Clinical Trial Results:
A Phase II study of Gemcitabine and Bexarotene (GemBex) in the treatment of cutaneous T-cell lymphoma
|
Summary
|
|
EudraCT number |
2006-000591-33 |
Trial protocol |
GB |
Global end of trial date |
23 Jan 2014
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
22 Oct 2017
|
First version publication date |
22 Oct 2017
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
UCL/06/009
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
ISRCTN18563749 | ||
US NCT number |
NCT00660231 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
JRO, University College London
|
||
Sponsor organisation address |
Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
|
||
Public contact |
Public contact, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
|
||
Scientific contact |
Scientific contact, CRUK and UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
17 Oct 2013
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
23 Jan 2014
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The primary research question is to confirm the feasibility and efficacy of using a combination of Gemcitabine and Bexarotene for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have disease that is no longer controlled by skin-directed therapy and who have had at least one prior systemic therapy.
|
||
Protection of trial subjects |
The risks to the safety of the participants were those generally associated with chemotherapy treatment, including nausea, alopecia, myelotoxicity and potential cardiotoxicity with high dosage. Adverse events were monitored throughout treatment and for 30 days post treatment.
Bexarotene is also associated with lipid abnormalities; therefore patients were started on lipid-lowering therapy one week prior to the initiation of Bexarotene therapy and periodic monitoring was mandated to ensure lipid levels were adequate for patients to continue treatment. A corresponding schedule of permitted dose modifications was also provided with the aim of stabilizing lipid levels. Patients were asked to abstain from or minimise alcohol consumption during the course of treatment and to ensure they remained well-hydrated with a view to avoiding pancreatitis; which is an uncommon consequence of hyperlipidaemia.
Women who could become pregnant were informed that they must use two effective forms of contraception during the course of the study and for at least six months after stopping treatment; and male patients were informed that they must use barrier contraception throughout and for six months after stopping treatment; because treatment might interfere with normal functioning of the female egg or male sperm.
|
||
Background therapy |
Prophylactic oral fenofibrate 160mg – 200mg daily for 7 days before commencing cycle 1. | ||
Evidence for comparator |
N/A | ||
Actual start date of recruitment |
29 Jul 2008
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
United Kingdom: 36
|
||
Worldwide total number of subjects |
36
|
||
EEA total number of subjects |
36
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
19
|
||
From 65 to 84 years |
17
|
||
85 years and over |
0
|
||
|
|||||||||||
|
Recruitment
|
|||||||||||
Recruitment details |
First patient recruited: 29/07/2008 Last patient recruited: 25/03/2011 Recruiting sites: Christie Hospital, Guys and St. Thomas' Hospital, Leicester Royal Infirmary, Nottingham City Hospital, Royal Bournemouth General Hospital, St James's University Hospital, Royal Liverpool University Hospital, Royal Cornwall Hospital, St Bartholomew's Hospital | ||||||||||
|
Pre-assignment
|
|||||||||||
Screening details |
Patients were screened for eligibility for inclusion into the study | ||||||||||
|
Period 1
|
|||||||||||
Period 1 title |
Overall trial (overall period)
|
||||||||||
Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Non-randomised - controlled
|
||||||||||
Blinding used |
Not blinded | ||||||||||
|
Arms
|
|||||||||||
|
Arm title
|
GemBex | ||||||||||
Arm description |
Four cycles of Gemcitabine 1000 mg/m2 (at days 1 and 8 of 21 day cycles) Bexarotene 300 mg/m2 daily concurrently At 12 weeks responding patients maintained on Bexarotene 300 mg/m2 until disease progression or until the drug could no longer be tolerated NB: One patient was registered but found to be ineligible and did not commence trial treatment. | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
Gemcitabine Hydrochloride
|
||||||||||
Investigational medicinal product code |
L01BC05
|
||||||||||
Other name |
|||||||||||
Pharmaceutical forms |
Powder for solution for infusion
|
||||||||||
Routes of administration |
Intravenous use
|
||||||||||
Dosage and administration details |
1000 mg/m2 intravenously on day 1 and day 8 of 21 day cycles for a maximum of four cycles.
|
||||||||||
Investigational medicinal product name |
Bexarotene
|
||||||||||
Investigational medicinal product code |
L01XX25
|
||||||||||
Other name |
|||||||||||
Pharmaceutical forms |
Capsule, soft
|
||||||||||
Routes of administration |
Oral use
|
||||||||||
Dosage and administration details |
Given for 14 days orally at 150mg/m2 orally. If tolerated, increased to 300mg/m2 orally daily from days 15-84.
At 12 weeks responding patients maintained on 300mg/m2 orally daily until PD or until Bexarotene can no longer be tolerated.
|
||||||||||
|
|||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Overall trial (overall period)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
- Aged ≥ 18 years - Histologically confirmed diagnosis of CTCL, including mycosis fungoides and Sézary syndrome - CTCL stages Ib, IIa, IIb, III, IVa and IVb. - Failed standard skin-directed therapy and have had at least one course of prior systemic therapy, to which they have either failed to respond or have subsequently progressed - Bexarotene naïve or previous response to single-agent bexarotene, but ≥3 months since last treatment - No treatment for lymphoma in the 4 weeks prior to study entry (except patients on stable low dose steroids; local radiotherapy allowed until 2 weeks prior to study entry) - Life expectancy > 6 months - Written informed consent - ECOG performance status 0-1 - Adequate bone marrow, hepatic & pancreatic function - HIV negative - Not pregnant or breastfeeding - No coexistent or prior malignancy in 5 years prior to study entry | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
GemBex
|
||
Reporting group description |
Four cycles of Gemcitabine 1000 mg/m2 (at days 1 and 8 of 21 day cycles) Bexarotene 300 mg/m2 daily concurrently At 12 weeks responding patients maintained on Bexarotene 300 mg/m2 until disease progression or until the drug could no longer be tolerated NB: One patient was registered but found to be ineligible and did not commence trial treatment. | ||
|
|||||||||||||||||||
End point title |
Objective Response Rate [1] | ||||||||||||||||||
End point description |
Objective Primary Disease Response Evaluation Criteria (OPDREC) combines the disease response observed in skin, lymph nodes, viscera and blood to a global disease response category. To be defined as CCR, CR or PR, the response must be confirmed with a repeat assessment at least 1 month after the initial assessment.
|
||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||
End point timeframe |
The rate of objective response was assessed at 24 weeks, defined as the proportion of patients with confirmed CR, clinical complete response (CCR) or PR, as determined by OPDREC.
|
||||||||||||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Justification: As advised on 23/06/16 by Chersoni Raffaella from the EMA service desk, we can post the result without specifying details of the statistical analyses done because the system currently cannot accommodate one arm studies. |
|||||||||||||||||||
|
|||||||||||||||||||
| Notes [2] - All subjects were analysed with only 5 subjects reaching the end point definition |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||
End point title |
Reduction change from baseline in mSWAT score | ||||||
End point description |
Within 2 weeks of starting treatment, during the initial 12-week combination and subsequently at weeks 13, 17, and 24, and every 8 weeks thereafter, patients underwent various assessments including disease assessment using the modified Severity-Weighted Assessment Tool (mSWAT) score that represents the product of the percentage Total Body Surface Area (%TBSA) involvement of each lesion type multiplied by a weighting factor.
The Change from baseline in mSWAT score is defined as the difference in mSWAT score at the assessment time point and the score at baseline. A reduction in mSWAT at week 12 was observed in this group of patients. the data shows the number of patients with reduced mSWAT scores.
|
||||||
End point type |
Secondary
|
||||||
End point timeframe |
The modified Severity-Weighted Assessment Tool (mSWAT) scores used for this end point are those assessed at baseline and at week 12, end of combination treatment
|
||||||
|
|||||||
| No statistical analyses for this end point | |||||||
|
|||||||||
End point title |
Median Progression Free Survival | ||||||||
End point description |
Out of the 35 patients that were analysed, 30 had either died (n=15) or were alive with progression (n=15)
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Progression free survival (PFS) defined as the time from the first date of treatment to the date of first progression or death due to any cause, whichever one comes first.
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Median Overall Survival | ||||||||
End point description |
|||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Overall Survival (OS) defined as the time from the first date of treatment to the date of death due to any cause.
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
All adverse events that occurred between informed consent and 28 days post last trial treatment administration had to be reported
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Trial subjects were assessed for adverse events prior the start of each treatment cycle. All adverse events (AEs) were recorded in the patient notes and the trial CRFs. Those meeting the definition of SAEs were also reported using the trial specific SAE Reporting template.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
NCI - CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
3.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
GemBex
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Four cycles of Gemcitabine 1000 mg/m2 (at days 1 and 8 of 21 day cycles) Bexarotene 300 mg/m2 daily concurrently At 12 weeks responding patients maintained on Bexarotene 300 mg/m2 until disease progression or until the drug could no longer be tolerated NB: One patient was registered but found to be ineligible and did not commence trial treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
14 Feb 2007 |
The protocol was amended to use a more appropriate method of skin disease assessment known as the Severity Weighted Assessment Tool (SWAT). A Quality of Life Assessment was also added to the study as it is felt that Cutaneous T-Cell Lymphoma has a substantial impact on the quality of life of these patients due to the very nature of the disease. |
||
10 Aug 2007 |
The address of where to send histology specimens was changed in the protocol. Changes were also made to the PIS, Consent form and an additional appendix (addition of skindex).
The PIS was updated with additional information regarding patient anonymity when taking photographs of the disease and also included information on the use of photos for publication with consent, a statement was included asking for patient permission. Appendix 8 was been added to incorporate a QOL element to the study given the disease and the impact it's 'visability' can have on a patients physical and/or psychological wellbeing. |
||
20 Dec 2007 |
Several changes were made to the protocol to assist site staff with various aspects of the study including:
1. The assessment of patients using the Severity-Weighted Assessment Tool (SWAT) - Appendix 14 provided sites with a guide to skin scoring patients using SWAT
2. The updated guidelines for the management of patients who experienced hyperlipidamia prior and during Bexarotene therapy was added to section 6.3
3. The Safety Reporting section of the protocol was amended to provide sites with comprehensive information regarding the current regulatory requirements that were in place and how adverse events should have been assessed and reported. Two additional appendices were also added which detailed the expected adverse events that arose from treatment with Gemcitabine and Bexarotene. This information was compiled from the Summary of Product Characteristics available for both drugs. Information on Pregnancy was also added.
|
||
03 Dec 2008 |
Patient diary cards were introduced allowing clinicians give written instructions to the patient about the dose of bexarotene that they should take each day, and also to allow patients to record whether the full dose was taken each day. |
||
21 Jul 2009 |
Following the start of the trial, Bexarotene had become more widely used in standard clinical practise, including prolonged maintenance, therefore it was decided to bring the trial in line with standard clinical practice in terms of the duration of maintenance, and also in allowing patients previously treated with single agent Bexarotene to be entered into the trial. Various other practical issues arising from the first year of recruitment into the trial were also addressed.
o Bexarotene maintenance no longer stopped at week 20, but continued until the patient either had disease progression, or could no longer tolerate bexarotene
o Bone marrow aspirates /trephines and baseline chest x-ray were no longer required for the purposes of the trial
o CT scan was only required at end of chemo and maintenance if patient had an abnormal CT scan at baseline
o Photography requirements significantly reduced to baseline, end of combination chemo, week 24 and disease progression
o Rules governing concomitant use of steroids changed so patients on a stable, low dose of steroids were allowed to enter the trial
|
||
23 Jun 2010 |
An audit of the patient information sheet (PIS) showed that contraception guidelines given to patients in the PIS was not accurate thus leading to an Urgent Safety Measure being taken.
The Patient information sheet was updated advising patients to use adequate contraception during the duration of the study and for at least 6 months after stopping trial treatment (as suggested in the SmPC for Gemcitabine, which is one of the trial drugs for the study).
A paragraph justifying the need of using contraception and listing examples of reliable forms of contraception was also added.
The PIS was further modified to emphasise that the study doctor should be notified also in cases where a male trial patient’s partner became pregnant. |
||
02 Feb 2011 |
The Bexarotene labels were amended to comply with Annexe 13 and labelling exemption for Gemcitabine was proposed as it was provided from hospital stock. The sponsor believed it fell under the remit of Regulation 46(2) of the Medicines for Human Use (Clinical Trials) Regulations
|
||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Non serious AEs: 'occurrences all number' cannot be given as only highest grade experienced by patients were collected on CRFs; Subjects affected number is entered instead. Serious and non-serious AEs are listed under non-serious adverse events | |||
Online references |
|||
| http://www.ncbi.nlm.nih.gov/pubmed/24136145 |
|||
