Contact information
Type
Scientific
Primary contact
Dr Najib Rahman
ORCID ID
Contact details
Oxford Respiratory Trials Unit
University of Oxford
Oxford
OX3 0DF
United Kingdom
+44 (0)1865 225256
najib.rahman@ndm.ox.ac.uk
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
2.1
Study information
Scientific title
Acronym
Study hypothesis
The hypothesis that forms the basis for this study is that the intrapleural administration of lipoteichoic acid-T (LTAT-T) could reduce the recurrence of malignant pleural effusion and thereby alleviate a significant cause of morbidity in metastatic solid malignancies. The mechanism by which this might occur is not fully elucidated.
Pleural infection is characterised by fibrotic obliteration of the pleural cavity (pleurodesis) during an indolent illness, and therapeutic replication of this response could produce a clinically effective pleurodesis. Gram positive pathogens are immunologically recognised by the binding of their cell wall motifs to toll-like receptors (TLRs) on the cell surface. One such motif is LTA-T, which mediates its effects through TLRs.
We hypothesised that LTA-T may be capable of inducing a therapeutically effective pleurodesis for the control of malignant pleural effusion. We have performed a dose escalation study to assess the toxicity/tolerability of LTA-T administered into the pleural space, and to produce preliminary data assessing potential pleurodesis efficacy.
The purpose of this study is to confirm the favourable safety profile of LTA-T when administered intrapleurally and to define a maximum tolerated dose.
Ethics approval
Ethics approval received from the Central Oxford Research Ethics Committee in July 2004 (ref: 04/Q1606/53).
Study design
Single centre, open label phase I toxicity trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Malignant pleural effusion
Intervention
An indwelling pleural catheter (PleurX, Denver, Colorado) was placed in the pleural effusion and the pleural space fully drained. After initial complete fluid drainage, 30 ml intra-pleural saline (saline control) was administered (day 1). The daily pleural fluid drainage was then recorded for seven days to quantify the rate of production of pleural fluid. On day seven, subjects received a single intra-pleural injection of LTA-T, according to an escalating dosing schedule. Over the next 7 days (days 7 - 14), daily pleural fluid volume drainage and pleural fluid cytology for malignant cells was performed unless pleural fluid flow ceased. On day 14, the intra-pleural catheter was flushed and closed (but left in situ) and not used again for the duration of the study unless recurrent pleural fluid caused dyspnoea.
The starting dose of LTA-T was 250 µg, with three patients planned at each dose and an increase in dose determined by side effects seen in these patients.
Intervention type
Drug
Phase
Phase I
Drug names
Lipoteichoic acid-T (LTA-T, Oncomycin™)
Primary outcome measures
Adverse events (phase I toxicity trial), measured over the entire course of the study (i.e 12 weeks).
Secondary outcome measures
1. To compare the daily production of pleural fluid over days 5 to 10 after administration
of intra-pleural LTA-T with that of the previous five days after the administration of intra-pleural saline, compared from week 1 (saline control) to week 2 (LTA-T)
2. To define the time to symptomatic pleural effusion recurrence - 'pleurodesis failure' following LTA-T administration and to estimate by comparison with the published time to recurrence after simple drainage, whether LTA-T reduces the requirement for later pleural effusion drainage, assessed at 1 month
3. To assess whether intra-pleural LTA-T alters the presence of cancer cells in drained pleural fluid and whether it induces a cellular inflammatory pleural fluid response, assessed at 2 weeks and whenever fluid available subsequently
4. To assess whether intra-pleural LTA-T influences the levels of pleural fluid cytokines known to be associated with pleural fluid production, assessed post LTAT administration (3 days)
Overall trial start date
09/11/2004
Overall trial end date
24/11/2005
Reason abandoned
Eligibility
Participant inclusion criteria
1. Aged greater than or equal to 18 years, either sex
2. Histocytologically proven malignant pleural effusion
3. A Karnofsky Performance Status of greater than or equal to 60%
4. Life expectancy of more than three months
5. Written informed consent
6. Participants were required to be willing and able to comply with the protocol
7. Participants who were at least 4 weeks from their last chemotherapy cycle
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Unknown initially as dose finding study - 14 patients recruited in total
Participant exclusion criteria
1. Serious uncontrolled intercurrent infection
2. Proven infection in this episode of pleural effusion
3. Any bleeding diathesis such that chest tube insertion would be hazardous
4. Previous surgical pleurodesis for this pleural effusion
5. Any of the following abnormal laboratory results:
5.1. Haemoglobin less than 8 g/dl (correction by transfusion allowed)
5.2. Neutrophils less than 2.0 x10^9/l
5.3. Platelet count less than 100 x 10^9/l
5.4. Serum creatinine greater than 3 x upper normal limit
5.5. Serum bilirubin greater than 5 x upper normal limit
5.6. Alanine transaminase or aspartate aminotransferase greater than 5 x upper normal limit
6. A known sensitivity to lipoteichoic acid (LTA-T)
7. If female patients were pregnant or lactating; to include all women of childbearing potential unless using a reliable and appropriate contraceptive method was used and a negative pregnancy test was confirmed
8. Any patient with organ allografts, significant cardiac disease, uncontrolled seizures, central nervous system disorders or psychiatric disability
9. Participation in any other investigational drug study within 4 weeks
10. Living too far from the study centre to attend for study follow up
Recruitment start date
09/11/2004
Recruitment end date
24/11/2005
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Oxford Respiratory Trials Unit
Oxford
OX3 0DF
United Kingdom
Sponsor information
Organisation
Oxford University (UK)
Sponsor details
Clinical Trials Research and Governance
Manor House
John Radcliffe Hospital
Headington
Oxford
OX3 9DU
United Kingdom
Heather.House@admin.ox.ac.uk
Sponsor type
University/education
Website
Funders
Funder type
Other
Funder name
Lunamed AG (Switzerland) - unrestricted grant
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
National Institute for Health Research (NIHR) (UK) - Biomedical Research Centre Programme (salary for Chief Investigator)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
The funders had no role or influence on the study design, analysis or execution.
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Results - basic reporting
Publication summary
1. 2008 results in http://www.ncbi.nlm.nih.gov/pubmed/18775668
Publication citations
-
Results
Rahman NM, Davies HE, Salzberg M, Truog P, Midgely R, Kerr D, Clelland C, Hedley EL, Lee YC, Davies RJ, Use of lipoteichoic acid-T for pleurodesis in malignant pleural effusion: a phase I toxicity and dose-escalation study., Lancet Oncol., 2008, 9, 10, 946-952, doi: 10.1016/S1470-2045(08)70205-5.