time Frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose ]
    AUC(0-8) was defined as area under the plasma concentration time-curve from time zero to 8 hours post dose. SU012662 is the metabolite of Sunitinib.


Secondary Outcome Measures :
  1. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to end of study (up to Cycle 18) that were absent before treatment or that worsened relative to pretreatment state. AEs included both non-serious adverse events (AEs) and SAEs.

  2. Number of Participants With Treatment-Emergent Adverse Events (AEs) Greater Than or Equal to (>=) Grade 3, Based on National Cancer Institute (NCI) Common Terminology Criteria (CTC) for AEs (CTCAE), Version 4.0 [ Time Frame: Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) ]
    An AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. As per NCI CTCAE, Grade 3 events =medically significant but not immediately life-threatening, unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment, Grade 4 events =participant to be in imminent danger of death. Grade 5 events =death. Treatment-emergent events are events between first dose of study drug and up to end of study (up to Cycle 18) that were absent before treatment or that worsened relative to pretreatment state. Number of participants with AEs of any of the Grade 3 or above (Grade 4, 5) were reported.

  3. Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) ]
    An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both non-serious adverse events (AEs) and SAEs.

  4. Number of Participants With Clinically Significant Laboratory Abnormalities [ Time Frame: Baseline up to end of study (up to Cycle 18, each cycle was of 42 days) ]
    Criteria for clinically significant laboratory abnormalities: Hemoglobin (Hb), hematocrit: less than (<) 0.8*lower limit of normal (LLN), platelet: <75 or greater than (>) 700*10^3/millimeter (mm)^3*upper limit of normal (ULN), leukocyte: <2.5 or >17.5*10^3/mm^3*ULN; total bilirubin 1.5*ULN, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase: >3.0*ULN, total protein, albumin: <0.8*LLN or >1.2*ULN ;blood urea nitrogen, creatinine: >1.3*ULN, uric acid >1.2*ULN; sodium <0.95*LLN or >1.05*ULN, potassium, calcium: <0.9*LLN or >1.1*ULN, albumin, total protein <0.8*LLN or >1.2*ULN; glucose <0.6*LLN or >1.5*ULN, creatine kinase >2.0*ULN; urine (red blood cell, white blood cell >6/high power field).

  5. Number of Participants With Objective Response [ Time Frame: Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) ]
    Objective response in participants was defined as the number of participants with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Confirmed response were those that persisted on repeat imaging study for at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and non-target). PR was defined as at least 30 percentage (%) decrease in the sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non-target lesions not increased or absent.

  6. Duration of Response [ Time Frame: Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) ]
    Duration of response was defined as time (in months) from the first documentation of objective tumor response (confirmed CR or PR) to the first documentation of disease progression or death due to any cause. Confirmed response were those that persisted on repeat imaging study for at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and non-target). PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non-target lesions not increased or absent. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

  7. Progression-Free Survival [ Time Frame: Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) ]
    Progression free survival was defined as time (in months) from date of enrollment to the first documentation of disease progression or to death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

  8. Overall Survival [ Time Frame: Baseline until death or discontinuation from the study whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) ]
    Overall survival was defined as time (in months) from enrollment to the date of death due to any cause. Analysis was performed using Kaplan-Meier method.

  9. Number of Participants With Adverse Events Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) for Pharmacokinetic (PK) Subgroups [ Time Frame: Cycle 1 Day 28 up to Cycle 3 (each cycle 42 days) ]
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI CTCAE version 4.0, Grade1= asymptomatic or mild symptoms, Grade 2= Moderate;local or noninvasive intervention indicated; Grade 3 events =medically significant but not immediately life-threatening, unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment, Grade 4 events =participant to be in imminent danger of death. Grade 5 events =death. Participants with any of the Grade 1 to Grade 5 AEs were reported. The PK evaluable participants were divided into 2 PK subgroups on Day 28 of Cycle 1: those with total drug (sunitinib + SU012662) trough plasma concentration (Ctrough) value less than (<) the median Ctrough value(lower exposure) and those with total drug (sunitinib + SU012662) Ctrough values greater than or equal to (>=) the median Ctrough value(higher exposure).

  10. Pearson Correlation Coefficient Between Percent Change From Baseline in Laboratory Parameters With Total Drug (Sunitinib + SU012662) Concentration [ Time Frame: Baseline, Day 28 of Cycle 1, Cycle 2 and Cycle 3 (each cycle was of 42 days) ]
    Pearson correlation coefficient between percent change from baseline in laboratory parameters with total drug (Sunitinib + SU012662) concentration were calculated on Day 28 of Cycles 1, 2, and 3. Laboratory parameters included absolute neutrophil count, platelet count, lymphocyte count and hemoglobin.

  11. Pearson Correlation Coefficient Between Percent Change From Baseline in Vital Sign Results With Total Drug (Sunitinib + SU012662) Concentration [ Time Frame: Baseline, Day 28 of Cycle 1, Cycle 2 and Cycle 3 (each cycle was of 42 days) ]
    Pearson correlation coefficient between percent change from baseline in vital sign results with total drug (Sunitinib + SU012662) concentration were calculated on Day 28 of Cycles 1, 2, and 3. Vital signs included systolic blood pressure and diastolic blood pressure.

  12. Number of Participants With Stable Disease (SD), Partial Response (PR), Complete Response (CR) and Progressive Disease (PD) for PK Sub-groups [ Time Frame: Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) ]
    SD:when there is no sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR: as at least 30% decrease in the sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non-target lesions not increased or absent. CR: disappearance of all lesions (target and non-target). PD:at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). Participants with SD, PR, CR and PD responses were assessed according to 2 PK subgroups created on Day 28 of Cycle 1: those with total drug (sunitinib + SU012662) trough plasma concentration (Ctrough) value less than (<) the median Ctrough value(lower exposure) and those with total drug (sunitinib + SU012662) Ctrough values greater than or equal to (>=) the median Ctrough value(higher exposure).

  13. Progression Free Survival for PK Subgroups [ Time Frame: Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days) ]
    Progression free survival was defined as time (in months) from date of enrollment to the first documentation of disease progression or to death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The PK evaluable participants were assessed according to 2 PK subgroups created on Day 28 of Cycle 1: those with total drug (sunitinib + SU012662) trough plasma concentration (Ctrough) value less than (<) the median Ctrough value(lower exposure) and those with total drug (sunitinib + SU012662) Ctrough values greater than or equal to (>=) the median Ctrough value(higher exposure).

  14. Pearson Correlation Coefficient Between Progression Free Survival With Total Drug (Sunitinib + SU012662) Concentration [ Time Frame: Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (maximum duration: up to Cycle 18; each cycle was of 42 days ]
    Pearson correlation coefficient between Progression Free Survival (PFS) with total drug (Sunitinib + SU012662) concentration at Day 28 of Cycle 1 was calculated. PFS was defined as time (in months) from date of enrolment to the first documentation of disease progression or to death (due to any cause), whichever occurred first. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

  15. Estimated Sunitinib Plasma Concentration at Which 50% of the Maximum Effect (EC50) for Each Selected Efficacy Parameter (e.g., Sum of Largest Diameters for Target Tumors) Was Observed [ Time Frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose ]
  16. Estimated Sunitinib Plasma Concentration at Which 50% of the Maximum Effect (EC50) for Each Selected Safety Endpoint (e.g., Absolute Neutrophil Count) Was Observed [ Time Frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, and 8 hours post-dose ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   6 Years to 20 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histological diagnosis of GIST.
  • Patients must have demonstrated either disease progression or intolerance to imatinib mesylate, have non-mutant Stem Cell Factor Receptor gene (KIT) GIST, or cannot obtain imatinib in their country
  • Measurable by Response Evaluation Criterion in Solid Tumors (RECIST) or evaluable disease.

Exclusion Criteria:

  • Current treatment with another investigational agent.
  • Prior sunitinib treatment.
  • Prior therapy with known risk for cardiovascular complications.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01396148


Locations
United States, California
Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
Czechia
Fakultni nemocnice Brno
Brno, Czechia, 613 00
FN Brno
Brno, Czechia, 625 00
Masarykuv onkologicky ustav
Brno, Czechia, 656 33
France
CHU de La Timone, Hopital enfants
Marseille cedex 5, France, 13385
Hopital d'Enfants de la Timone
Marseille cedex 5, France, 13385
Hopital de la Timone
Marseille cedex 5, France, 13385
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  Study Documents (Full-Text)

Documents provided by Pfizer:
Study Protocol  [PDF] July 31, 2017
Statistical Analysis Plan  [PDF] July 15, 2011


Additional Information:
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01396148     History of Changes
Other Study ID Numbers: A6181196
2011-002008-33 ( EudraCT Number )
First Posted: July 18, 2011    Key Record Dates
Results First Posted: March 12, 2018
Last Update Posted: March 12, 2018
Last Verified: February 2018

Keywords provided by Pfizer:
Children and young adults with GIST
sunitinib malate
pharmacokinetics
tumor response
overall survival
tumor KIT mutation status

Additional relevant MeSH terms:
Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Sunitinib
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors