Entry Detail
| General information | |
| Database: | DB00702 |
| Objective: | The primary objectives of this study were to determine the maximum tolerated dose (MTD) and doselimiting toxicities (DLTs) of ZK 304709, a novel multitargeted growth inhibitor (MTGI(trade mark)), in man. Secondary endpoints included safety evaluation, tolerability, pharmacokinetic profiling and assessment of response using standard and novel surrogate pharmacodynamic endpoints. |
| Authors: | Graham JS, et al |
| Title: | Openlabel, nonrandomised, interindividual dose escalation of ZK 304709 with the evaluation of safety, tolerability, pharmacokinetics, oral bioavailability and orientating efficacy after daily administration in patients with advanced cancer (7 d treatment and 14 d recovery). |
| Journal: | Eur J Cancer |
| Year: | 2008 |
| PMID: | 18653327 |
| Trial Design | |
| Clinical Trial Id: | NA |
| Agent: | ZK 304709 |
| Target: | Cell division protein kinase 4 Cell division control protein 2 homolog Cell division protein kinase 9 Cell division protein kinase 7 Cell division protein kinase 2 |
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced cancer Tumour types ColorectalBiliary/gallbladder/pancreatic Oesophageal Lung Mesothelioma Ovarian Retroperitoneal Renal Head and neck Cervical Thyroid |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | a multicentre, openlabel, nonrandomised, interindividual dose escalation |
| Key Patients Feature: | Patients aged P18 years with histologically confirmed advanced solid tumours refractory to standard therapy or forwhom no effective therapy was available were eligible. Inclusion criteria included written informed consent, baselineWHO performance status score of 0-2, adequate function ofmajor organs, life expectancy of at least 3 months, absoluteneutrophil count >1.5 . 109/l, haemoglobin >9 g/dl, platelets>100 . 109/l, aspartate aminotransferase (ASAT) and alanineaminotransferase (ALAT) <2.5 . upper limit of normal (ULN), <5 . ULN for patients with liver metastases, serum bilirubin<1.5 . ULN, serum creatinine <1.5 . ULN and for women ofchildbearing potential a negative pregnancy test within 24 hprior to first administration of ZK 304709. |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | Patients were treated with ZK 304709, administered orally once daily for 7 d with 14 d recovery. Doses were escalated in sequential cohorts of three patients with expansion to 67 patients should a doselimiting toxicity occur. |
| Primary End Point: | maximum tolerated dose (MTD) and doselimiting toxicities (DLTs) |
| Secondary End Point: | safety evaluation, tolerability, pharmacokinetic profiling and assessment of response using standard and novel surrogate pharmacodynamic endpoints |
| Patients Number: | 40 |
| Trial Results | |
| DLT_MTD: | Sixteen drugrelatedAEs with a maximum NCI CTC grade of 3 and twodrugrelated AEs with a maximum grade of 4 were reportedin thirteen patients |
| Objective Response Rate: | no partial responses (PRs)or complete responses (CRs) were observed. Best overall responseaccording to RECIST could be determined for 28 of40 patients, with 16 patients having stable disease (SD) and11 patients having progressive disease (PD); 1 patient wasnot evaluable |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | The most frequent drugrelated AEs were nausea (58%), vomiting (55%), diarrhoea and lymphopaenia (both 35%), fatigue (23%), anaemia (20%), lethargy (18%), anorexia (13%), and dizziness (10%). |
| Conclusions: | Due to the lack of further increment in blood concentrations above a dose of 90mg, which was felt from previous animal studies to be unlikely to result in meaningful pharmacologic or clinical activity, this study was stopped early. |