novel antiangiogenic agents: current clinical development george w. sledge, jr. md indiana...

Novel Antiangiogenic Agents:Current Clinical Development

George W. Sledge, Jr. MD

Indiana University Cancer Center

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

VEGF Is a Key Mediator of Angiogenesis

Upstream activators of VEGF synthesis

Downstreamsignaling pathways

Ligand sequestration: Ligand sequestration: MAbs, soluble receptorsMAbs, soluble receptors

Receptor blockingReceptor blockingMabs, soluble receptorsMabs, soluble receptors

Tyrosine kinase Tyrosine kinase inhibition: TKIsinhibition: TKIs

Inhibition of tyrosine Inhibition of tyrosine phosphorylation phosphorylation and downstreamand downstream

signalingsignalinginhibitioninhibition

p85p85

PLCPLC GRB2GRB2 SOSSOS

rasras

TranscriptionTranscriptionfactor inhibitionfactor inhibition

Inhibit receptor Inhibit receptor production; production; ribozymesribozymes

Methods of VEGF Signal Inhibition

Indirect - inhibition Indirect - inhibition of growth factors, of growth factors,

HER-2HER-2

rhuMAb VEGF (Recombinant HumanizedrhuMAb VEGF (Recombinant HumanizedMonoclonal Antibody to VEGF)Monoclonal Antibody to VEGF)

vascular endothelial growth

Humanized to avoidimmunogenicity (93%human, 7% murine).

Recognizes all isoforms of

factor, K d = 8 x 10 -10 M

Terminal half life 17-21days

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 -

Eligibility:- One or two prior therapies OR- Relapse within 12 months of adjuvant anthracycline and taxane- No CNS mets

RANDOMIZE

Capecitabine + rhuMAb VEGF

Capecitabine

Refractory Metastatic Disease

Accrual goal: 400 patients

Toxicities of Anti-VEGF Therapy

• Hemorrhage (lung cancers)

• Hypertension (anti-VPF)

• Headaches/migraines

• Clots (maybe)

• Proteinura/nephrotic syndrome

Intracellular Signaling Pathways Activated by VEGF Binding to VEGFR2

ZD6474

Biochemical Cellular IC50

Receptor Ki

(M)Receptor

Phosphorylation (M)Ligand-dependentProliferation (M)

Flk-1/KDR 0.009 0.01 0.004PDGFR 0.008 0.01 0.031

c-kit ND 0.01 0.01FGFR 0.83 ND 0.70EGFR > 100 ND 8.9Flt-3 ND 0.25 0.01-0.1

SU11248 Potently Inhibits VEGFR, PDGFR and Kit in Biochemical and

Cellular Assays

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.

The Problem With Anti-Angiogenic Therapy:

Resistance

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

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

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

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

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

Eligibility:- No prior Rx for mets- Adjuvant taxane if >12 mos.Exclusion:- Her-2 +- CNS mets- Proteinuria- Uncontrolled HTN

RANDOMIZE

Arm A: Paclitaxel + rhuMAb VEGF

Arm B: Paclitaxel

E2100

Accrual goal: ~690

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

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

*P < 0.001 relative to Control, **P < 0.001 rel. to DC101.

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3

4

Control DC101 C225 DC101/C225Mea

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Effect of Anti-angiogenic Therapy on Mice With Colon Cancer Carcinomatosis

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

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

Adjuvant Angiogenesis: Requirements

• Chronic safety

• Combinatorial safety

• Chronic dose maintenance

• Large Proof-of-Concept trials

• Disease-specific rationale

• Proof of efficacy in advanced disease (???)

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

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