Clinical Trial Results:
Phase II Study of Reduced Intensity Allogeneic Transplantation for Refractory Hodgkin Lymphoma
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Summary
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EudraCT number |
2008-004956-60 |
Trial protocol |
GB |
Global end of trial date |
02 Jul 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Dec 2020
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First version publication date |
19 Dec 2020
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
UCL/08/0121
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00908180 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University College London Cancer Trial Centre (UCL CTC)
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Sponsor organisation address |
90 Tottenham Court Road, London, United Kingdom, W1T 4TJ
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Public contact |
PAIReD Trial Coordinator, University College London & Cancer Trial Centre, +44 20 7679 9860, ctc.paired@ucl.ac.uk, +44 02076799283, ctc.paired@ucl.ac.uk
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Scientific contact |
PAIReD Trial Coordinator, University College London & Cancer Trial Centre, +44 20 7679 9860, ctc.paired@ucl.ac.uk, +44 02076799283, ctc.paired@ucl.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Nov 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Jul 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The trial objectives were to document the toxicity, feasibility and survival following reduced intensity transplantation from HLA-compatible sibling or unrelated donors in patients with primary refractory or relapsed refractory Hodgkin Lymphoma. More specifically, the trial included patients who were refractory to initial multi-agent induction or in first relapse and achieved <CR following salvage, but excluded those who havd progressive disease.
The primary end point was to assess progression free survival after reduced intensity allogeneic transplantation in a poor prognostic group of patients with Hodgkin lymphoma with persistent disease after treatment (either primary refractory or relapsed refractory disease).
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Protection of trial subjects |
Patients underwent screening evaluations to confirm eligibility for the trial, these included: medical history, biochemistry tests (liver and renal function), bone marrow, infection screening, imaging, and cardiac function assessment. The donor also had serology testing and HLA typing.
Patients were given appropriate anti-bacterial, anti-fungal and anti-viral drugs to minimise the infection risks. This was according to local policy. Prophylaxis against GVHD was stipulated in the protocol - Campath infusion on D-1 and cyclosporine.
All patients were assessed for toxicity and monitored regularly for adverse events.
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Background therapy |
Not applicable | ||
Evidence for comparator |
Not applicable- no comparator used | ||
Actual start date of recruitment |
19 Mar 2010
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 34
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Worldwide total number of subjects |
34
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EEA total number of subjects |
34
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
2
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Adults (18-64 years) |
32
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 32 patients were to be recruited over a period of 4 years. The 1st site was opened 19/03/2010 and the 1st patient recruited 14/05/2010. The trial recruited a total of 34 patients across 13 sites & closed to recruitment 13/02/2014. (2 ineligible and not transplanted,1 transplanted but with a mismatched donor, all 3 counted ineligible). | ||||||
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Pre-assignment
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Screening details |
A total of 18 patients failed screening for the study. The reason for screen failure are outlined below: Progressive disease=1 Patient death=2 Patient declined to enter trial=1 Complete remission=5 Absence of suitable donor=1 Patient referred to different hospital=2 Clinical decision=1 unable to arrange scan=1 private pt=2 previous HDT=2 | ||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||
Blinding implementation details |
Not applicable
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Arms
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Arm title
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Safety & Efficacy Population | ||||||
Arm description |
34 patients were enrolled into the PAIReD trial and received conditioning with BEAm + Alemtuzumab (10mg/day for 5 days) with cyclosporine A as additional GVHD prophylaxis. DLI was used for the eradication of mixed chimerism and for the management of residual or relapsed disease. 3 patients were not included in the analysis as 2 patients were found to be ineligible and 1 patient was transplanted with a mismatch so not eligible. | ||||||
Arm type |
Safety & Efficacy | ||||||
Investigational medicinal product name |
Alemtuzumab
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
A dose of 10mg should be given IV on days –5 to –1 inclusive. Patients should be premedicated with methylprednisolone 2mg/kg IV prior to the first dose; paracetamol (1g po), pethidine (25mg iv) and chlorpheniramine (10 mg iv) may also be required. During the first dose, the rate of infusion should be incrementally increased according to local policy or as follows: 1mg/h for 1st hour, 2mg/h for 2nd and 3rd hours, 3mg/h for 4th and subsequent hours.
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Investigational medicinal product name |
Carmustine
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Investigational medicinal product code |
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Other name |
BiCNU, BCNU
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Pharmaceutical forms |
Powder and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
300mg/m2 should be given by IV infusion over a 1-2 hour period, on day –6.
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Investigational medicinal product name |
Melphalan
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Investigational medicinal product code |
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Other name |
Alkeran
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Pharmaceutical forms |
Powder for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
140mg/m2 IV on day –1. It is recommended that melphalan Injection solution is injected slowly into a fast-running infusion solution via a swabbed injection port. If direct injection into a fast-running infusion is not appropriate, melphalan administered diluted in an infusion bag.
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Investigational medicinal product name |
Cytarabine
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Investigational medicinal product code |
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Other name |
Cytarabine, Cytosine arabinoside, Cytosar-U, Tarabine
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Pharmaceutical forms |
Solution for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
A dose of 200 mg/m2 should be given IV twice daily (12 hourly over 15 mins) on days –5 to –2 inclusive. Water for injection, sodium chloride 0.9% or 5% dextrose are commonly used infusion fluids for Cytarabine.
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Investigational medicinal product name |
Etoposide
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Investigational medicinal product code |
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Other name |
Etopophos, Vepesid, Etoposide phosphate, Eposin, Vepesid, VP-16
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
A dose of 200 mg/m2 should be given IV on days –5 to –2 inclusive. Etoposide should not be used without diluting. It should be diluted with sodium chloride 0.9% or 5% dextrose. Solutions showing any signs of precipitation should not be used.
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Investigational medicinal product name |
Lomustine
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Investigational medicinal product code |
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Other name |
CCNU
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Pharmaceutical forms |
Capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Lomustine should be given by mouth at a dose of 200mg/m2 on day –6, if carmustine is unavailable.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 3 patients were not included in the analysis as 2 patients were found to be ineligible and 1 patient was transplanted with a mismatch so not eligible |
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial (overall period)
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Reporting group description |
34 patients were enrolled into the PIAReD trial and received conditioning with BEAM + Alemtuzumab ( 10 mg/day for 5 days) with cyclosporine A as additional GvHD prophylaxis. DLI was used for the eradication of mixed chimerism and for the management of residual or relapsed disease. 3 patients were not included in the analysis as 2 patients were found to be ineligible and 1 patient was transplanted with a mismatch so not eligible. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety and Efficacy Population
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
This subject population represents the whole trial population excluding 3 patients: 2 patients were found to be ineligible and excluded. These 2 patients were not transplanted. 1 patient was transplanted with a mismatched donor so he/she was excluded from all analyses.
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End points reporting groups
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Reporting group title |
Safety & Efficacy Population
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Reporting group description |
34 patients were enrolled into the PAIReD trial and received conditioning with BEAm + Alemtuzumab (10mg/day for 5 days) with cyclosporine A as additional GVHD prophylaxis. DLI was used for the eradication of mixed chimerism and for the management of residual or relapsed disease. 3 patients were not included in the analysis as 2 patients were found to be ineligible and 1 patient was transplanted with a mismatch so not eligible. | ||
Subject analysis set title |
Safety and Efficacy Population
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
This subject population represents the whole trial population excluding 3 patients: 2 patients were found to be ineligible and excluded. These 2 patients were not transplanted. 1 patient was transplanted with a mismatched donor so he/she was excluded from all analyses.
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End point title |
Progression Free Survival at 3 years [1] | |||||||||||||||
End point description |
The sample size was calculated using a Fleming design requiring 26 patients, but was inflated to 32 to allow for dropouts. Success was defined as 10 patients alive and progression free at 3 years. However, as 31 patients were recruited with no dropouts the primary analysis presented in the paper focused on the 3 year Kaplan-Meier rate presented with a 95% CI. This has also been added to these results.
This was a single arm design based on a number of “successes” i.e. patients alive and progression free at 3 years. No statistical analyses which generate p-values were performed.
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End point type |
Primary
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End point timeframe |
Progression Free Survival times were measured from the date of transplant until the date of the first event (progression or death from any cause). Patients not experiencing an event were censored at the date last seen. This is presented at 3 years.
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| 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: This was a single arm design based on a number of “successes” i.e. patients alive and progression free at 3 years. No statistical analyses which generate p-values were performed. |
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Attachments |
PFS all transplanted patients |
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| Notes [2] - First 26 patients: 19/26 alive and progression free. K-M rate (N=31): 67.7% (95% CI: 48.4 - 81.2) [3] - First 26 patients: 19/26 alive and progression free. K-M rate (N=31): 67.7% (95% CI: 48.4 - 81.2) |
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| No statistical analyses for this end point | ||||||||||||||||
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End point title |
Donor engraftment rates at day 100 | ||||||||||
End point description |
This is the number of patients who engrafted by D100. Patients were excluded if they died or progressed (N=4) before this time point.
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End point type |
Secondary
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End point timeframe |
Engraftment measured at day 100 post transplant
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| Notes [4] - Patients who died before D100 have been excluded (N=4) |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Cumulative incidence of non-relapse mortality at 3 years | ||||||||
End point description |
Cumulative incidence of Non Relapse Mortality is calculated using a competing risks model which treats relapse as a competing risk.
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End point type |
Secondary
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End point timeframe |
Non Relapse Mortality is presented at 3 years
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Attachments |
CI curve NRM |
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| No statistical analyses for this end point | |||||||||
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End point title |
Incidence, severity and timing of acute GvHD | ||||||||||||||
End point description |
The incidence, severity and timing of acute GvHD in the analysis population was calculated and presented.
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End point type |
Secondary
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End point timeframe |
Acute GvHD is measured within 100 days of transplant, patients who died before day 100 are excluded (N=4)
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| Notes [5] - Patients who died before day 100 have been excluded (N=4) |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Cumulative incidence of relapse | ||||||||
End point description |
The cumulative incidence of relapse is caculated treating death in remission as a competing risk.
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End point type |
Secondary
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End point timeframe |
The cumulative incidence of relapse is given at 3 years.
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Attachments |
CI relapse curve |
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| No statistical analyses for this end point | |||||||||
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End point title |
Response to donor lymphocyte infusions (DLI) | ||||||||||
End point description |
Patients were given DLI for mixed chimerism (MC) or residual disease/disease progression (PD). 10 patients were given DLI, 8 for MC and 2 for residual disease/progression. Data reported here are for MC only.
Patients treated for PD: 1 progressed further and was retreated with chemotherapy, the second was also given RT along with DLI. Both remain in remission.
One patient was reported to have DLI for MC but had also progressed. This patient went back into remission with DLI alone but still has MC.
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End point type |
Secondary
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End point timeframe |
Post transplant
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| Notes [6] - This is the 8 patients given DLI for MC |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Overall survival | ||||||||
End point description |
Overall survival was defined as time from registration to death from any cause. Patients who were still alive were censored at the time they were last known to be alive. An additional survival time calculated from time of admission for transplant to death from any cause was also calculated to account for patients who did not receive a transplant because of disease progression or an inability to collect stem cells.
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End point type |
Secondary
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End point timeframe |
Overall survival times were measured from the date of transplant until the date of death (any cause). Patients who were alive were censored at the date last seen. The Kaplan Meier rate was presented at 3 years.
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Attachments |
OS K-M curve |
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| No statistical analyses for this end point | |||||||||
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End point title |
Incidence, severity and timing of Chronic GvHD | ||||||||||||
End point description |
Incidence, severity and timing of Chronic GvHD
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End point type |
Secondary
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End point timeframe |
Chronic GvHD is measured post day 100, patients who died before day 100 were excluded (N=4)
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| Notes [7] - Patients who died before day 100 have been excluded (N=4) |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Between informed consent and 30 days post transplant (or after this date if the site investigator feels the event is related to the trial treatment).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4.0
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Reporting groups
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Reporting group title |
Transplanted patients
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Reporting group description |
All patients recruited into the PAIReD trial who have received a matched transplant | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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07 May 2010 |
Protocol amendment, Addition of pregnant partner consent form and information sheet, Change of contact person at UCL CTC. |
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02 Feb 2011 |
Submission of amended PIS (now v1.2-26jan11) |
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21 Nov 2011 |
Amended protoocl to v 3.0. Main changes:
• Patient population (section 2.2.4): The list of salvage regimens that a patient can have had before entering the trial has been relaxed to allow for differences in local practice.
• Patient population (section 2.2.4): clarification that ‘CR’ refers to ‘metabolic CR’.
• Patient population (section 2.2.4): removal of requirement for CT scans for re-evaluation of disease status.
• Trial design (section 2.2.5): clarification that an alternative regimen can be used for the second cycle of salvage chemotherapy, if required. Further clarification that patients in CR after any additional therapy are considered eligible, providing they fulfilled study eligibility criteria following the first 2 cycles of salvage.
• Site selection (section 3.1): Changed to reflect that mobile PET-CT scanners are now permitted for use in this trial.
• Appendix 6 – Assessment of GVHD: Insertion of text to state that reactions to DLI occurring at any time-point during the trial are defined as acute GVHD. |
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29 May 2012 |
Protocol amendment to v4.0 and Consent form to v2.0, PIS 11-15 – v1.0, PIS 16+ - v2.0, PIS parents – v1.0. Main changes:
- Changes to the inclusion criteria
- Sample size reduced from 47 to 32 patients
- Trial Objectives updated to incorporate patients in first relapse achieving <CR following salvage
- Detailed explanation of which patients will now be eligible for the trial
- Instructions regarding eligibility of primary refractory patients and patients in first relapse. Broadening of age range to allow patients >11 years of age to be recruited (previous lower age limit was >16 years of age).
- adding Republic of Ireland as a target country (previously trial was conducted only in the UK) |
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11 Feb 2013 |
Amendment of Patient Information sheets & consent forms. Main changes:
- Include the possibility of patient data being provided to a drug supplier after Genzyme Therapeutics surrendered the licence for Mabcampath (Alemtuzumab). This was not previously included in the patient information and consent as all drugs were previously sourced from hospital stock. |
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25 Oct 2013 |
Change of supply arrangements for Alemtuzumab:
Genzyme provided commercial stock Alemtuzumab free of charge for use in the PAIReD trial. When Genzyme surrendered the manufacturing authorisation for MabCampath (Alemtuzumab), there was no further commercial stock available for patients on the PAIReD trial. To ensure continued supply of the IMP , Genzyme have agreed to provide sites with MabCampath manufactured on their behalf by Boehringer Ingelheim for the remainder of the trial. The IMP will be labelled and distributed by Penn. The CTA was amended to reflect the updated arrangements. |
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29 Oct 2013 |
Amendment to protocol v5 to bring it in line with the sponsor's current protocol at that time and to reflect changes to the trial monitoring plan following aan update to the risk assessment of the trial in Nov 2012.
Reference Safety Information for the trial has changed: Appendix 4 which lists adverse events (AEs) expected for the treatment regimen, based on the clinical literature has been updated. The change was in response to discussions at the MHRA statutory GCP inspection of the UCL CTC in January 2013. Previously, the appendix 4 list of AEs expected for the treatment regimen was a generic list for transplants as a whole, and included AEs that were expected for combination conditioning chemotherapy regimens (including BEAM + Alemtuzumab, the regimen used in this trial), radiotherapy (TBI), and infused cells as a whole. This gave rise to concerns regarding a potential for under-reporting of SUSARs if AEs that were expected for the cells but not the drugs were classified as expected in line with the protocol appendix. The list in appendix 4 has been amended to remove any effects associated with total body irradiation, as it is not given as part of the transplant conditioning in this trial, and adverse events specifically associated with chemotherapy agents such as cyclophosphamide that are not used in the BEAM-Campath regimen. Expected AEs for transplanted cells were identified as exempt from SAE reporting. Details of complications of the stem cell infusion were collected as Urgent Events, to ensure the safety of the cell source continues to be assessed and recorded in the trial. Reported Serious Adverse Events not included in the list of AEs as expected for the chemotherapy conditioning continued to be assessed using the current SmPCs at that time for the individual IMPs. |
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15 Sep 2015 |
Change to the Reference Safety Information- New SPCs for Cytarabine, Etoposide and Carmustine |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| AEs&SAES:Only events experienced by>=5% patients given Relationships are to any IMP Nonserious AEs:all events reported as AEs presented (include some serious events) Total # of events:#patients experiencing an event as only worst grades reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/31869413 |
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