PURO Panitumumab in Combination With Gemcitabine/Cisplatin in Advanced Urothelial Cancer
The primary objective of the study is to assess the efficacy of the combination consisting of gemcitabine/cisplatin and panitumumab in patients with urothelial carcinoma and wild-type HRAS (non-mutated status). The progression-free survival rate at 12 months will be compared to expectations derived from historical data, which are verified by a randomised control group without the antibody.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||PURO - An Open-label, Randomised, Multicentre, Phase II Study to Evaluate the Efficacy of Chemotherapy With Gemcitabine and Cisplatin in Combination With the EGF Receptor Antibody Panitumumab (GemCisP) Versus GemCis in the First-line Therapy of Locally Advanced/Metastatic Urothelial Carcinoma in Patients With Wild-type HRAS|
- Primary end point: Progression-free survival rate after 12 months. [ Time Frame: 12 months ] [ Designated as safety issue: No ]
- Determination of best response (CR, PR and SD) rates in accordance with the RECIST criteria [ Time Frame: up to 18 weeks ] [ Designated as safety issue: No ]
- Duration of response, progression-free and overall survival time [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- Documentation of adverse effects in accordance with the NCI CTC criteria [ Time Frame: up to 18 weeks ] [ Designated as safety issue: Yes ]
- Documentation of quality of life on the basis of the EORTC questionnaire [ Time Frame: up to 18 weeks ] [ Designated as safety issue: No ]
|Study Start Date:||July 2010|
|Estimated Study Completion Date:||July 2014|
|Estimated Primary Completion Date:||April 2014 (Final data collection date for primary outcome measure)|
Experimental: Arm A (GemCis + Panitumumab)
gemcitabine + cisplatin + panitumumab
Drug: GemCis + Panitumumab
Gemcitabine: 1250 mg/m², day 1 and 8, i.v., q3 Cisplatin: 70 mg/m², day 2, i.v., q3 Panitumumab 9 mg/kg/body weight, i.v., day 1,q3
Other Name: Vectibix (Panitumumab)
Active Comparator: Arm B (GemCis)
gemcitabine + cisplatin
Gemcitabine: 1250 mg/m², day 1 and 8, i.v., q3 Cisplatin: 70 mg/m², day 2, i.v., q3
Mutation of ras oncogenes is frequently observed in human tumours and occurs in approximately 30% of all cancer types. Frequent mutation "hot spots" occur in codon 12 (glycine to valine), codon 13 (glycine to cysteine) and codon 61 (glutamine to arginine, lysine and leucine) (Bonner et al. 1993, Levesque et al. 1993). Point mutations in ras genes result in blockade of intrinsic GTPase activity, the physiological mechanism that switches off ras GTPases. The consequence is persistent up-regulation of the signal pathway and increased cell proliferation. The first HRAS mutation in association with bladder cancer was described during establishment of the human urinary bladder carcinoma cell line T24. In further studies, a research group led by Fitzgerald was able to demonstrate that HRAS gene mutations were present in the urine sediment of up to 44% of patients with urinary bladder cancer (Fitzgerald et al. 1995).
Viola et al. subsequently investigated whether an increased mutation rate is accompanied by increased expression of ras proteins in bladder cancer. It was shown that there is indeed increased expression of ras proteins in dedifferentiated tumours and carcinomas in situ, whereas highly differentiated tumours do not exhibit this rate of expression (Viola et al. 1985).
At present, there is no clinical evidence, that the findings of an obvious lack of activity of EGFR antibodies in colorectal cancer with RAS-related mutations, is likewise valid in urothelial carcinoma. However, as it is the aim of this study to detect a first signal of activity in this type of cancer, and the chance of missing such evidence in a phase II trial with limited patient numbers is high anyway, it seems sensible, not to miss this opportunity of "enrichment". In case of a clearly positive signal of efficacy in the present trial, a subsequent phase II study may focus on HRAS mutated tumors.
Overexpression of the EGF receptor in bladder cancer has been described by many research groups (Colquhuon & Mellon, 2002) and is associated with an advanced stage of the tumour, progression of the tumour and a poor clinical prognosis. The EGFR antibody cetuximab (Erbitux®) has been investigated in a human urothelial carcinoma cell line and in a mouse model with human bladder carcinoma. Cetuximab was found to inhibit tumorigenesis and metastatic progression in vivo and in vitro by means of suppression of angiogenesis and simultaneous induction of apoptosis (Perotte et al., 1999; Inoue et al., 2000). Similar results have also been reported in urothelial carcinoma for the tyrosine kinase inhibitor gefitinib (Villares et al., 2007, Shrader et al., 2007).
There are currently two on-going studies of cetuximab in metastatic bladder cancer: a randomised phase II study of first-line treatment with Gemcitabine and Cisplatin +/- Erbitux (NCT00645593) and a randomised phase II study of second-line treatment with Erbitux +/- Paclitaxel (NCT00350025).
The HRAS mutation rate in urothelial carcinoma is approximately 40%. The primary objective of the study is to assess the efficacy of the combination consisting of gemcitabine/cisplatin and panitumumab in patients with wild-type HRAS (non-mutated status). The progression-free survival rate at 12 months will be compared to expectations derived from historical data, which are verified by a randomised control group without the antibody.
|Krankenhaus am Urban|
|Berlin, Germany, 10967|
|Berlin, Germany, 10115|
|Dortmund, Germany, 44263|
|Dresden, Germany, 01307|
|Düsseldorf, Germany, 40225|
|Erlangen, Germany, 91054|
|Fulda, Germany, 36043|
|Universitätsklinikum Hamburg Eppendorf|
|Hamburg, Germany, 20246|
|Medizinische Hochschule Hannover, Urologie|
|Hannover, Germany, 30625|
|Heidelberg, Germany, 69121|
|Kassel, Germany, 34215|
|Köln, Germany, 50737|
|Ludwigshafen, Germany, 67063|
|Mainz, Germany, 55131|
|Markkleeberg, Germany, 04416|
|Münster, Germany, 48149|
|Stendal, Germany, 39576|
|Universitätsklinikum Ulm, Urologische Klinik|
|Ulm, Germany, 89075|
|Weiden, Germany, 92637|
|Gemeinschaftspraxis für Urologie DGU|
|Wuppertal, Germany, 742103|
|Principal Investigator:||Kurt Miller, Prof. Dr.||Universitätsmedizin Charité Berlin, Klinik für Urologie|