Interim Analysis of SARC022, A Phase II study of Linsitinib in Pediatric and Adult Wild Type (WT) Gastrointestinal

Stromal Tumors (GIST)M von Mehren, M Heinrich, S Schuetze,

K Ganjoo, J Yu, J Yap, AD Van den Abbeele, J Wright, S George

Background WT GIST in adults and children are less responsive to

tyrosine kinase inhibitors compared to GIST tumors with KIT/PDGFRA mutations

Insulin-like growth factor-1 receptor (IGF-1R), a member

of the insulin receptor family (IR), has been demonstrated to be highly expressed on WT GIST

We hypothesized that growth and proliferation in these tumors may be IGF-1R-dependent, and therefore, linsitinib, a dual inhibitor of IGF-1R and IR, might demonstrate clinical benefit in this patient population

Study Schema

N=40

Linsitinib(150 mg PO BID on days 1-28, courses

repeat every 28 days in the absence of

disease progression or unacceptable

toxicity)

Pediatric WT Eligibility Criteria:• Diagnosis ≤18 years of age or

diagnosis of Carney Triad or Carney-Stratakis Dyad

• Progressed on or intolerant to at least sunitinib

Adult WT Eligibility Criteria:• Diagnosis >18 years of age and no

diagnosis of Carney Triad or Carney-Stratakis Dyad

• Progressed on or intolerant to at least imatinib Primary end point: ORR

Secondary end points: SD ≥9 months, PFS, OS, time to progression, metablic responses

http://clinicaltrials.gov/ct2/show/NCT01560260

Patient Demographics, n=20Gender Female Male

12 8

Age 18-62, average 41

Pediatric type Carney Triad

62

Performance Status 0/1/2 12/7/1Primary Site Stomach (Gastroesophageal) Small bowel Peritoneum

16 (1)21

Metastatic Sites Liver Peritoneum Lymph Nodes

17114

Prior Therapies Imatinib Sunitinib Sorafenib

1-7, median 319197

Toxicities Hyperglycemia:

One grade 2 episode in a patient on steroids for Iodine IV contrast allergy prophylaxis

No increases in HgbA1c levels No evidence of drug induced:

Hepatotoxicity QTc prolongation

Primary Objective:ORR by RECIST 1.1

Data as of 9/30/13

-40

-20

0

20

40

60

80

100

% C

hang

e in

Tum

or V

olum

e

Metabolic ResponderBaseline

Week-8 Follow-up

Metabolic ProgressorBaseline

Week 8 Follow-up

-100%

-75%

-50%

-25%

0%

25%

50%

EORTC Metabolic Response, N=13

Ranked Patients

Perc

ent c

hang

e in

sum

med

SU

Vmax PMR

SMDPMD

**

*Progression due to new lesions

Clinical Benefit Rate (CR, PR and SD > 9 months)

As of last data cut off of 9/30/13: 15% (3/20 patients) have remained on study

for greater than 9 months 55% (11/20 patients) have had stable disease

for at least 6 months, with 10 remaining on study

1 additional patients remains on study for greater than 4 months

Time on Study based on Gender

Days on StudyLighter color bars are patients off study

0 50 100 150 200 250 300 350

Fem

ale

M

ale

Time on Study by Primary Site

Time on Study in DaysBlack boxed patients are off study

0 50 100 150 200 250 300 350

GE junc-tion

Stomach

Small Bowel

PFS and OS

Progression-Free Survival, SARC022

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Months from enrollment

SARC022Events / N

6 / 20

6-MonthEstimate

70% (46, 94)

Overall Survival, SARC022

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12Months from enrollment

SARC022Deaths / N

3 / 20

6-MonthEstimate

85% (69, 100)

6-Month PFS Estimate: 70%Events/N: 6/20

6-Month OS Estimate: 85%Events/N: 3/20

Conclusions Clinical trials in WT GIST are feasible Linsitinib is well tolerated without any

unanticipated toxicities We have not seen Recist 1.1 ORR to date 55% of patients have had stable disease for six

months or longer Of the patients reviewed, 15% have had EORTC

metabolic response by FDG-PET Additional correlative studies are being completed

Acknowledgements

The Patients and their families

Correlative Science: Funding:Martin Belinsky NCI R21 CA150381 Katherine Janeway NCI R01 CA106588 FCCC Molecular Diagnostics SARC

Laboratory

SARC Clinical Trials Office: Ann Johnson, Brenda Steltzriede, Denise Reinke

CRAB.org: John Crowley, Antje HoeringCTEP: John Wright, MD, PhD