FOX CHASE Cancer Center

1. A Phase I trial of KX2-391, a novel non-ATP competitive substrate-pocket directed SRC inhibitor, in patients with advanced malignancies A. A. Adjei, R. B. Cohen, R. Kurzrock, G. S. Gordon, D. Hangauer, L. Dyster, G. Fetterly, S. Barrientes, D. S. Hong, A. Naing Roswell Park Cancer Inst, Buffalo, NY; Fox Chase Cancer Center, Philadelphia, PA; MD Anderson Cancer Center, Houston, TX; Kinex Pharmaceuticals, Buffalo, NY FOX CHASE Cancer Center 1

2. Disclosure InformationASCO ANNUAL MEETING 2009Alex A. Adjei I have no financial relationships to disclose.

3. Src signaling in tumor cells Yeatman, Nat Rev Cancer, 2004

4. Src Kinase in Cancer There are over 500 serine and tyrosine kinases in humans; Src is a member of the tyrosine kinase family and the 1st oncogene discovered Src activity is high in a majority of primary tumors with further increases during metastasis Since Src activity generally increases as cells progress from benign to invasive to metastatic, Src inhibition may inhibit primary tumor growth as well as metastasis 4

5. Src kinase Inhibitors in the clinic Dasatinib (Sprycel): (approved for resistant CML, Phase I-II in solid tumors) Bosutinib (SKI-606): (Phase III in resistant CML, Phase I-II in solid tumors) AZD0530: (Phase I-II in solid tumors) XL228: (Phase 1 in resistant CML & solid tumors) 5

6. KX2-391 Mechanism of action Non-ATP competitive Src signaling inhibitor 2nd MOA (not a kinase) currently under investigation 6

7. Efficacy of KX2-391 in Solid Tumor Cell Lines KX2-391 has very potent activity (<50 nM) against a broad range of solid tumor cell lines

8. KX2-391 Compared to Dasatinib in Resistant Solid Tumor Cell Lines Average IC50 = 72 nM Average IC50 = 888 nM • Literature reported Dasatinib resistant cell lines: • Johnson et al, Clin. Cancer Res 2005; 11(19), 6924 • Serrels et al, Mol Cancer Ther 2006; 5(12), 3014 Dasatinib 10X less potent than KX2-391 at IC50 and ca. 100X less potent at IC90

9. KX2-391 Compared to Dasatinib in Leukemia and Multiple Myeloma Cell lines KX2-391 has a second MOA beyond Src signaling inhibition that might provide broader activity than dasatinib

10. KX2-391 Pre-clinical Toxicology Oral continuous bid dosing 28-day toxicity studies Rodent GI Toxicity is Dose-Limiting No cardiotoxicity No renal toxicity Non-Rodent (Dog) GI and Hematologic Toxicities are Dose-Limiting No cardiotoxicity No renal toxicity 10

11. Objectives of Phase I Trial Primary Objective: To define the maximum tolerated dose (MTD) of KX2-391 in patients with advanced refractory malignancies Secondary Objectives: To determine the safety and tolerability of KX2-391 given as single and multiple doses as an oral solution in patients with advanced refractory malignancies To characterize the pharmacokinetic profile after single and multiple oral dosing of KX2-391 To determine the biological effects of KX2-391 To evaluate antitumor activity of KX2-391 11

12. Trial Design Multi-center Phase 1 trial Standard ‘3+3’ dose escalation design Dosing Single oral dose, followed by one week evaluation Then BID oral dosing for 3 of 4 weeks Efficacy evaluation every 2 cycles (8 weeks) PK evaluation after single and multiple doses 12

13. Inclusion/Exclusion Criteria Adults over age 18 years of age Confirmed advanced solid tumor or lymphoma for which standard curative or palliative measure do not exist or are no longer effective ECOG performance status of 0-2 Adequate bone marrow reserve Adequate liver and renal function No investigational agents within 28 days of first day of study No recent hormone therapy Not using moderate or strong P450 modulators (inducers or inhibitors) within 2 weeks or 5 half-lives (whichever is shorter) No major surgery within 4 weeks No major GI disease No signs or symptoms of other major diseases or toxicities 13

14. Patient Demographics 14

15. Dose Escalation MTD 15

16. Pharmacokinetics of KX2-391 Conclusions: KX2-391 PK is dose-dependent and linear with increasing dose. Terminal T1/2 is approximately 4 hr. T max – 1 hour

17. Treatment Related Adverse Events Other Grade 3 or 4 events in one patient: Abdominal pain, bilirubin increased, edema, failure to thrive, hyponatremia, mucositis, rash, thrombocytopenia 17 * Number of patients

18. Dose Limiting Toxicities Dose Limiting Toxicities at 50, 60 and 80 mg BID Grade 4 Neutropenia – 2 patients (60 mg and 80 mg dose) Grade 3 elevated ALT/AST – 2 patients (50 and 60 mg dose) Grade 4 thrombocytopenia – 1 patient (50 mg dose) Grade 3 ALT/AST/Failure to Thrive – 1 patient (80 mg dose) Serious Adverse Events (possibly related, at any dose level) Febrile Neutropenia, pancytopenia, hyponatremia – 1 patient Febrile Neutropenia, pancytopenia, edema – 1 patient Neutropenia and mucositis – 1 patient Rash – 1 patient Failure to thrive – 1 patient All DLTs and SAEs reversible within 7 days No pulmonary edema or cardiotoxicity noted 18

19. Efficacy Results (N = 37) Treatment duration Median 2 cycles (range 1 – 11) 11 pts treated for 4 or more cycles 6 pts treated for 6 or more cycles Patients with suggestion of efficacy Prostate – PSA decline : 205 to 39, 6 cycles Pancreas – CA19-9 decline : 38,838 to 267, 4 cycles Ovary – CA-125 decline : 665 to 207, 4+ cycles Thyroid – 3 patients on for 8, 8, and 6+ cycles Appendicealcarcinoid – 11+ cycles Melanoma – 6 cycles Merkel cell – mixed response at 2 cycles 19

20. Prostate Cancer Patient Change in PSA On Trial Off Trial 20

21. Pancreas Cancer Patient Change in CA19-9 On Trial Off Trial 21

22. Ovary Cancer PatientChange in CA125 On Trial 22

23. Conclusions KX2-391 is well-tolerated at a dose of 40 mg po BID for 3 out of 4 weeks Pulmonary and cardiac toxicities have not been seen Linear and dose-dependent PK profile Half-life of 4 hours supports BID dosing Demonstrates preliminary evidence of antitumor activity Should be further evaluated in Phase II trials Future trials planned Prostate Pancreas Breast AML 23

24. Acknowledgements To the patients and their families To the staff: MDAnderson Saneese K Stephen PA , MPAS , MPA ChandtipChandhasin, PhD Senait N  Fessahaye , Data Coordinator Roswell Park Cancer Institute Grace Dy, MD Wen Wee Ma, MD Kathy Galus, Pharm D Deborah Yoon, BSN Kinex Pharmaceuticals Allen Barnett, PhD Kristen Thomas, MS Johnson Lau, MD, PhD Jane Fang, MD Fox Chase Cancer Center Ranee Mehra, MD Holly Dushkin, MD Igor Astsaturov, MD, PhD Elizabeth Zeidler, RN Christine Malizzia AHRM, Inc Laura Dalfonso Ben Finkel Mary Caparole Amy Hayward 24