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SARC022 A Phase 2 Study of OSI-906 in Pediatric and Adult Wild Type Gastrointestinal Stromal Tumors Study PI: Margaret von Mehren, MD Fox Chase Cancer.

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Presentation on theme: "SARC022 A Phase 2 Study of OSI-906 in Pediatric and Adult Wild Type Gastrointestinal Stromal Tumors Study PI: Margaret von Mehren, MD Fox Chase Cancer."— Presentation transcript:

1 SARC022 A Phase 2 Study of OSI-906 in Pediatric and Adult Wild Type Gastrointestinal Stromal Tumors Study PI: Margaret von Mehren, MD Fox Chase Cancer Center

2 Background  WT GIST in adults and children are less responsive to current tyrosine kinase inhibitors compared to tumors with mutations  IGF-1R, a member of the insulin receptor family, has been demonstrated to be expressed on WT GIST tumors  It is hypothesized that growth and proliferation in these tumors may be IGF-1R-dependent, and therefore, targeting IGF-1R will inhibit tumor growth.

3 Primary Objective To determine the response rate (CR and PR) to treatment with OSI-906 (Linsitinib) in patients with advanced wild-type GIST (WT) as determined by RECIST 1.1.

4 Secondary Objectives 1. To determine the clinical benefit rate (SD≥9 months, PR or CR) in patients with advanced WT GIST treated with OSI- 906 (Linsitinib). 2. To determine the response duration, progression free survival, and overall survival in patients with advanced WT GIST treated with OSI-906 (Linsitinib). 3. To determine the tolerability and adverse event profile of OSI-906 (Linsitinib) 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 in advanced wild-type GIST treated with OSI- 906 (Linsitinib)

5 Imaging Objectives  To evaluate the metabolic response to OSI-906 (Linsitinib) using FDG-PET.  Determine if tumor metabolic response correlates with anatomic response and clinical benefit.  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 CT-response evaluation and correlate the findings with size changes as defined by conventional cross-sectional imaging scans.  To investigate correlations between glucose, insulin and candidate tumor tissue and blood biomarkers with FDG-PET metabolic response.

6 Key Inclusion Criteria  Measurable GIST with confirmed genotype of wild- type by central pathology review  Age ≥ 18 years  Performance status: ECOG 0-2  Patients will be stratified into Pediatric and Adult cohorts  Pediatric cohort must have received at least sunitinib and have had progression on or intolerance to sunitinib therapy  Adult cohort must have received at least imatinib and have had progression on or intolerance to imatinib therapy

7 Key Laboratory Inclusion Criteria  Platelet count ≥ 75 x 10 9 /L  Total bilirubin ≤ 1.5 times the upper limit of normal for age  ALT /AST (SGPT/SGOT) ≤ 3x the ULN for the reference lab (≤ 5 x the ULN for the reference lab in the presence of known hepatic metastasis, adjusted for age).  QTc interval <450 msec at baseline, without use of con- meds that prolong the QTc interval  Fasting blood glucose <150 mg/dL at baseline  HbA1c < 7% at screening  Patients with diabetes mellitus should have controlled disease on oral medications, defined as:  no diabetic ketoacidosis within 30 days prior to enrollment  no change in oral medications greater than 10% within 30 days prior to enrollment.

8 Key Exclusion Criteria  ≥ 3 weeks from prior therapy, except TKI therapy: ≥ 7 days.  Patients with insulin requiring diabetes for control of their diabetes.  Patients with known brain metastases  History of allergic reactions to compounds of similar chemical or biologic composition to OSI-906 (Linsitinib)  Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine are prohibited.  Prior treatment with TKI targeting IGF-1R pathway.  Known HIV-positive patients on combination antiretroviral therapy  Use of drugs that have a known risk of causing Torsades de Pointes (TdP) are prohibited within 14 days prior to randomization.  Patients with a history of solid organ transplant are ineligible because of the potential for pharmacokinetic interactions with OSI-906.

9 Treatment Plan  Within 12weeks from date of enrollment Pathology samples for confirmation of diagnosis and KIT and PDGFRA genotyping  After confirmation of eligibility, patients will be assessed  Day 1: drug initiation; OSI-906 (Linsitinib) 150 mg po BID  Day 14  Week 4 and every 4 weeks through week 16  Week 24 and then every 12 weeks while remaining on study  At each visit: CMP, PO4, CBC, HbA1c  EKG in triplicate on Day 1, 14, week 4, 8, and12  Pharmacodynamic correlative studies on Days 1, 14, week 4 and 8  CT/MRI every 8 weeks until week 24; after than imaging will be every 12 weeks  Week 12: HbA1c for all patients; diabetics will have HbA1c every 12 weeks while receiving OSI-906 (Linsitinib)  Week 16: CT/MRI scan including abdomen and pelvis imaging; imaging of lung if clinically indicated

10 Biomarker Assessments CorrelativesEndpointAssayLab Tissue-based assays: KIT/PDGFRA/BRAF mutation testing +/- mutationsSequencing (tumor DNA) Fox Chase Cancer Center IGF-1R /+/- quantitationIHCFox Chase Cancer Center pAKT+/- quantitationIHCFox Chase Cancer Center IGF-I/-II /IGF-1R/IGF-2R/IR-A/-B+/- quantitationRT-PCRFox Chase Cancer Center SDHB+/- quantitationIHCDana-Farber/Brigham and Women’s IGF-1R, AKT, pAKT, ERK, pERK, mTOR, pmTOR quantitationWestern Blot (when frozen tumor available) Dana Farber Cancer Institute / Brigham and Women’s Hospital Serum-based assays: Total serum IGF-I, IGF-2+/- quantitationELISAFox Chase Cancer Center Free serum IGF+/- quantitationELISAFox Chase Cancer Center IGFBP1-7QuantitationFox Chase Cancer Center

11 Imaging Correlatives  PET Scan will be performed at baseline and at 8 weeks  Will be reviewed along with anatomic imaging at Dana Farber and FCCC  Glucose and IGF ligands and inhibitor levels will also be evaluated

12 Statistical Plan Desirable 6 months Non-relevant 6 months Patient number Stage 1 Final sample size Number of Response to Continue to Stage 2 Number of Responses for positive study 20%5%  The probability of early termination if the true response rate = 20% is 12%.  The null hypothesis will be rejected after the second stage if there are 5 or more patients with a response out of 40 evaluable patients.  With a sample size of 40 evaluable patients, the power to detect a 20% clinical benefit rate is 92%, with a significance level (alpha) of 0.05.

13 Secondary Endpoints  The clinical benefit rate, defined as SD≥9 mos., PR or CR, will be determined.  Safety Analysis: the study will be suspended if the rate of grade 4 toxicities is 20% or greater.  Exploratory Analyses for pharmacodynamic endpoints


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