Linsitinib in Treating Patients With Gastrointestinal Stromal Tumors

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01560260
• Collaborator: (none)
• Enrollment: 20
• Locations: 8
• Arm: 1
• Duration (Months): 43
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Carney Complex; Chondrosarcoma; Gastrointestinal Stromal Tumor; Paraganglioma	Other: Laboratory Biomarker Analysis; Drug: Linsitinib; Other: Pharmacological Study	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

2. To determine the response duration, progression free survival (PFS), and overall survival (OS) in patients with advanced WT GIST treated with OSI-906.

3. To determine the tolerability and adverse event profile of OSI-906 in patients with advanced GIST.

4. 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.

5. To evaluate the metabolic response to OSI-906 using fludeoxyglucose F 18 (FDG)-positron emission tomography (PET).

6. To determine if tumor metabolic response correlates with anatomic response and clinical benefit.

7. 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.

8. 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 Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Linsitinib (OSI-906) in Pediatric and Adult Wild Type Gastrointestinal Stromal Tumors
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (linsitinib) 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; Correlative studies; Drug: Linsitinib; Given PO; Other Names: IGF-1R inhibitor OSI-906 OSI-906 OSI-906AA ; Other: Pharmacological Study; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Complete Response or Partial Response Using Response Evaluation Criteria in Solid Tumors Guideline Version 1.1 [At 6 months]

   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.

Secondary Outcome Measures

1. Clinical Benefit Rate Defined as Stable Disease (SD) >= 9 Months, Partial Response (PR) or Complete Response (CR) [Up to 2 years]

   Prolonged non-progression is of clinical benefit (CR + PR + SD at 9 months).

2. Overall Survival (OS) [Estimates at 9 months]

   Analyzed using Kaplan-Meier curves for the all treated and per protocol populations.

3. Progression Free Survival (PFS) [Time from date of enrollment to time of progression or death due to any cause, estimates at 9 months]

   Analyzed using Kaplan-Meier curves for the all treated and per protocol populations.

4. Response Duration [Up to 37 weeks]

   Analyzed using Kaplan-Meier curves for the all treated and per protocol populations.

5. Failure-free Survival [Up to 37 weeks]

   Analyzed using Kaplan-Meier curves for the all treated and per protocol populations

6. Tolerability and Adverse Event Profile of Linsitinib [Up to 37 weeks]

   To determine the tolerability and adverse event profile of OSI-906 in patients with advanced GIST.

7. Patterns of Protein Expression in Serum and Tumor Tissues as Predictors of Response and PFS [Up to 37 weeks]

   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.

8. Number of Participants With Metabolic Response to Linsitinib Using FDG-PET. [Up to 37 weeks]

   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).

9. Changes in Tumor Metabolism by FDG-PET Qualitatively and Semi-quantitatively With Standard Uptake Value (SUV) [Baseline and 8 weeks]

   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.

10. Correlations Between Glucose, Insulin, Tumor Tissue and Blood Biomarkers With FDG-PET Metabolic Response. [Up to 37 weeks]

    To investigate correlations between glucose, insulin, tumor tissue and blood biomarkers with FDG-PET metabolic response.

Other Outcome Measures

1. Time to Progression [Up to 3 years]

   Time to progression will be evaluated using cumulative incidence.

2. Determine the Number of Participants With Tumor Metabolic Response Correlating With Anatomic Response and Clinical Benefit. [Up to 37 weeks]

   To determine if the number of participants with tumor metabolic response correlates with anatomic response and clinical benefit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford Cancer Institute	Palo Alto	California	United States	94304
2	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
3	National Institutes of Health Clinical Center	Bethesda	Maryland	United States	20892
4	Dana-Farber/Harvard Cancer Center	Boston	Massachusetts	United States	02115
5	Sarcoma Alliance for Research Through Collaboration	Ann Arbor	Michigan	United States	48106
6	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
7	Oregon Health and Science University	Portland	Oregon	United States	97239
8	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Margaret von Mehren, Sarcoma Alliance for Research through Collaboration

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01560260
• Other Study ID Numbers: NCI-2012-00708; NCI-2012-00708; CDR0000728619; SARC-022; SARC 022; SARC022; 8945
• First Posted: Mar 22, 2012
• Last Update Posted: Sep 21, 2018
• Last Verified: Aug 1, 2018

• Additional relevant MeSH terms: Gastrointestinal Stromal Tumors; Chondrosarcoma; Paraganglioma; Carney Complex

Study Results

Participant Flow

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Period Title: Overall Study
STARTED	20
COMPLETED	20
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	Patients receive linsitinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Overall Participants	20
Age (Count of Participants)
<=18 years	1 5%
Between 18 and 65 years	19 95%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41 (13)
Sex: Female, Male (Count of Participants)
Female	12 60%
Male	8 40%
Region of Enrollment (participants) [Number]
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Complete Response or Partial Response Using Response Evaluation Criteria in Solid Tumors Guideline Version 1.1
Description	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

Outcome Measure Data

Analysis Population Description

0 out of 20 patients had a response

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	Patients receive linsitinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	20
Number [participants]	0 0%

2. Secondary Outcome

Title	Clinical Benefit Rate Defined as Stable Disease (SD) >= 9 Months, Partial Response (PR) or Complete Response (CR)
Description	Prolonged non-progression is of clinical benefit (CR + PR + SD at 9 months).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	Patients receive linsitinib 150mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	20
Number [percentage of participants]	40 200%

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Analyzed using Kaplan-Meier curves for the all treated and per protocol populations.
Time Frame	Estimates at 9 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	Patients receive linsitinib 150mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	20
Number [percentage of participants]	80 400%

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	Patients receive linsitinib 150mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	20
Number [percentage of participants]	52 260%

5. Secondary Outcome

Title	Response Duration
Description	Analyzed using Kaplan-Meier curves for the all treated and per protocol populations.
Time Frame	Up to 37 weeks

Outcome Measure Data

Analysis Population Description

No responses were observed.

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	Patients receive linsitinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	0

6. Secondary Outcome

Title	Failure-free Survival
Description	Analyzed using Kaplan-Meier curves for the all treated and per protocol populations
Time Frame	Up to 37 weeks

Outcome Measure Data

Analysis Population Description

Data was not collected for this outcome measure due to limited activity seen with the study treatment.

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	Patients receive linsitinib 150mg PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	0

7. Secondary Outcome

Title	Tolerability and Adverse Event Profile of Linsitinib
Description	To determine the tolerability and adverse event profile of OSI-906 in patients with advanced GIST.
Time Frame	Up to 37 weeks

Outcome Measure Data

Analysis Population Description

285 Adverse Events reported during the study.

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	20
Measure Adverse Events	285
Related to study drug	101
Related to study drug Grade 3 or higher	2

8. Secondary Outcome

Title	Patterns of Protein Expression in Serum and Tumor Tissues as Predictors of Response and PFS
Description	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

Outcome Measure Data

Analysis Population Description

Depending on the patient samples available, the available samples varied from 17 to 14.

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	17
SDHA deficiency	6 30%
SDHB deficiency	15 75%
High to intermediate paKT stain	6 30%
High expression of IGFR	10 50%
Intermediate levels of IGFR	4 20%

9. Secondary Outcome

Title	Number of Participants With Metabolic Response to Linsitinib Using FDG-PET.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	17
Partial metabolic response rate	2 10%
Stable disease metabolic response rate	11 55%

10. Secondary Outcome

Title	Changes in Tumor Metabolism by FDG-PET Qualitatively and Semi-quantitatively With Standard Uptake Value (SUV)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	17
SUVmax	19
SUVpeak	16

11. Secondary Outcome

Title	Correlations Between Glucose, Insulin, Tumor Tissue and Blood Biomarkers With FDG-PET Metabolic Response.
Description	To investigate correlations between glucose, insulin, tumor tissue and blood biomarkers with FDG-PET metabolic response.
Time Frame	Up to 37 weeks

Outcome Measure Data

Analysis Population Description

Data was not collected in correlation to FDG-PET response results.

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	0

12. Other Pre-specified Outcome

Title	Time to Progression
Description	Time to progression will be evaluated using cumulative incidence.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	Patients receive linsitinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	20
Median (Full Range) [months]	9.1

13. Other Pre-specified Outcome

Title	Determine the Number of Participants With Tumor Metabolic Response Correlating With Anatomic Response and Clinical Benefit.
Description	To determine if the number of participants with tumor metabolic response correlates with anatomic response and clinical benefit.
Time Frame	Up to 37 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	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. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
Measure Participants	17
Partial metabolic response	2 10%
Stable disease metabolic response	11 55%

Adverse Events

Arm/Group Title	Treatment (Linsitinib)
Arm/Group Description	Patients receive linsitinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Linsitinib: Given PO Pharmacological Study: Correlative studies
All Cause Mortality
	Treatment (Linsitinib)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Linsitinib)
	Affected / at Risk (%)	# Events
Total	8/20 (40%)
Cardiac disorders
Supraventricular Tachycardia - Grade 2 (Unrelated)	1/20 (5%)	1
Gastrointestinal disorders
Abdominal Distension - Grade 3 (Unrelated)	1/20 (5%)	1
Abdominal Pain - Grade 3 (Unrelated)	3/20 (15%)	4
Constipation - Grade 2 (Unrelated)	1/20 (5%)	1
Gastric Hemorrhage - Grade 3 (Unrelated)	1/20 (5%)	1
Intra-abdominal hemorrhage - Grade 3 (Unrelated)	1/20 (5%)	1
Pancreatitis - Grade 3 (Unlikely Related)	1/20 (5%)	2
Upper gastrointestinal hemorrhage - Grade 3 (Unlikely Related)	1/20 (5%)	2
Upper gastrointestinal hemorrhage - Grade 3 (Unrelated)	1/20 (5%)	1
Abdominal Pain - Grade 3 (Unlikely Related)	1/20 (5%)	1
General disorders
Edema Limbs - Grade 2 (Unlikely Related)	1/20 (5%)	1
Infections and infestations
Lung Infection - Grade 3 (Unrelated)	1/20 (5%)	1
Metabolism and nutrition disorders
Hyperglycemia - Grade 3 (Definitely Related)	1/20 (5%)	1
Nervous system disorders
Seizure - Grade 2 (Unrelated)	1/20 (5%)	1
Renal and urinary disorders
Renal Calculi - Grade 3 (Unrelated)	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia - Grade 3 (Unlikely Related)	1/20 (5%)	1
Pleural Effusion - Grade 2 (Unlikely Related)	1/20 (5%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular - Grade 3 (Unrelated)	1/20 (5%)	1
Surgical and medical procedures
Fistula Repair - Grade 3 (Unrelated)	1/20 (5%)	1
Vascular disorders
Thromboembolic event (Grade 2 - Unlikely Related)	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Linsitinib)
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Blood and lymphatic system disorders
Anemia	4/20 (20%)	5
Blood and Lymphatic System Disorders - Other	1/20 (5%)	1
Blood and Lymphatic System Disorders - Other	1/20 (5%)	1
Cardiac disorders
Atrial Fibrillation	1/20 (5%)	1
Palpitations	2/20 (10%)	2
Paroxysmal Atrial Tachycardia	1/20 (5%)	1
Ear and labyrinth disorders
Vertigo	1/20 (5%)	1
Endocrine disorders
Hypothyroidism	1/20 (5%)	1
Eye disorders
Blurred Vision	1/20 (5%)	1
Eye Disorders - Other	1/20 (5%)	1
Gastrointestinal disorders
Abdominal Distension	1/20 (5%)	1
Abdominal Pain	8/20 (40%)	10
Ascites	2/20 (10%)	3
Constipation	8/20 (40%)	8
Dental Caries	1/20 (5%)	1
Diarrhea	8/20 (40%)	13
Dry Mouth	1/20 (5%)	1
Dyspepsia	1/20 (5%)	1
Dysphagia	1/20 (5%)	1
Flatulence	1/20 (5%)	1
Gastrointestinal Disorders - Other	1/20 (5%)	1
Gastrointestinal Disorders - Other	1/20 (5%)	1
Gastrointestinal Disorders - Other	1/20 (5%)	1
Gastrointestinal Pain	2/20 (10%)	2
Nausea	13/20 (65%)	17
Toothache	1/20 (5%)	1
Vomiting	8/20 (40%)	12
General disorders
Chills	3/20 (15%)	4
Edema Limbs	2/20 (10%)	3
Fatigue	15/20 (75%)	22
Fever	1/20 (5%)	1
Flu-like Symptoms	1/20 (5%)	1
General Disorders and Administration Site Conditions - Other	1/20 (5%)	1
Pain	2/20 (10%)	3
Hepatobiliary disorders
Hepatobiliary Disorders - Other	1/20 (5%)	1
Infections and infestations
Sinusitis	1/20 (5%)	1
Upper Respiratory Infection	2/20 (10%)	2
Investigations
Alanine Aminotransferase Increased	2/20 (10%)	3
Alkaline Phosphatase Increased	2/20 (10%)	3
Aspartate Aminotransferase Increased	2/20 (10%)	6
Creatinine Increased	3/20 (15%)	3
Investigations - Other	1/20 (5%)	1
Lipase Increased	1/20 (5%)	7
Serum Amylase Increased	1/20 (5%)	4
Weight Loss	1/20 (5%)	1
Metabolism and nutrition disorders
Anorexia	5/20 (25%)	7
Hyperglycemia	2/20 (10%)	3
Hyperkalemia	1/20 (5%)	1
Hypoalbuminemia	1/20 (5%)	1
Hyponatremia	1/20 (5%)	1
Hypophosphatemia	1/20 (5%)	1
Metabolism and Nutrition Disorders - Other	1/20 (5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/20 (5%)	2
Back Pain	3/20 (15%)	4
Generalized Muscle Weakness	1/20 (5%)	1
Musculoskeletal and Connective Tissue Disorders - Other	1/20 (5%)	1
Musculoskeletal and Connective Tissue Disorders - Other	1/20 (5%)	1
Musculoskeletal and Connective Tissue Disorders - Other	1/20 (5%)	1
Musculoskeletal and Connective Tissue Disorders - Other	1/20 (5%)	1
Musculoskeletal and Connective Tissue Disorders - Other	1/20 (5%)	1
Myalgia	5/20 (25%)	5
Pain in Extremity	2/20 (10%)	2
Nervous system disorders
Dizziness	5/20 (25%)	6
Dysgeusia	1/20 (5%)	1
Headache	2/20 (10%)	2
Memory Impairment	1/20 (5%)	1
Nervous System Disorders - Other	1/20 (5%)	1
Nervous System Disorders - Other	1/20 (5%)	1
Peripheral Sensory Neuropathy	3/20 (15%)	3
Sinus Pain	1/20 (5%)	1
Psychiatric disorders
Confusion	1/20 (5%)	1
Depression	3/20 (15%)	3
Insomnia	5/20 (25%)	5
Renal and urinary disorders
Renal Colic	1/20 (5%)	1
Urinary Frequency	1/20 (5%)	1
Urinary Tract Infection	1/20 (5%)	1
Reproductive system and breast disorders
Erectile Dysfunction	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/20 (5%)	2
Dyspnea	6/20 (30%)	7
Epistaxis	1/20 (5%)	1
Hoarseness	1/20 (5%)	1
Nasal Congestion	1/20 (5%)	1
Pleural Effusion	1/20 (5%)	1
Pneumonitis	1/20 (5%)	1
Postnasal Drip	1/20 (5%)	1
Productive Cough	1/20 (5%)	1
Respiratory, Thoracic and Mediastinal Disorders - Other	1/20 (5%)	1
Respiratory, Thoracic and Mediastinal Disorders - Other	1/20 (5%)	1
Sinus Disorder	1/20 (5%)	1
Sore Throat	1/20 (5%)	2
Skin and subcutaneous tissue disorders
Alopecia	1/20 (5%)	1
Dry Skin	3/20 (15%)	3
Hyperhidrosis	1/20 (5%)	1
Nail Discoloration	1/20 (5%)	1
Palmar-plantar Erythrodysesthesia Syndrome	2/20 (10%)	2
Pruritus	3/20 (15%)	3
Rash Maculo-papular	3/20 (15%)	3
Skin and Subcutaneous Tissue Disorders - Other	1/20 (5%)	1
Skin and Subcutaneous Tissue Disorders - Other	1/20 (5%)	1
Skin and Subcutaneous Tissue Disorders - Other	1/20 (5%)	1
Vascular disorders
Hypertension	1/20 (5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.