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

This study has been terminated.
(The study was terminated due to insufficient recruitment.)
Sponsor:
Collaborator:
Gesellschaft fur Medizinische Innovation – Hamatologie und Onkologie mbH
Information provided by (Responsible Party):
WiSP Wissenschaftlicher Service Pharma GmbH
ClinicalTrials.gov Identifier:
NCT01374789
First received: March 30, 2011
Last updated: March 7, 2014
Last verified: March 2014
  Purpose

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 Intervention Phase
Urinary Bladder Cancer
Drug: GemCis + Panitumumab
Drug: GemCis
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by WiSP Wissenschaftlicher Service Pharma GmbH:

Primary Outcome Measures:
  • Primary end point: Progression-free survival rate after 12 months. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 124
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)
Arms Assigned Interventions
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

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01374789

Locations
Germany
Krankenhaus am Urban
Berlin, Germany, 10967
Bundeswehrkrankenhaus Berlin
Berlin, Germany, 10115
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
Heilig-Geist-Krankenhaus
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
Investigators
Principal Investigator: Kurt Miller, Prof. Dr. Universitätsmedizin Charité Berlin, Klinik für Urologie
  More Information

No publications provided

Responsible Party: WiSP Wissenschaftlicher Service Pharma GmbH
ClinicalTrials.gov Identifier: NCT01374789     History of Changes
Other Study ID Numbers: WiSP_AG48, 2009-015119-42, GMIHO-007/2008
Study First Received: March 30, 2011
Last Updated: March 7, 2014
Health Authority: Germany: Paul-Ehrlich-Institut

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

ClinicalTrials.gov processed this record on September 29, 2014