Transcript Slide 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
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 OSI906 (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 OSI906 (Linsitinib)
Imaging Objectives
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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 109/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
Correlatives
Endpoint
Assay
Lab
Tissue-based assays:
KIT/PDGFRA/BRAF mutation
testing
+/- mutations
Sequencing (tumor DNA)
Fox Chase Cancer Center
IGF-1R /
+/- quantitation
IHC
Fox Chase Cancer Center
pAKT
+/- quantitation
IHC
Fox Chase Cancer Center
IGF-I/-II /IGF-1R/IGF-2R/IR-A/-B
+/- quantitation
RT-PCR
Fox Chase Cancer Center
SDHB
+/- quantitation
IHC
Dana-Farber/Brigham and
Women’s
IGF-1R, AKT, pAKT, ERK,
pERK, mTOR, pmTOR
quantitation
Western Blot (when
frozen tumor available)
Dana Farber Cancer Institute /
Brigham and Women’s Hospital
Serum-based assays:
Total serum IGF-I, IGF-2
+/- quantitation
ELISA
Fox Chase Cancer Center
Free serum IGF
+/- quantitation
ELISA
Fox Chase Cancer Center
IGFBP1-7
Quantitation
Fox 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%
20
40
1
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.
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