A randomized, double-blind, placebo-controlled, phase III study in patients (Pts) with metastatic adenocarcinoma of the colon or rectum receiving first-line chemotherapy with oxaliplatin/5-fluorouracil/leucovorin and PTK787/ZK 222584 or placebo (CONFIRM-1)

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


Background: PTK/ZK is a novel, oral small molecule that blocks angiogenesis and lymphangiogenesis by inhibiting tyrosine kinase signaling from all vascular endothelial growth factor (VEGF) receptors. PD studies using DCE-MRI showed biologic activity.

Methods: multinational study evaluated FOLFOX4 with PTK/ZK (1250 mg po qd) or placebo (PBO) in mCRC. The early primary endpoint, PFS, was assessed by investigators and independent central radiology every 8 wks. The late primary endpoint will be overall survival.

Results: 1168 pts were randomized from Feb 03-May 04. Baseline characteristics were balanced. Preplanned analysis of PFS by investigator review demonstrated a statistically significant improvement in patients receiving PTK/ZK (17% reduction in risk). PFS also favored PTK/ZK as assessed by central review (primary analysis), but did not achieve statistical significance. AEs attributable to PTK/ZK were generally reversible and similar to other VEGF pathway inhibitors, but with no increase in bleeding or bowel perforation compared to placebo.

Conclusions: These results suggest a positive effect of PTK/ZK. Exploratory analysis, performed by pooling preplanned strata, showed patients with high LDH experienced the greatest improvement in PFS. Complete results including survival will be needed to fully assess the benefit of PTK/ZK in mCRC.

PFS	FOLFOX + PTK/ZK	FOLFOX + PBO	HR	p-value ‡
Randomized (N)	585	583
PFS (mos, investigator) PFS (mos, EA †) LDH High (N= 316) LDH Low (N= 852)	7.7 (7.7- 9.3) 261 events 9.6 (7.5- 9.6) 7.7 (7.6- 9.0)	7.5 (7.5- 7.7) 319 events 5.8 (5.8- 7.1) 7.7 (7.5- 8.5)	0.83 0.61 0.93	0.026 0.002 0.432
PFS (mos, central) PFS (mos, EA †) LDH High LDH Low	7.7 (7.7- 9.2) 260 events 7.7 (7.1- 9.6) 7.7 (7.7- 9.2)	7.6 (7.5- 7.7) 302 events 5.8 (5.6- 7.4) 7.7 (7.6- 7.7)	0.88 0.67 0.97	0.118 0.010 0.785

AE (>1 %)	FOLFOX + PTK/ZK Gr 3*	FOLFOX + PBO Gr 3*
Hypertension	20.6	5.9
Diarrhea	14.5	10.3
Dizziness	6.6	2.1
DVT	4.7	3.0
	Gr 1-4	Gr 1-4
Pulmonary embolism	6.0	1.4
Arterial thromboembolism	3.6	1.7
† Exploratory analysis: LDH high > 1.5 X ULN, LDH low ? 1.5 X ULN ‡ log-rank * No Gr 4 >1%