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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).

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Ptk zk an oral multi vegf receptor inhibitor

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

Fit of PTK/ZK (green) into the ATP binding site

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


Ptk zk inhibits all known receptors of vegf
PTK/ZK Inhibits All Known Receptors of VEGF

VEGF-AVEGF-CVEGF-D

VEGF-CVEGF-D

VEGF-A VEGF-B

PlGF

Extracellular

Endothelial Cell

PTK/ZK

PTK/ZK

PTK/ZK

Intracellular

VEGFR-1/Flt-1

VEGFR-2/KDR

VEGFR-3/Flt-4

Angiogenesis

Angiogenesis

Lymphangiogenesis

Tumor metastasis


Proof of concept in mcrc
Proof of Concept in mCRC

Baseline

Baseline

Day 2 PTK/ZK

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

  • Subsequent PTK/ZK-FOLFOX combination showed promising activity

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

Steward W, et al. ASCO 2004


Ptk zk an oral multi vegf receptor inhibitor

CONFIRM-1 Trial Design

R

A

N

D

O

M

I

Z

E

D

1168 Patients

Stratification Factors:

PS: 0, 1-2

LDH: ≤, >1.5 x ULN

FOLFOX 4 +

PTK/ZK 1250 mg po qd

FOLFOX 4 +

Placebo

Multinational randomized phase III trial in previously untreated mCRC


Main eligibility criteria
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


Primary study objectives
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)



Patient disposition
Patient Disposition

  • 1168 patients were randomized between February 2003 and May 2004








Progression free survival central assessment primary analysis

PTK/ZK + FOLFOX4

Placebo + FOLFOX4

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

HR 0.88

(95% CI) (0.74, 1.03)

P-value 0.118

*If assessment is delayed or missed, date of PD

is adjusted to previous planned assessment date


Progression free survival investigator assessment
Progression-Free Survival: Investigator Assessment

HR 0.82

(95% CI) (0.69, 0.97)

P-value 0.019


Pfs hazard ratio
PFS:Hazard Ratio

HR P-value

Overall

Central

0.88

0.118

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

In favor of PTK/ZK

In favor ofplacebo


Pfs hazard ratio1
PFS:Hazard Ratio

HR P-value

Overall

Central

0.88

0.83

0.118

0.026

Investigator

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

In favor of PTK/ZK

In favor ofplacebo


Pfs by pre planned stratum hazard ratio

Central

Investigator

PFS by Pre-Planned Stratum:Hazard Ratio

HR P-value

0.88

0.83

0.118

0.026

Overall Population

High LDH, PS 0

High LDH, PS 1-2

Low LDH, PS 0

Low LDH, PS 1-2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

In favor of PTK/ZK

In favor ofplacebo


Progression free survival exploratory analysis in patients with high ldh n 316
Progression-Free Survival:Exploratory Analysis in Patients with High LDH (n=316)

Central Assessment

Investigator Assessment

HR 0.60

(95% CI) (0.44, 0.82)

P-value 0.001

HR 0.68

(95% CI) (0.50, 0.92)

P-value 0.012

PTK/ZK + FOLFOX4

Placebo + FOLFOX4

PTK/ZK + FOLFOX4

Placebo + FOLFOX4


Future directions
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


Conclusions
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


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

Acknowledgments

  • 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