1. CONFIRM 2 INTERIM ANALYSIS Results of an Interim Analysis of a Multinational Randomized, Double-Blind, Phase III Study in Patients With Previously Treated Metastatic Colorectal Cancer (mCRC) Receiving FOLFOX4 and PTK787/ZK (PTK/ZK) or Placebo
C.-H. Koehne, E. Bajetta, E. Lin, E. Van Cutsem, J.R. Hecht, J.-Y. Douillard, M. Moore, C. Germond, D. Laurent, C. Jacques

2. PTK/ZK Inhibits All Known VEGF Receptors
VEGF-A VEGF-B
PlGF
VEGF-A VEGF-C VEGF-D
VEGF-C VEGF-D
Extracellular
Endothelial Cell
Intracellular
PTK/ZK
PTK/ZK
PTK/ZK
PTK/ZK mechanism of action and the VEGF pathway
In order for a tumor cell to grow past 1-2mm, it requires the development of new blood vessels. To develop new vasculature, tumor cells secrete molecules that belong to the VEGF family of ligands (VEGF-A, -B, -C, -D) that bind to a specific set of VEGF receptors located on the cell surfaces of nearby endothelial cells.
Illustrated here is the cell surface of a target endothelial cell.
When a VEGF ligand binds to its cell surface receptor, the receptor tyrosine kinase is activated. The activated receptor tyrosine kinase induces a signal transduction cascade inside the cell. If VEGF-R1 or VEGF-R2 is activated, the ultimate outcome of the signal transduction is tumor angiogenesis. If VEGF-R3 is activated, lymphangiogenesis occurs.
PTK/ZK blocks the tyrosine kinase activity of all VEGF receptors, preventing activation of signaling pathways required for tumor angiogenesis and lymphangiogenesis.
PTK/ZK also inhibits c-KIT and/ or PDGFR- receptor which may also play a role in dimerizing with VEGFRs to promote the growth and spread of tumors. PDGFR-  is stimulated by PDGF and c-KIT is likewise stimulated by SCF.
References:
1. Bold G, Altmann KH, Frei J, et al. New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem. 2000;43(12):
2. Wood JM, Bold G, Buchdunger E, et al. PTK787/ZK , a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. Cancer Res. 2000;60:
Abbreviations: Flt, fms-like tyrosine kinase; KDR, kinase domain-containing receptor; PlGF, placenta growth factor; PDGF, platelet-derived growth factor; SCF, stem cell factor ; VEGF, vascular endothelial growth factor
VEGFR-1/Flt-1
VEGFR-2/KDR
VEGFR-3/Flt-4
Angiogenesis
Angiogenesis
Lymphangiogenesis
Tumor metastasis
PTK/ZK also inhibits PDGFR-b and c-KIT

3. CONFIRM 2 Study Design CONFIRM 2 855 patients FOLFOX 4 +
Stratification Factors: PS: 0, 1-2
LDH: ≤, >1.5 x ULN R A N D O M I Z E
FOLFOX 4 +
PTK/ZK (n=426) 1250 mg po qd
Multinational randomized phase III trial in irinotecan-pretreated mCRC patients
CONFIRM patients
FOLFOX 4 +
Placebo (n=429)
CONFIRM-2 study design
CONFIRM-2 is a large multinational, randomized trial of 855 patients with previously treated for metastatic disease with irinotecan/fluoropyrimidine-based therapies.
Patients were randomized from January 2003 through October 2004.
Patients were pre-stratified based on WHO performance status (PS 0 vs 1-2) and serum lactate dehydrogenase (LDH) levels (< 1.5 or > 1.5 x ULN). Performance status and LDH levels have been shown in previous studies to be strong prognostic indicators of clinical outcome.
Patients were then randomized to receive FOLFOX-4 with oral PTK/ZK (1250 mg daily) or placebo.

4. CONFIRM Study Design CONFIRM 1 1168 patients CONFIRM 2 855 patients
Stratification Factors: PS: 0, 1-2
LDH: ≤, >1.5 x ULN
1st line mCRC
CONFIRM patients R A N D O M I Z E
FOLFOX 4 +
PTK/ZK mg po qd
CONFIRM patients
2nd line mCRC
FOLFOX 4 +
Placebo
CONFIRM-2 study design
CONFIRM-2 is a large multinational, randomized trial of 855 patients with previously treated for metastatic disease with irinotecan/fluoropyrimidine-based therapies.
Patients were randomized from January 2003 through October 2004.
Patients were pre-stratified based on WHO performance status (PS 0 vs 1-2) and serum lactate dehydrogenase (LDH) levels (< 1.5 or > 1.5 x ULN). Performance status and LDH levels have been shown in previous studies to be strong prognostic indicators of clinical outcome.
Patients were then randomized to receive FOLFOX-4 with oral PTK/ZK (1250 mg daily) or placebo.

5. CONFIRM 1: Progression Free Survival (ASCO 2005)
Overall Patients
High LDH Patients
100
100
HR = 0.88 (95% CI: 0.74, 1.03)
P value = 0.118
HR = 0.60 (95% CI: 0.44, 0.82)
P value = 0.001 75 75
Progression-Free Survival, % 50
Progression-Free Survival, % 50 25 25
FOLFOX4 + PTK/ZK
FOLFOX4 + Placebo
The primary overall PFS endpoint was not met by central review.
However the subgroup analysis of patients with high LDH showed a clear benefit.
FOLFOX4 + PTK/ZK
FOLFOX4 + Placebo 2 4 6 8 10 12 2 4 6 8 10
Time Since Randomization, mo
Time Since Randomization, mo

6. CONFIRM 2: Main Patient Eligibility Criteria
Patients with mCRC
Pretreatment for metastatic disease with irinotecan/fluoropyrimidine-based chemotherapy
Measurable disease per RECIST
WHO PS of 0-2
Adequate hematological and organ function
No exclusions for prior coagulopathy or bleeding
Patients were NOT excluded due to prior coagulopathy or bleeding.
RECIST = Response Evaluation Criteria in Solid Tumors.

7. CONFIRM 2: Study Objectives
Primary end point: Overall survival
Statistical hypothesis: One-year overall survival rate from 36% to 45% (HR 0.782, 90% power, 5% level of significance with 692 events)
Key secondary end points:
Overall survival in high LDH (> 1.5 x ULN) patients
Progression free survival*
Overall population
High LDH population (> 1.5 x ULN)
Overall response rate (RECIST)
*Assessed by investigators following RECIST criteria.

8. Patient Characteristics
FOLFOX4 Plus
Characteristics
PTK/ZK
(n = 426)
Placebo
(n = 429)
Median age, y
62.0
60.0
Number of patients, n (%)
Low LDH (≤ 1.5 x ULN)
302 (71)
303 (71)
High LDH (> 1.5 x ULN)
124 (29)
126 (29)
Prior adjuvant chemotherapy, % 31
Male/female ratio, %
62/38
WHO PS, 0/1-2, %
53/47
Colon/rectum, %
68/30
72/26
Metastasis, %
Liver 73 77
Lung 48 44
Number of organs involved, % 1 40 41 2 34 33
≥ 3 26 27
Patient characteristics
The arms of the trial were balanced. There are slightly more male patients in the PTK/ZK arm. A higher number of patients in the PTK/ZK arm had colon cancer rather than rectal cancer.
Liver metastases were common in both arms. The majority of the patients had PS 0. Median LDH level in both arms were 0.95 X ULN
Note to presenter:
The percentages for “Number of organs involved” in the Placebo group are 40.6, 32.6, 26.6 and 0.2% for 1, 2, >/=3, and missing groups, respectively.

9. Patient Disposition FOLFOX4 Plus PTK/ZK, % (n = 426) Placebo, %
Patients ongoing* 12 11
Patient discontinuation
Progressive disease 52 70
Adverse event 15 8
Withdrawal of consent 13 5
Other reasons 6
Patient disposition was measured at the time of data cut-off.
Note that more patients discontinued the study in the placebo arm due to progressive disease (by 18%),
Whereas more patients discontinued due to adverse events or withdrawal of consent in the PTK/ZK arm (7 and 8% respectively)
*At time of data cut-off, patients are continuing study treatment.

10. Safety and Tolerability
FOLFOX4 Plus
Adverse Events
PTK/ZK, %
(n = 421)
Placebo, %
( > 5% Patients)
Grade 3
Grade 4
Neutropenia 17 12 16
Thrombocytopenia 5
< 1 4
Peripheral neuropathy
Diarrhea 8
Nausea 11
Vomiting 9
Abdominal pain 1
Hypertension 21
Dizziness
Venous thrombosis
Toxicity is outline in the slide in: Hematologic, GI-related,
Hypertension is anticipated.
Dizziness was a frequent complaint, however was seldom severe and was well-managed by taking medication

11. Other Clinically Important Adverse Events
FOLFOX4 Plus
Adverse Events, n (%)
PTK/ZK (n = 421)
Placebo (n = 421)
Bleeding, all grades 59
(14%) 48
(11%)
Bleeding, grade 3/4 9
(2.5%) 10
(2.2%)
Arterial thrombosis, grade 3/4 13
(3%) 6
(1.5%)
Bowel perforation
Encephalopathy 4
(1%)
All cause mortality 36
(9%) 26
(6%)
(within 28 days of last study drug administration)
Adverse events associated with inhibition of VEGF pathway
Listed here are adverse events associated with the inhibition of VEGF pathway. In contrast to another anti-VEGF therapy, PTK/ZK did not result in an increase of bleeding, arterial thrombosis or bowel perforation.
Overall deaths from any cause within 28 days of last study drug administration were similar in both study arms.

12. Response Rate FOLFOX4 Plus Responses PTK/ZK, % (n = 426)
Placebo, % (n = 429)
Overall response Complete response Partial response
Stable disease 43
Progressive disease 31 35
Duration of disease stabilization (duration of CR/PR/SD):
7.7 mo
5.8 mo
Response rate
Response rates were similar in both arms with approximately 20% of patients responding and 31-35% with progressive disease.

13. Overall Survival*: Overall Population
12.1 mo PTK/ZK vs 11.8 mo Placebo HR = 0.94 (95% CI: 0.77, 1.14) P value = 0.51 25 50 75
100
Time Since Randomization, mo
Overall Survival, % 4 8 12 16 20 24
FOLFOX4 + PTK/ZK
FOLFOX4 + Placebo
PTK/ZK
Placebo
426
429
373
377
239
234
115
119 48 56 14 5
*Overall survival results based on interim analysis values; final data available end of 2006.

14. Progression Free Survival: Overall Population
100
5.6 mo PTK/ZK vs 4.1 mo Placebo HR = 0.83 (95% CI: 0.71, 0.98) P value = 0.026 75 75
Progression-Free Survival, % 50 25
FOLFOX4 + PTK/ZK
FOLFOX4 + Placebo 4 8 12 16 20
Time since randomization, mo
PTK/ZK
Placebo
426
429
194
182 49 38 10 6 2

15. Progression Free Survival: High LDH Patients
100
5.6 mo PTK/ZK vs 3.8 mo Placebo HR = 0.61 (95% CI: 0.46, 0.80) P value = < 0.001 75
Progression-Free Survival, % 50 25
FOLFOX4 + PTK/ZK
FOLFOX4 + Placebo 4 8 12 16
Time Since Randomization, mo
PTK/ZK
Placebo
124
126 68 48 18 8 5 2 2

16. Overall Survival*: High LDH Patients
100
9.6 mo PTK/ZK vs 7.5 mo Placebo HR = 0.78 (95% CI: 0.58, 1.05) P value = 0.105 75
Overall Survival, % 50 25
FOLFOX4 + PTK/ZK
FOLFOX4 + Placebo
Approximate 2 months difference in OS
0.78 HR is favorable for PTK/ZK and clinically meaningful, even though the nominal p value does not reach statistical significance 4 8 12 16 20 24
Time Since Randomization, mo
PTK/ZK
Placebo
124
126
108 94 61 45 21 16 8 2 1
*Overall survival results based on interim analysis values; final data available end of 2006.

17. Progression Free Survival by LDH Stratum: HR in CONFIRM 2
PFS by LDH Stratum: Hazard Ratio in CONFIRM 2
and 1
HR P value
Overall Population
0.83
0.026
CONFIRM 2
0.83
0.026
CONFIRM 1*
High LDH
Low LDH
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Favors PTK/ZK
Favors Placebo
*Investigator-based assessment of CONFIRM 1.

18. Bulky/Hypoxic Tumors Boost HIF-1a Which Upregulates VEGF and LDH
HIF-1a stabilization
HIF-1a/ARNT
LDH-A
HRE
VEGF-A VEGFR-1
nucleus
LDH-5
As tumors grow and expand in excess of 2 mm in diameter, they become bulky and take on a hypoxic-like phenotype. Hypoxia-like stressors lead to the stabilization and translocation of HIF-1a into the nucleus to transactivate a number of tumor sustaining pathways, including:
LDH-A and glucose transporters for anaerobic glycolysis
VEGF-A and VEGFR-1 to stimulate angiogenesis
Literature and research support for high LDH in bulky/ hypoxic tumors include:
Strong correlation between serum LDH and intratumoral VEGF-A or VEGFR-1 gene expression in mCRC patient tumor samples (Azuma et al, ASCO #3530)
Up-regulation of LDH5 in CRC cells associated with invasion, metastasis and tumor hypoxia (Koukourakis et al., Clin. Exp. Metas. 2005; 22(1):25-30.)
GLUT-1, -3
NOS
Anaerobic glycolysis
Angiogenesis
EPO
Erythropoiesis
Adapted from Harris AL. Nature Rev Cancer. 2002;2:38-47.

19. PTK/ZK Summary CONFIRM 2
Well-tolerated safety profile with anticipated antiangiogenic drug-related effects
No OS benefit for overall population based on interim analysis
PTK/ZK improved PFS for overall population (HR = 0.83, P = 0.026)
PTK/ZK significantly improved PFS in high LDH patients (HR = 0.61, P < 0.001)
PTK/ZK improved OS for patients with high LDH (HR = 0.78, P = 0.105)
Efficacy and safety results in overall population and high LDH patients are highly consistent between CONFIRM 1 and CONFIRM 2
New studies in mCRC patients with high LDH are planned
Further development of PTK/ZK is ongoing in mCRC and additional tumor types
Slightly increases GI toxicity, hypertension and dizziness

20. Acknowledgments The patients and their families
The investigators in over 200 medical centers worldwide
The Novartis Pharmaceutical Corp, US and Schering AG, Germany CONFIRM team
Related PTK/ZK ASCO presentations
Major et al. #3529 CONFIRM 1/2 meta-analysis
Azuma et al. #3530 Association of serum LDH with genes in the angiogenesis pathways in mCRC patients