A Randomized, Double-blind, Placebo-controlled Phase III Study in Patients with Metastatic Colorectal

Cancer Receiving First-line Chemotherapy with FOLFOX 4 and PTK/ZK or Placebo

(CONFIRM-1)

J R Hecht, T Trarbach, E Jaeger, J Hainsworth, R Wolff, K Lloyd, G Bodoky, M Borner, D Laurent, C Jacques

PTK/ZK: An Oral Multi-VEGF Receptor Inhibitor

Potent inhibitor of all known VEGF receptors

Also inhibits PDGFR and c-Kit

Half life of 3 to 6 hours

Oral once-daily dosing Fit of PTK/ZK (green)

into the ATP binding site

3

VEGF-AVEGF-CVEGF-D

VEGF-A VEGF-BPlGF

VEGF-CVEGF-D

VEGFR-1/Flt-1 VEGFR-2/KDR VEGFR-3/Flt-4

PTK/ZK

Extracellular

Intracellular

Angiogenesis Angiogenesis LymphangiogenesisTumor metastasis

PTK/ZK Inhibits All Known Receptors of VEGF

Endothelial Cell

PTK/ZK PTK/ZK

4

Proof of Concept in mCRC

Baseline

Day 2 PTK/ZK

Morgan B, et al. J Clin Oncol. 2003;21: 3955-3964 Steward W, et al. ASCO 2004

Baseline

Tumor vascularity and permeability decreased rapidly with PTK/ZK and correlated with clinical benefit

Subsequent PTK/ZK-FOLFOX combination showed promising activity

5

1168 Patients

Stratification Factors:PS: 0, 1-2

LDH: ≤, >1.5 x ULN

FOLFOX 4 +PTK/ZK 1250 mg po qd

CONFIRM-1 Trial Design

FOLFOX 4 +Placebo

Multinational randomized phase III trial in previously untreated mCRC

RANDOMIZED

6

Main Eligibility Criteria

Metastatic colorectal cancer patients

No prior chemotherapy for metastatic disease

Prior adjuvant chemotherapy allowed (> 6 mo)

Measurable disease per RECIST criteria

WHO PS 0-2

Adequate hematological and organ function

No exclusions for prior coagulopathy or bleeding

7

Primary Study Objectives

Progression-free survival Independent central radiological review

Primary analysis Investigator assessment Statistical hypothesis

25% reduction in risk of progression (HR 0.75)

Overall survival Statistical hypothesis

One-year OS rate from 71% to 76% (HR 0.80)

8

Patient Characteristics

CharacteristicsFOLFOX 4 + PTK/ZK

N=585FOLFOX 4 + Placebo

N=583

Median Age (yrs) 59 61

Male / Female (%) 63 / 37 60 / 40

WHO PS 0 / 1 / 2 (%) 55 / 41 / 4 54 / 40 / 6

Colon / Rectum (%) 71 / 26 68 / 30

Liver Metastasis (%) 80 74

Lung Metastasis (%) 26 31

Number of Organs Involved (%)

1 46 43

2 33 34

> 3 19 22

Median LDH at Baseline 0.95 x ULN 0.95 x ULN

Prior Adjuvant Chemotherapy (%) 26 28

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Patient Disposition

FOLFOX 4 + PTK/ZK

N= 585

(%)

FOLFOX 4 + Placebo

N=583

(%)

Patients ongoing 25 32

Patients discontinued due to:

Progressive disease 33 42

Adverse event 21 11

Withdrawal of consent 12 7

Other reasons 9 8

1168 patients were randomized between February 2003 and May 2004

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Safety

11

Grade 3/4 NCI Adverse Events in >5% of Patients

Adverse Events

FOLFOX 4 + PTK/ZK

N=579

(%)

FOLFOX 4 + Placebo

N=574

(%)

Grade 3 Grade 4 Grade 3 Grade 4

Neutropenia 17 14 21 11

Thrombocytopenia 6 <1 4 <1

Diarrhea 15 <1 10 <1

Nausea 9 N/A 5 N/A

Vomiting 7 <1 6 <1

Abdominal pain 4 <1 5 <1

Peripheral neuropathy 9 <1 7 <1

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Grade 3/4 NCI Adverse Events in >5% of Patients

Adverse Events

FOLFOX 4 + PTK/ZK

N=579

(%)

FOLFOX 4 + Placebo

N=574

(%)

Grade 3 Grade 4 Grade 3 Grade 4

Hypertension 21 <1 6 <1

Dizziness 7 <1 2 0

Venous thrombosis 7 <1 4 <1

Pulmonary embolism N/A 6 N/A 1

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Other Clinically Important Adverse Events

Adverse Events

FOLFOX 4 + PTK/ZK

N=579

(%)

FOLFOX 4 + Placebo

N=574

(%)

Bleeding (gr 3-4) 2.9 2.8

Arterial thrombosis (gr 3-4) 1.9 1.4

Bowel perforation 0.2 0.7

Reversible posterior encephalopathy

0.5 0

Deaths of any cause within 28 days of last study drug administration

5 6

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Efficacy

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Response Rate

FOLFOX 4 + PTK/ZK

N=585

(%)

FOLFOX 4 + Placebo

N=583

(%)P-value

CR 3 3 N.S.

PR 39 43 N.S.

SD 37 33 N.S.

PD 16 15 N.S.

UNK 6 6 N.S.

16

0

25

50

75

100

0 2 4 6 8 10 12Time since randomization, months

Progression-free survival,

%

Progression-Free Survival: Central Assessment (Primary Analysis)*

HR 0.88

(95% CI) (0.74, 1.03)

P-value 0.118

PTK/ZK + FOLFOX4Placebo + FOLFOX4

*If assessment is delayed or missed, date of PDis adjusted to previous planned assessment date

17

Progression-Free Survival: Investigator Assessment

HR 0.82

(95% CI) (0.69, 0.97)

P-value 0.019

0

25

50

75

100

0 2 4 6 8 10 12Time since randomization, months

Progression-free survival, %

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PFS:Hazard Ratio

0.80.60.4 1.61.41.2

Overall

1.0

0.118

1.8

HR P-value

In favor of PTK/ZK In favor of placebo

0.88Central

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PFS:Hazard Ratio

0.80.60.4 1.61.41.2

Overall

1.0

0.118

0.026

1.8

HR P-value

In favor of PTK/ZK In favor of placebo

0.88

0.83

Central

Investigator

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High LDH, PS 1-2

PFS by Pre-Planned Stratum:Hazard Ratio

0.80.60.4 1.61.41.2

Low LDH, PS 0

Overall Population

1.0

High LDH, PS 0

Low LDH, PS 1-2

1.8

In favor of PTK/ZK In favor of placebo

CentralInvestigator

0.118

0.026

HR P-value

0.88

0.83

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Progression-Free Survival:Exploratory Analysis in Patients with High LDH (n=316)

0

25

50

75

100

0 2 4 6 8 10

Time since randomization, months

Progression-free survival, %

Central Assessment Investigator Assessment

0

25

50

75

100

0 2 4 6 8 10

Time since randomization, months

Progression-free survival, %PTK/ZK + FOLFOX4Placebo + FOLFOX4

PTK/ZK + FOLFOX4Placebo + FOLFOX4

HR 0.68(95% CI) (0.50, 0.92)P-value 0.012

HR 0.60(95% CI) (0.44, 0.82)P-value 0.001

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Future Directions

CONFIRM 1 overall survival data expected second half

2006

CONFIRM 2 final results expected 2006

FOLFOX +/- PTK/ZK in second-line CRC

Optimize dosing schedule to reduce early treatment

discontinuation and improve efficacy

Explore the biology and clinical relevance of predictive

factors such as LDH in CRC

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Conclusions

PFS based on central review showed a modest benefit of adding PTK/ZK to FOLFOX which did not reach statistical significance

Preplanned secondary analysis of PFS based on investigator assessment showed a statistically significant improvement favoring PTK/ZK

PTK/ZK in combination with FOLFOX is generally well tolerated

High LDH levels may predict which patients are most likely to benefit from PTK/ZK

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Acknowledgments

UCLA/TORI Dennis Slamon Nancy Ryba David Reese David Chan, Ravi Patel NCCRA Mike and Michele Richman

University of Essen Krankenhaus Nordwest, Frankfurt Sarah Cannon Cancer Center MD Anderson Cancer Center Virginia Cancer Institute Szent Laszlo Hospital, Budapest Institute for Medical Oncology,

Bern

The Patients and Their Families

The Investigators in Over 200 Medical Centers Worldwide

Novartis David Lebwohl Andrea Kay Bee-Lian Chen Andrew Henry Eric Masson

Schering AG Germany Andrea Wagner Christine Gonschorek Michael Kretschmann Martina Poethig Silke Zaun