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
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