| General information |
| Database: | DB00721 |
| Objective: | Treatment options for patients with previously treated metastatic colorectal cancer (mCRC) are limited, and treatments with differing mechanisms of action are needed. PTK787/ZK 222584 (PTK/ZK) is a novel oral angiogenesis inhibitor with therapeutic potential for the treatment of solid tumors. |
| Authors: | Van Cutsem E, et al |
| Title: | Randomized, placebocontrolled, phase III study of oxaliplatin, fluorouracil, and leucovorin with or without PTK787/ZK 222584 in patients with previously treated metastatic colorectal adenocarcinoma. |
| Journal: | J Clin Oncol. |
| Year: | 2011 |
| PMID: | 21464401 |
| Trial Design |
| Clinical Trial Id: | NCT00056446 |
| Agent: | PTK787/ZK 222584
|
| Target: | Vascular endothelial growth factor receptor 2
|
| Cancer Type: | colorectal cancer |
| Cancer Subtype: | advanced colorectal cancer |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | PTK787/ZK 222584 + chemotherapy |
| Study Type: | multinational, randomized, doubleblind, phase III study |
| Key Patients Feature: | Eligible patients were those older than 18 years with histologically orcytologically confirmed mCRC, a WHO performance status score (PS) of 0 to2, life expectancy of at least 12 weeks, measurable lesion(s) per modifiedResponse Evaluation Criteria in Solid Tumors (RECIST), one prior chemotherapy regimen for metastatic disease (firstline irinotecan in combinationwith a fluoropyrimidine), and written informed consent. |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | PTK/ZK VS placebo |
| Treatment Info: | Patients (N = 855) were randomly assigned to treatment with PTK/ZK or placebo once daily in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4). Stratification factors included WHO performance status (PS; 0 v 1 to 2) and lactate dehydrogenase ([LDH] less than and equal to 1.5¡Á the upper limit of normal [ULN] v > 1.5 ¡Á ULN). Treatment was given until disease progression or unacceptable toxicity. |
| Primary End Point: | overall survival (OS) |
| Secondary End Point: | progression free survival (PFS), safety, tolerability, and pharmacokinetics of PTK/ZK |
| Patients Number: | 855 |
| Trial Results |
| DLT_MTD: | The most frequent AEs were nausea(64.5%), diarrhea (55.3%), fatigue (50.5%), and vomiting (49.0%).Diarrhea, vomiting, dizziness, anorexia, and hypertension were reportedby a higher percentage of patients in thePTK/ZKgroup than inthe placebo group Grade 3/4 AEs were reported in 77.6% of patients overall andmost frequently included neutropenia, hypertension, diarrhea, fatigue, nausea, and vomiting |
| Objective Response Rate: | No statistically significant differences were seen between the treatment groups for the overallcomparison of OS. With PTK/ZK and placebo, respectively, median OS was 13.1 and 11.9 months(hazard ratio [HR], 1.00; 95% CI, 0.87 to 1.16; P .957). |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | Median PFS was longer with PTK/ZK than with placebo (5.6 and 4.2 months, respectively; HR, 0.83; 95% CI, 0.71 to 0.96; P .013). |
| Median OS A vs. C: | With PTK/ZK and placebo, respectively, median OS was 13.1 and 11.9 months (hazard ratio [HR], 1.00; 95% CI, 0.87 to 1.16; P .957). |
| Adverse Event(agent arm): | The most frequent AEs were nausea (64.5%), diarrhea (55.3%), fatigue (50.5%), and vomiting (49.0%). Diarrhea, vomiting, dizziness, anorexia, and hypertension were reportedbya higher percentage ofpatients in thePTK/ZKgroupthan in the placebo group. Serious AEs (45.0% v 34.5%), other clinically significant AEs (93.6% v 80.5%), and discontinuations from the study because of these AEs (35.5% v 17.9%) were more frequent in the PTK/ZK group than in the placebo group, respectively. |
| Conclusions: | PTKZK in combination with FOLFOX4 did not improve OS of patients with pretreated mCRC but did improve PFS. The effect of PTKZK was more pronounced in patients with high LDH at baseline. |