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:
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
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.
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.
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)
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.
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
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.
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.
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
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
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
Statistical Plan Desirable RR @ 6 months Non-relevant RR @ 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%204015 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.
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