Linsitinib To Treat Patients With Gastrointestinal Stromal Tumors

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