Linsitinib To Treat Patients With Gastrointestinal Stromal Tumors

• Clinical benefit rate defined as SD ≥ 9 months [ Designated as safety issue: No ]
• Response duration, PFS, overall survival, and failure-free survival up to 37 weeks of treatment using Kaplan-Meier curves [ Designated as safety issue: No ]
• Adverse event profile of linsitinib on an ongoing basis [ Designated as safety issue: Yes ]

• Clinical benefit rate defined as SD ≥ 9 months [ Designated as safety issue: No ]
• Response duration, PFS, overall survival, and failure-free survival up to 37 weeks of treatment using Kaplan-Meier curves [ Designated as safety issue: No ]
• Adverse event profile of OSI-906 in an ongoing basis [ Designated as safety issue: Yes ]

RATIONALE: Linsitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase II trial studies how well linsitinib works in treating younger and adult patients with gastrointestinal stromal tumors.

OBJECTIVES:

Primary

• To determine the response rate (complete response [CR] and partial response [PR]) to treatment with linsitinib (OSI-906) in patients with advanced wild-type (WT) gastrointestinal stromal tumor (GIST) as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Secondary

• To determine the clinical benefit rate (stable disease [SD] ≥ 9 months, PR, or CR) in patients with advanced WT GIST treated with linsitinib.
• To determine the response duration, progression-free survival (PFS), and overall survival in patients with advanced WT GIST treated with linsitinib.
• To determine the tolerability and adverse event profile of linsitinib in patients with advanced GIST.
• To explore patterns of protein expression in serum and tumor tissues as predictors of response and PFS in advanced WT GIST treated with linsitinib.
• To evaluate the metabolic response to linsitinib using fludeoxyglucose F 18 (FDG)-positron emission tomography (PET).
• To determine if tumor metabolic response correlates with anatomic response and clinical benefit.
• 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. (exploratory)
• To investigate correlations between glucose, insulin, and candidate tumor tissue and blood biomarkers with FDG-PET metabolic response. (exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to type of gastrointestinal stromal tumor (GIST): Pediatric wild-type (WT) GIST: diagnosed at a young age (< 18) or having characteristics consistent with Carney triad of Carney-Stretakis syndrome vs Adult WT GIST: all others.

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.

Patients undergo blood sample collection at baseline and periodically during treatment for biomarker studies. Tumor tissue samples from biopsy or time of relapse may also be collected for correlative studies.

After completion of study treatment, patients are followed up for 30 days, every 12 weeks for 2 years (from date of first dose of linsitinib), and then annually thereafter.

• Carney Complex
• Gastrointestinal Stromal Tumor
• Paraganglioma
• Sarcoma

• Drug: linsitinib
  Other Name: OSI-906
• Genetic: nucleic acid sequencing
• Genetic: reverse transcriptase-polymerase chain reaction
• Genetic: western blotting
• Other: enzyme-linked immunosorbent assay
• Other: immunohistochemistry staining method
• Other: laboratory biomarker analysis
• Other: pharmacological study
• Procedure: positron emission tomography
• Radiation: fludeoxyglucose F 18

DISEASE CHARACTERISTICS:

• Patients must have histologically confirmed gastrointestinal stromal tumor (GIST) with confirmed genotype of wild-type in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory

  • At a minimum, mutation analysis should include exons 9, 11, 13, and 17 of KIT and exons 12 and 18 of PDGFRA

• Patients will be stratified into Pediatric and Adult cohorts (age at diagnosis)

  • 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 malate (sunitinib) and have had progression on or intolerance to therapy

  • Adult cohort: age at diagnosis > 18 years AND no diagnosis of Carney Triad or Carney-Stratakis Diad

    • Must have had progression on or intolerance to imatinib mesylate (imatinib) therapy as documented by treating physician
• Patients must have measurable disease defined as lesions that can be measured in 2 dimensions by medical-imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI); ascites, pleural fluid, and lesions seen on positron emission tomography (PET) scan only are not considered measurable
• Patients with known brain metastases should be excluded from this clinical trial

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• White blood cell count ≥ 2.0 x 10^9/L
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (≥ 14 days off growth factors)
• Platelet count ≥ 75 x 10^9/L
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) for age
• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) (serum glutamic pyruvate transaminase [SGPT]/serum glutamic oxaloacetic transaminase [SGOT]) ≤ 3 times the ULN for the reference lab (≤ 5 times the ULN for the reference lab in the presence of known hepatic metastasis, adjusted for age)
• Creatinine clearance > 70 mL/min OR serum creatinine < 1.5 times ULN per age and gender
• QTc interval < 450 msec at baseline
• No significant cardiac disease
• Fasting blood glucose < 150 mg/dL at baseline
• Glycosylated hemoglobin (HbA1c) < 7% at screening

• Patients with diabetes mellitus should have controlled disease on oral medications, defined as no diabetic ketoacidosis (hyperglycemia, ketonuria, pH < 7.3, and bicarbonate < 15 mEq/L) at the time of enrollment or within 30 days prior to enrollment

  • No change in oral medications greater than 10% within 30 days prior to enrollment
  • No patients with diabetes mellitus requiring insulin for control of their diabetes
• Patient must be able to swallow to participate in the study
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to OSI-906
• No 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
• Pregnant women are excluded from this study and breastfeeding should be discontinued

• No 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 β-HCG) within the 7 days prior to study drug administration

  • Women of childbearing potential includes both pre-menopausal women and women within the first 2 years of the onset of menopause
  • Effective methods of birth control include: surgically sterile, barrier device (condom, diaphragm), contraceptive coil, abstinence; oral contraceptives (OCPs) alone are not considered an effective method
• Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
• No patients with a history of liver cirrhosis

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No concomitant drugs that prolong the QTc interval
• 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
• No patients who are receiving any other investigational agents or other anti-cancer therapies other than those administered in this study during protocol treatment
• Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine are prohibited; other less potent CYP1A2 inhibitors/inducers are not excluded
• No prior treatment with another kinase inhibitor targeting IGF-1R pathway
• Use of drugs that have a known risk of causing Torsades de Pointes (TdP) are prohibited within 14 days prior to initiation of linsitinib
• Patients with a history of solid organ transplant are ineligible
• Patients requiring palliative radiotherapy will be discontinued from study drug

• Surgery done for progressive symptom management will be considered evidence of progressive disease and patients will be removed from study

  • Patients that are deemed appropriate for surgical debulking because of response or prolonged stable disease will be allowed to undergo resection without being removed from study as long as:

    • They do not undergo complete resection

    • They have had stable or responding disease for > 9 months

      • Patients who undergo surgical resection prior to 9 months who do not have evidence of progressive disease will be removed from study