Neoplasms

Digestive System Diseases

All Conditions

Heart and Blood Diseases

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Rare Diseases

Gastrointestinal Stromal Tumors

Paraganglioma

Chondrosarcoma

Carney Complex

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Sarcoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Myxoma

Heart Neoplasms

Thoracic Neoplasms

Heart Diseases

Congenital Abnormalities

Abnormalities, Multiple

Skin Abnormalities

Paragangliomas 1

Soft Tissue Sarcoma

Neuroendocrine Tumor

Neuroepithelioma

Heart Tumor

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.

Laboratory Biomarker Analysis

Linsitinib

Pharmacological Study

Margaret von Mehren

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.

Linsitinib in Treating Patients With Gastrointestinal Stromal Tumors

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

Time to progression will be evaluated using cumulative incidence.

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

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.

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

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

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

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

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.

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).

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.

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

National Cancer Institute (NCI)

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

Treatment (Linsitinib)

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Kristen Nuyen, Research Project Manager

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

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

Clinical Benefit Rate Defined as Stable Disease (SD) >= 9 Months, Partial Response (PR) or Complete Response (CR)

Overall Survival (OS)

Progression Free Survival (PFS)

Response Duration

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

Failure-free Survival

Related to study drug

Related to study drug Grade 3 or higher

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

285 Adverse Events reported during the study.

Tolerability and Adverse Event Profile of Linsitinib

SDHA deficiency

SDHB deficiency

High to intermediate paKT stain

High expression of IGFR

Intermediate levels of IGFR

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

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

Partial metabolic response rate

Stable disease metabolic response rate

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

SUVmax

SUVpeak

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

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

Correlations Between Glucose, Insulin, Tumor Tissue and Blood Biomarkers With FDG-PET Metabolic Response.

Time to Progression

Partial metabolic response

Stable disease metabolic response

Determine the Number of Participants With Tumor Metabolic Response Correlating With Anatomic Response and Clinical Benefit.

Overall Study

Symptoms and General Pathology

Nervous System Diseases

Gland and Hormone Related Diseases

Syndrome

Adenoma

Pituitary Diseases

Cushing Syndrome

Peutz-Jeghers Syndrome

Pituitary Neoplasms

Neoplasms, Glandular and Epithelial

Hypothalamic Diseases

Brain Diseases

Central Nervous System Diseases

Endocrine System Diseases

Adrenocortical Hyperfunction

Adrenal Gland Diseases

Endocrine Gland Neoplasms

Hypothalamic Neoplasms

Supratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Neoplastic Syndromes, Hereditary

Intestinal Polyposis

Intestinal Diseases

Genetic Diseases, Inborn

Lentigo

Melanosis

Hyperpigmentation

Pigmentation Disorders

Skin Diseases

Cushing's Syndrome

Primary Pigmented Nodular Adrenocortical Disease

Hyperadrenalism

families with PPNAD and/or Carney complex

oCRH

Christina Tatsi, M.D.

Lentiginosis refers to groups of diseases marked by the presence of pigmented spots on the skin. These conditions are most commonly associated with multiple tumors and changes in hormone producing glands. The cause of these diseases is unknown, but researchers suggest there may be a level of inheritance involved in their development. Meaning to say that some of these diseases may "run in the family" and be passed down form generation to generation.

Primary pigmented nodular adrenocortical disease (PPNAD) is a pituitary-independent, primary adrenal form of hypercortisolism characterized by;

1. Resistance to suppression by the drug dexamethasone
2. The body is unable to secrete cortisol in a normal rhythm
3. Distinct microscopic changes of both adrenal glands

PPNAD can be associated with tumors (myxomas) of the skin, heart, breast, tumors (swannomas) of the nerve sheaths, pigmented spots (nevi and lentigines) of the skin, growth hormone (GH) producing tumors of the pituitary gland, and tumors of the testicles, ovaries, and thyroid gland. In the presence of these associations the condition is referred to as the Carney Complex. Presently there are no tests for screening of PPNAD and the Carney Complex. In addition, it is unknown how these conditions are genetically transferred from generation to generation.

This study proposes to use standard methods of clinical testing for endocrine and nonendocrine diseases and genetic testing in order to;

1. Define the genetic basis for PPNAD and/or the Carney Complex.
2. Determine the molecular changes associated with the development of the tumors.
3. Identify carriers of the disease.
4. Determine the prognosis for carriers and affected individuals.
5. Provide sufficient data for genetic counseling of families with PPNAD and/or Carney Complex.\<TAB\>...

Primary pigmented nodular adrenocortical disease (PPNAD) is a pituitary-independent, primary adrenal form of hypercortisolism characterized by (a) resistance to suppression by dexamethasone and abolition of the normal diurnal rhythm of cortisol secretion, and (b) distinctive, bilateral, histopathologic changes of the adrenal glands, such as the formation of variably sized, pigmented nodular adenomas, loss of normal zonation and atrophy of the extranodular cortex. PPNAD can be associated with a variety of other manifestations, such as myxomas of the skin, heart, breast and other sites, psammomatous melanotic swannomas involving the peripheral nervous system (PNS), lentigines and blue nevi of the skin and mucosae, growth hormone (GH)-producing adenomas of the pituitary, testicular Sertoli cell tumors, and possibly other neoplasms (adrenocortical and thyroid follicular carcinoma, and ovarian cysts). These associations constitute a distinct clinical syndrome, Carney complex, a genetic syndrome. At present, there are no standardized screening tests for the members of families with affected individuals and the molecular mechanism(s) of this hereditary single and/or multiple neoplasia syndrome have not been completely elucidated (e.g. patients who meet clinical criteria for Carney complex but test negative for PRKAR1A mutation . This study seeks to define the genetic basis of PPNAD and/or Carney complex in sporadic and familial cases and the molecular pathogenesis of their tumors, to identify the carriers of the familial forms of the disease, and to determine the prognosis for carriers and affected individuals. The methods include standard clinical testing for endocrine and nonendocrine pathologic conditions of the subjects of the study, linkage analysis with DNA markers from areas of the genome likely to harbor the responsible gene(s), and finally genetic screening of these genes. Molecular studies of the tumors of the patients will provide additional clues for the pathophysiologic mechanisms leading to PPNAD/Carney complex. The study will ultimately provide sufficient data for genetic counseling of families with PPNAD and/or Carney complex, and, ultimately, the means for genetic screening and prenatal testing.

Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and the Carney Complex

Definition of the Genotype and Clinical Phenotype of Primary Pigmented Nodular Adrenocortical Disease (PPNAD), Carney Complex, Peutz-Jeghers Syndrome and Related Conditions

Genotype and clinical phenotype correlation in patients with PPNAD, Carney Complex, Peutz-Jeghers Syndrome and related conditions.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Linsitinib in Treating Patients With Gastrointestinal Stromal Tumors	NCT01560260	Carney Complex Chondrosarcoma Gastrointestina... Paraganglioma	Laboratory Biom... Linsitinib Pharmacological...	18 Years -	National Cancer Institute (NCI)
Defining the Genetic Basis for the Development of Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and the Carney Complex	NCT00001452	Cushing's Syndr... Pituitary Adeno... Carney Complex Primary Pigment... Peutz-Jeghers S...	oCRH	3 Years - 70 Years	National Institutes of Health Clinical Center (CC)

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