This phase II trial studies how well linsitinib works in treating younger and adult patients with gastrointestinal stromal tumors. Linsitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES: I. To determine the response rate to treatment with OSI-906 (linsitinib) 150mg BID in patients with advanced wild-type (WT) gastrointestinal stromal tumor (GIST). SECONDARY OBJECTIVES: I. To determine the clinical benefit rate (CBR) (stable disease \[SD\] \>= 9 months, partial response \[PR\], or complete response \[CR\]) in patients with advanced WT GIST treated with OSI-906. II. To determine the response duration, progression free survival (PFS), and overall survival (OS) in patients with advanced WT GIST treated with OSI-906. III. To determine the tolerability and adverse event profile of OSI-906 in patients with advanced GIST. IV. To explore patterns of protein expression in serum and tumor tissues as predictors of response and progression-free survival (PFS) in advanced WT GIST treated with OSI-906. V. To evaluate the metabolic response to OSI-906 using fludeoxyglucose F 18 (FDG)-positron emission tomography (PET). VI. To determine if tumor metabolic response correlates with anatomic response and clinical benefit. VII. To measure changes in tumor metabolism by FDG-PET qualitatively and semi-quantitatively with standard uptake value (SUV) and tumor body ratio (TBR) from baseline to first computed tomography (CT)-response evaluation and correlate the findings with size changes as defined by conventional cross-sectional imaging scans. VIII. To investigate correlations between glucose, insulin, and candidate tumor tissue and blood biomarkers with FDG-PET metabolic response. OUTLINE: Patients receive linsitinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days, every 12 weeks for 2 years, and then annually thereafter.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
20
Stanford Cancer Institute
Palo Alto, California, United States
University of Iowa/Holden Comprehensive Cancer Center
Iowa City, Iowa, United States
National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Dana-Farber/Harvard Cancer Center
Number of Participants With Complete Response or Partial Response Using Response Evaluation Criteria in Solid Tumors Guideline Version 1.1
Determine the response rate, Complete Response (CR) or Partial Response (PR), to treatment with linsitinib (OSI-906) in patients with advanced wild-type (WT) gastrointestional stromal tumor (GIST) as determined by RECIST 1.1.
Time frame: At 6 months
Clinical Benefit Rate Defined as Stable Disease (SD) >= 9 Months, Partial Response (PR) or Complete Response (CR)
Prolonged non-progression is of clinical benefit (CR + PR + SD at 9 months).
Time frame: Up to 2 years
Overall Survival (OS)
Analyzed using Kaplan-Meier curves for the all treated and per protocol populations.
Time frame: Estimates at 9 months
Progression Free Survival (PFS)
Analyzed using Kaplan-Meier curves for the all treated and per protocol populations.
Time frame: Time from date of enrollment to time of progression or death due to any cause, estimates at 9 months
Response Duration
Analyzed using Kaplan-Meier curves for the all treated and per protocol populations.
Time frame: Up to 37 weeks
Failure-free Survival
Analyzed using Kaplan-Meier curves for the all treated and per protocol populations
Time frame: Up to 37 weeks
Tolerability and Adverse Event Profile of Linsitinib
To determine the tolerability and adverse event profile of OSI-906 in patients with advanced GIST.
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Boston, Massachusetts, United States
Sarcoma Alliance for Research Through Collaboration
Ann Arbor, Michigan, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
Oregon Health and Science University
Portland, Oregon, United States
Fox Chase Cancer Center
Philadelphia, Pennsylvania, United States
Time frame: Up to 37 weeks
Patterns of Protein Expression in Serum and Tumor Tissues as Predictors of Response and PFS
To explore patterns of protein expression in serum and tumor tissues as predictors of response and progression-free survival in advanced WT GIST treated with OSI-906. All Insulin Growth Factor Receptor (IGFR) and phosphorylated AKT (pAKT) evaluation was performed in a blinded manner. Distribution and intensity of positive tumor cell staining was assessed for these markers. Loss of succinate dehydrogenase complex flavoprotein subunit A (SDHA) protein expression has been correlated with the presence of a mutation in SDHA. Loss of succinate dehydrogenase complex iron sulfur subunit B (SDHB) protein expression occurs from bi-allelic inactivation of any of the succinate dehydrogenase (SDH) subunit genes. Loss of expression of one member of the complex alters the structure or production of SDH proteins such that the complex is no longer able to form. This results in elevated intracellular levels of succinate as well as loss of demethylase activity.
Time frame: Up to 37 weeks
Number of Participants With Metabolic Response to Linsitinib Using FDG-PET.
Evaluate the number of participants with metabolic response to OSI-906 using fluorodeoxyglucose positron emission tomography (FDG-PET). Evaluation of metabolic response to linsitinib based on two criteria (EORTC and PERCIST).
Time frame: Up to 37 weeks
Changes in Tumor Metabolism by FDG-PET Qualitatively and Semi-quantitatively With Standard Uptake Value (SUV)
To measure changes in tumor metabolism by FDG-PET qualitatively and semi-quantitatively with SUV from baseline to first CT response evaluation and correlate the findings with size changes as defined by conventional cross-sectional imaging scans. SUVmax determined by: SUVmax = \[VOI activity (mCi/ml) \* body wt (g)\]/injected dose (mCi) SUVpeak determined by identifying the hottest cubic centimeter within a VOI centered on the lesion with the highest FDG.
Time frame: Baseline and 8 weeks
Correlations Between Glucose, Insulin, Tumor Tissue and Blood Biomarkers With FDG-PET Metabolic Response.
To investigate correlations between glucose, insulin, tumor tissue and blood biomarkers with FDG-PET metabolic response.
Time frame: Up to 37 weeks