Linsitinib in Treating Patients With Gastrointestinal Stromal Tumors

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 2 Study of Linsitinib (OSI-906) in Pediatric and Adult Wild Type Gastrointestinal Stromal Tumors

Conditions
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Carney Complex, Chondrosarcoma, Gastrointestinal Stromal Tumor, Paraganglioma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Linsitinib
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed gastrointestinal stromal tumor (GIST) with confirmed genotype of wild-type in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory Patients will be stratified into pediatric and adult cohorts; patients in the pediatric cohort (age at diagnosis =< 18 years OR diagnosis of Carney Triad or Carney-Stratakis Diad (paraganglioma, pulmonary chondroma) must have received at least sunitinib and have had progression on or intolerance to progression on therapy; patients in the adult cohort (age at diagnosis > 18 years AND no diagnosis of diagnosis of Carney Triad or Carney-Stratakis Diad) have had progression on or intolerance to imatinib therapy as documented by treating physician Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2 Patients must have measurable disease defined as lesions that can be measured in 2 dimensions by medical imaging techniques such as CT or magnetic resonance imaging (MRI); ascites, pleural fluid, and lesions seen on PET scan only are not considered measurable White blood cells count (WBC) >= 2.0 x 10^9/L (being >= 14 days off growth factors) OR Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (being >= 14 days off growth factors) Platelet count >= 75 x 10^9/L Total bilirubin =< 1.5 times the upper limit of normal for age Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) (serum glutamate pyruvate transaminase [SGPT]/serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x the upper limit of normal (ULN) for the reference lab (=< 5 x the ULN for the reference lab in the presence of known hepatic metastasis, adjusted for age) Creatinine clearance > 70 ml/min/1.73m^2 or Serum creatinine < 1.5 x ULN per age and gender QT interval corrected using Frederica formula (QTcF) interval average of < 450 msec at baseline using the Frederica formula (QTcF) No concomitant drugs that prolong the QT corrected (QTc) interval No significant cardiac disease Fasting blood glucose < 150 mg/dL at baseline Hemoglobin A1C (HbA1c) < 7% at screening Patients or their legal representative must be able to read, understand and provide written informed consent to participate in the trial Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; women of childbearing potential must provide a negative pregnancy test (serum or urine) within 7days prior to registration Patients with diabetes mellitus should have controlled disease on oral medications, defined as: no diabetic ketoacidosis (hyperglycemia, ketonuria, pH < 7.3 and bicarbonate < 15mEq/L) at the time of enrollment or within 30 days prior to enrollment and; no change in oral medications greater than 10% within 30 days prior to enrollment Patient must be able to swallow to participate in the study Signed informed consent Exclusion Criteria: Time elapsed from previous therapy must be >= 3 weeks except for prior tyrosine kinase inhibitor therapy which can be >= 7 days; patients must be recovered from the effects of any prior surgery, radiotherapy or systemic therapy Patients who are receiving any other investigational agents or other anti-cancer therapies other than those administered in this study during protocol treatment Patients with diabetes mellitus requiring insulin for control of their diabetes Patients with a history of liver cirrhosis Patients with known brain metastases should be excluded from this clinical trial History of allergic reactions attributed to compounds of similar chemical or biologic composition to linsitinib (OSI-906) While cytochrome P450 1A2 (CYP1A2) inhibitors/inducers are not specifically excluded, investigators should be aware that linsitinib (OSI 906) exposure may be altered by the concomitant administration of these drugs While cytochrome P450 2C9 (CYP2C9) substrates are not specifically excluded, investigators should be aware that levels of drugs metabolized by CYP2C9 may be increased by the concomitant administration of linsitinib (OSI-906); caution should be used when administering CYP2C9 substrates to patients who are on study drug Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine are prohibited; other less potent CYP1A2 inhibitors/inducers are not excluded Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Prior treatment with another kinase inhibitor targeting insulin-like growth factor 1 receptor (IGF-1R) pathway, including monoclonal antibodies targeting IGF-1R Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with linsitinib (OSI-906) Fertile men and women of childbearing potential not employing an effective method of birth control throughout the trial and for 3 months after last study drug administration in both sexes; women of childbearing potential must have a negative pregnancy test (serum or urine) within the 7 days prior to study drug administration NOTE: Women of childbearing potential include both pre-menopausal women and women within the first 2 years of the onset of menopause NOTE: Effective methods of birth control includes: surgically sterile, barrier device (condom, diaphragm), contraceptive coil, abstinence; oral contraceptive pills (OCPs) alone are not considered an effective method Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible Use of drugs that have a known risk of causing Torsades de Pointes (TdP) are prohibited within 14 days prior to initiation of linsitinib (OSI-906) Patients with a history of solid organ transplant are ineligible

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (linsitinib)<br>Patients receive linsitinib 150mg orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Linsitinib<br>* Given PO<br>* Other names: OSI-906AA;Other: Pharmacological Study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Up to 2 years | 
| Overall Survival (OS) | Analyzed using Kaplan-Meier curves for the all treated and per protocol populations. | Estimates at 9 months | 
| Progression Free Survival (PFS) | Analyzed using Kaplan-Meier curves for the all treated and per protocol populations. | 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. | Up to 37 weeks | 
| Failure-free Survival | Analyzed using Kaplan-Meier curves for the all treated and per protocol populations | 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. | 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. | 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). | 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. | 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. | Up to 37 weeks |