Novel Antiangiogenic Agents: Current Clinical Development

1. Novel Antiangiogenic Agents:Current Clinical Development George W. Sledge, Jr. MD Indiana University Cancer Center

2. Antiangiogenic Therapies:Potential Targets • Block pro-angiogenic molecules (e.g., VEGF) • Add anti-angiogenic regulators (e.g. angiostatin, endostatin, TSP-1) • Inhibit stroma-degrading enzymes (e.g., MMPIs) • Target vascular antigens (e.g., avb3 integrin) • Attack pericytes

3. VEGF Is a Key Mediator of Angiogenesis Upstream activators of VEGF synthesis Downstream signaling pathways

4. Methods of VEGF Signal Inhibition Ligand sequestration: MAbs, soluble receptors Indirect - inhibition of growth factors, HER-2 Receptor blockingMabs, soluble receptors p85 ras GRB2 SOS PLCg Inhibition of tyrosine phosphorylation and downstream signaling inhibition Tyrosine kinase inhibition: TKIs Inhibit receptor production; ribozymes Transcription factor inhibition

5. Ø Humanized to avoid immunogenicity (93% human, 7% murine). Ø Recognizes all isoforms of vascular endothelial growth -10 factor, K = 8 x 10 M d Ø Terminal half life 17-21 days rhuMAb VEGF (Recombinant Humanized Monoclonal Antibody to VEGF)

6. Efficacy of rhuMAb VEGF Dose (mg/kg) 3 10 20 (n=18) (n=41) (n=16) CR 0 1 0 PR 1 3 1 Stable at 22 weeks 2 4 2 CR/PR/SD at 22 wks. 3 8 3 Rx > 1 year 0 3 -

7. Refractory Metastatic Disease RANDOMI ZE Capecitabine + rhuMAb VEGF Eligibility: - One or two prior therapies OR - Relapse within 12 months of adjuvant anthracycline and taxane - No CNS mets Capecitabine Accrual goal: 400 patients

8. Toxicities of Anti-VEGF Therapy • Hemorrhage (lung cancers) • Hypertension (anti-VPF) • Headaches/migraines • Clots (maybe) • Proteinura/nephrotic syndrome

9. Intracellular Signaling Pathways Activated by VEGF Binding to VEGFR2

10. ZD6474

11. SU11248 Potently Inhibits VEGFR, PDGFR and Kit in Biochemical and Cellular Assays

12. Anti-Flt-1 Ribozyme Uppercase = ribonucleotides; lowercase = 2’-O-methyl ribonucleotide; B = inverted 2’-deoxyribose abasics; s = phosphorothiolate linkage; u4 = 2’-C-allyl nucleotide. Sandberg JA et al. J Clin Pharmacol. 2000;40:1462-1469.

13. The Problem With Anti-Angiogenic Therapy: Resistance

14. Mechanisms of Resistance • Endothelial cell heterogeneity • Tumor heterogeneity • Impact of tumor microenvironment • Compensatory response to hypoxic insults • Re-growth independence from angiogenesis • Vascular mimicry • Vasculogenesis

15. Thwarting Resistance • Use chemotherapy with anti-angiogenic intent - ‘metronomic therapy’ • Combine with chemotherapy • Combine multiple anti-angiogenics • Combine with other biologics • Use anti-angiogenics as targeted therapy • Use anti-angiogenics in adjuvant setting

16. Use Standard Therapies With Anti-Angiogenic Intent • Concept: • Standard chemotherapeutic agents have potent anti-angiogenic activity • We use them poorly from an anti-angiogenic standpoint • Metronomic therapy (chronic low-dose chemotherapy) overcomes resistance

17. Metronomic Therapy in the Clinic: Colleoni • Study design: Phase II trial of CTX 50 mg p.o. qd + MTX 2.5 mg p.o. D 1,2 qwk. • Patient Characteristics: 64 MBC pts, 32 with 1 prior regimen, 20 with 2+ prior regimens, 41 with adjuvant regimen • Results: CR + PR = 19%; CR + PR + SD >24 wk = 31.7

18. Combine anti-angiogenic agents with standard chemotherapy • Concept: • Chemotherapeutics are anti-angiogenics • Pro-angiogenic factors protect tumor endothelium • Preclinical support for combinations of anti-angiogenics’s with CT

19. E2100 RANDOMI ZE Eligibility: - No prior Rx for mets - Adjuvant taxane if >12 mos. Exclusion: - Her-2 + - CNS mets - Proteinuria - Uncontrolled HTN Arm A: Paclitaxel + rhuMAb VEGF Arm B: Paclitaxel Accrual goal: ~690

20. Combine anti-angiogenic agents with each other • Concept: • Angiogenesis is a redundant process • Tumor progression is associated with angiogenic growth factor progression--> resistance to individual agents • Preclinical evidence of combinatorial benefit with anti-angiogenics

21. Combine anti-angiogenic agents with other biologics • Concept: • Angiogenesis is under control of numerous polypeptide growth factors • Targeting growth factor receptors decreases angiogenesis • Potential for additivity/synergy

22. Effect of Anti-angiogenic Therapy on Mice With Colon Cancer Carcinomatosis * * ** *P < 0.001 relative to Control, **P < 0.001 rel. to DC101.

23. Use anti-angiogenic therapy as targeted therapy • Concept: • Antiangiogenic therapy is viewed as general therapy • Resistance to specific agents implies specific resistance phenotypes/genotypes • Target therapy to specific tumors

24. Use anti-angiogenic therapy as adjuvant therapy • Concept: • Anti-angiogenic therapy has not eliminated drug resistance • Pro-angiogenic factors increase as tumors progress • Resistance is a function of tumor size/mutation rate • Treat tumors before they become resistant

25. Adjuvant Angiogenesis: Requirements • Chronic safety • Combinatorial safety • Chronic dose maintenance • Large Proof-of-Concept trials • Disease-specific rationale • Proof of efficacy in advanced disease (???)

26. BMS-275291 • Potent, peptidomimetic inhibitor of MMPs • rationally designed to spare sheddases • metalloproteinases which process TNF-a, TNF-aRII • Daily, oral, outpatient regimen • Expectations • No dose-limiting arthritis • Complementary efficacy to chemotherapy

27. BMS-275291 Adjuvant Pilot Patients with Stage I-IIIa breast cancer receiving standard therapies randomized (2:1) to: • BMS-275291 1200 mg/day x 12 months • Placebo daily x 12 months • All patients may continue open-label for one additional year; Accrual goal = 120