PURO Panitumumab in Combination With Gemcitabine/Cisplatin in Advanced Urothelial Cancer (PURO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01374789
Recruitment Status : Terminated (The study was terminated due to insufficient recruitment.)
First Posted : June 16, 2011
Last Update Posted : June 3, 2015
Gesellschaft fur Medizinische Innovation – Hamatologie und Onkologie mbH
Information provided by (Responsible Party):
WiSP Wissenschaftlicher Service Pharma GmbH

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Urinary Bladder Cancer Drug: GemCis + Panitumumab Drug: GemCis Phase 2

Detailed Description:

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : July 2010
Actual Primary Completion Date : March 2012
Actual Study Completion Date : March 2012

Arm Intervention/treatment
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
Drug: GemCis
Gemcitabine: 1250 mg/m², day 1 and 8, i.v., q3 Cisplatin: 70 mg/m², day 2, i.v., q3

Primary Outcome Measures :
  1. Primary end point: Progression-free survival rate after 12 months. [ Time Frame: 12 months ]

Secondary Outcome Measures :
  1. Determination of best response (CR, PR and SD) rates in accordance with the RECIST criteria [ Time Frame: up to 18 weeks ]
  2. Duration of response, progression-free and overall survival time [ Time Frame: 2 years ]
  3. Documentation of adverse effects in accordance with the NCI CTC criteria [ Time Frame: up to 18 weeks ]
  4. Documentation of quality of life on the basis of the EORTC questionnaire [ Time Frame: up to 18 weeks ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Histologically or cytologically confirmed, unresectable urothelial carcinoma of the bladder or the upper urinary tract
  • Wild-type HRAS
  • Male and female subjects > 18 years of age
  • General condition ECOG 0-1
  • Life expectancy at least 12 weeks
  • Women of child-bearing potential: negative pregnancy test and use of effective contraception(oral contraceptive, coil); men: use of adequate male contraception (condom) for up to 3 months after discontinuation of panitumumab therapy
  • Locally advanced or metastatic disease (T3b,T4 and/or N+ and/or M+)
  • At least one unidimensionally measurable lesion detectable in CT or MRI corresponding to the RECIST criteria
  • Adequate haematological, hepatic, renal and metabolic function parameters:

Leukocytes > 3000/mm³, ANC ≥ 1500/mm³, platelets ≥ 100,000/mm³, hemoglobin > 9 g/dl Creatinine clearance ≥ 50 ml/min and serum creatinine ≤ 1.5 x upper limit of normal Bilirubin ≤ 1.5 x upper limit of normal, GOT-GPT ≤ 2.5 x upper limit of normal in absence of liver metastases, or ≤ 5 x upper limit of normal in presence of liver metastases, AP ≤ 5 x upper limit of normal Magnesium ≥ lower limit of normal; calcium ≥ lower limit of normal INR and PTT < 1.5 x the upper limit of the normal reference range

Exclusion Criteria:

  • HRAS mutation
  • Absence of any of the above-listed inclusion criteria
  • Dialysis-dependence following nephrectomy
  • Patients with cerebral tumours and/or cerebral metastases
  • Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrolment.
  • Patients with uncontrolled hypertension; systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical treatment
  • History of interstitial lung disease, e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan.
  • Patients with thrombotic or embolic events, such as stroke or pulmonary embolism
  • Patients with recent or known history of haemorrhagic diathesis
  • Known significant neurological or psychiatric disorders, including dementia and epileptic seizures
  • Serious inflammatory eye conditions, hearing impairment
  • Pulmonary (pO2 < 60 mmHg), haemopoietic (e.g. serious bone marrow aplasia), hepatic or renal disorders
  • Patients with poorly controlled diabetes mellitus
  • Serious bacterial or fungal infections (>grade 2 NCI CTC Version 3)
  • Chronic hepatitis B or C; HIV infection
  • Autoimmune disease
  • Allergic reaction to one of the medications to be used
  • Status post organ transplantation
  • Status post autologous bone marrow transplantation or stem cell transplantation in the 4 months prior to study commencement
  • Manifest secondary malignancy or other form of cancer in the previous 5 years (excluding basalioma, in situ cervical cancer, incidental prostatic cancer)
  • Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment
  • Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 3 months (male or female) after the end of treatment (adequate: oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly).
  • Active participation in other clinical studies in the previous 4 weeks
  • Prior systemic therapy with cytostatics or immunotherapeutic agents
  • Concurrent use of other anticancer treatments after study commencement
  • Intravesical chemotherapy in the previous 4 weeks
  • Radiotherapy in the previous 4 weeks
  • Previous radiotherapy in which all lesions to be used for the evaluation of tumour response were irradiated
  • Patients in a closed institution according to an authority or court decision

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01374789

Bundeswehrkrankenhaus Berlin
Berlin, Germany, 10115
Krankenhaus am Urban
Berlin, Germany, 10967
St.-Josefs-Hospitals Dortmund
Dortmund, Germany, 44263
Universitätsklinikum Dresden
Dresden, Germany, 01307
Universitätsklinikum Düsseldorf
Düsseldorf, Germany, 40225
Universitätsklinikum Erlangen
Erlangen, Germany, 91054
Klinikum Fulda
Fulda, Germany, 36043
Universitätsklinikum Hamburg Eppendorf
Hamburg, Germany, 20246
Medizinische Hochschule Hannover, Urologie
Hannover, Germany, 30625
Universitätskllinikum Heidelberg
Heidelberg, Germany, 69121
Klinikum Kassel
Kassel, Germany, 34215
Köln, Germany, 50737
Klinikum Ludwigshafen
Ludwigshafen, Germany, 67063
Universitätsklinikum Mainz
Mainz, Germany, 55131
Uroloische Praxis
Markkleeberg, Germany, 04416
Universitätsklinikum Münster
Münster, Germany, 48149
Johanniter Krankenhaus
Stendal, Germany, 39576
Universitätsklinikum Ulm, Urologische Klinik
Ulm, Germany, 89075
Klinikum Weiden
Weiden, Germany, 92637
Gemeinschaftspraxis für Urologie DGU
Wuppertal, Germany, 742103
Sponsors and Collaborators
WiSP Wissenschaftlicher Service Pharma GmbH
Gesellschaft fur Medizinische Innovation – Hamatologie und Onkologie mbH
Principal Investigator: Kurt Miller, Prof. Dr. Universitätsmedizin Charité Berlin, Klinik für Urologie

Responsible Party: WiSP Wissenschaftlicher Service Pharma GmbH Identifier: NCT01374789     History of Changes
Other Study ID Numbers: WiSP_AG48
2009-015119-42 ( EudraCT Number )
GMIHO-007/2008 ( Other Identifier: GMIHO mbh )
First Posted: June 16, 2011    Key Record Dates
Last Update Posted: June 3, 2015
Last Verified: June 2015

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Antibodies, Monoclonal
Antineoplastic Agents
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs