Clinical Trial Results:
A Phase II Single Arm Study of the use of CODOX-M/IVAC with Rituximab (R-CODOX-M/IVAC) in the treatment of patients with Diffuse Large B-Cell Lymphoma (DLBCL) or Burkitt's Lymphoma (BL) of International Prognostic Index (IPI) High or High-Intermediate Risk
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Summary
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EudraCT number |
2005-003479-19 |
Trial protocol |
GB |
Global end of trial date |
26 May 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Jan 2020
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First version publication date |
03 Jan 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/05/134
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT00974792 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University College London
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Sponsor organisation address |
Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
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Public contact |
Public Contact, Cancer Research UK & UCL Cancer Trials Centre, ctc.sponsor@ucl.ac.uk
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Scientific contact |
Scientific Contact, Cancer Research UK & UCL Cancer Trials Centre, ctc.sponsor@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 |
03 Dec 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 |
26 May 2016
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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 |
Does the combination of Rituximab and CODOX-M/IVAC improve the progression free survival in patients with newly diagnosed diffuse large B cell lymphoma or Burkitt's lymphoma of international prognostic index high or high-intermediate risk?
Caveats
AEs: Only events experienced by 5% or more patients are given.
Relationships are to R-CODOX-M/R-IVAC treatment (i.e. any IMP)
Non-serious AEs:
• Non-serious adverse events includes both serious and non-serious events. Only grade 3+ events given.
• Some terms were not recorded as per CTCAE so e.g. “Neurological - NOS” so could not be categorised any further.
• The total number of events is the number of patients experiencing an event as only worst grades were reported
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Protection of trial subjects |
CODOX-M/IVAC had previously been given to patients with Burkitt lymphoma and it was suggested that DLBCL patients would do better with the more intense regimen. Rituximab was added as it was unlikely to alter the toxicity but could improve responses.
Etoposide was used outside its licensed indication (testicular tumour, small cell lung cancer and monoblastic leukaemia). Drug accountability logs were kept by sites, and sent to UCL CTC on request. Though DLBCL is not listed as an indication for etoposide in the SmPC, more than a dozen published clinical trials have used this drug in the treatment of DLBCL patients. Only investigators/nurses experienced in using these IMPs according to the protocol were delegated treatment responsibilities. IDMC committee met at least annually to review safety data.
Patients were closely monitored for toxicity and the protocol detailed non-haematological toxicity dose modifications.
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Background therapy |
Leucovorin (15mg/m^2, IV) was administered as part of the R-CODOX-M regimen. It was administered at hour 36 and then every three hours until hour 48. From then it was administered every 6 hours until methotrexate level was below 5x10^-8M. Patients also received Mesna as part of the R-IVAC regimen on days 1-5. Intravenous Mesna 300mg/m^2 was administered mixed with ifosfamide (1.5g/m^2) over a one hour period. Co-trimoxazole 480mg (PO) was administered twice daily on Mondays, Wednesdays and Fridays during treatment and for six months post therapy. Mouth care, antacids and anti-emetics were given according to local protocols. The suggested regimen was: Corsdyl 5ml qd mouthwash; Acyclovir 200mg qd or 400mg bd; lansoprazole 30mg od (po); metoclompramide 10mg tds for 3 days. Radiotherapy was permitted in specific situations and the protocol detailed guidance on CNS prophlyaxis and treatment, and post-treatment neutropenia. | ||
Evidence for comparator |
This trial was a single arm study and therefore no comparator was used. | ||
Actual start date of recruitment |
05 Dec 2007
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy | ||
Long term follow-up duration |
5 Years | ||
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: 150
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Worldwide total number of subjects |
150
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EEA total number of subjects |
150
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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) |
0
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Adults (18-64 years) |
146
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From 65 to 84 years |
4
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85 years and over |
0
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Recruitment
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Recruitment details |
The first site opened on the 5th December 2007 and the first patient was recruited on the 21st May 2008. Recruitment completed on the 2nd April 2013 with a total of 150 patients recruited to the trial. A total of 52 sites participated in the trial, 36 sites recruited patients and 16 sites did not recruit any patients. | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
No screening information to provide for this trial. Patients were screened for eligibility for inclusion into the trial as per trial protocol. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Main trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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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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CODOX-M/IVAC with Rituximab | ||||||||||||||||||||||||||||||
Arm description |
A phase II single arm study of the use of CODOX-M/IVAC with rituximab (R-CODOX-M/IVAC) in the treatment of patients with diffuse large B-cell lymphoma DLBCL) or Burkitt's lymphoma (BL) of international Prognostic Index (PI) high or high intermediate risk. Efficacy, compliance and Baseline tables are given for eligible patients only (N=27 BL and N=111). Toxicity is given for all patients who started treatment (N=145) | ||||||||||||||||||||||||||||||
Arm type |
Single | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Rituximab
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Investigational medicinal product code |
L01XC02
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Other name |
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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 |
Four 375mg/m2 IV doses of rituximab given with 2 cycles of CODOX-M on Day 1 and Day 11, and two IV 375mg/m2 doses of rituxmimab given with 2 cycles of IVAC on Day 1. Two further IV doses of rituximab given on Day 21 and Day 42 after day one of the final course of IVAC.
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Investigational medicinal product name |
Cyclophoshamide
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Investigational medicinal product code |
L01AA01
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Other name |
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Cyclophosphamide given IV on Day 1 800mg/m2 and Day 2-5 200mg/m2 daily of CODOX-M treatment.
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Investigational medicinal product name |
Vincristine
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Investigational medicinal product code |
L01C A02
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Given IV on Day 1 1.5mg/m2 (max 2mg) and Day 8 1.5mg/m2 (max 2mg) of CODOX-M.
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Investigational medicinal product name |
Doxorubicin
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Investigational medicinal product code |
L01DB01
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
40mg/m2 given IV on Day 1 of CODOX-M.
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Investigational medicinal product name |
Cytarabine
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Investigational medicinal product code |
L01BC01
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intrathecal use, Intravenous use
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Dosage and administration details |
Given on Day 2 70mg intrathecal, Day 4 70mg intrathecal, Day 6 (for patients with proven or suspected CNS disease) 70mg intrathecal of CODOX-M.
For IVAC - given on Day 1 & 2 2g/m2 IV over 3 hours, 12 hourly total of 4 doses; Day 7 (for patients with proved or suspected CNS disease) 70mg intrathecal; Day 9 (for patients with proven or suspected CNS disease) 70mg intrathecal.
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Investigational medicinal product name |
Methotrexate
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Investigational medicinal product code |
L01BA01
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
For R-CODOX-M: Given on Day 10 300mg/m2 IV for 1 hour and 2700mg/m2 IV given over 23 hours. It was given on Day 15 12mg intrathecal and Day 17 (for patients with proven or suspected CNS disease) 12mg intrathecal.
For IVAC: Given on day 5 12mg intrathecal.
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Investigational medicinal product name |
Etoposide
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Investigational medicinal product code |
L01CB01
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
For IVAC: Days 1-5 etoposide 60mg/m2 IV (in 500ml of N. saline or 5% dextrose) daily over 1 hour.
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Investigational medicinal product name |
Ifosfamide
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Investigational medicinal product code |
L01AA06
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
For IVAC: Day 1-5 Ifosfamide IV 1.5g/m2 daily over an hour.
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Investigational medicinal product name |
Pegylated G-CSF
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Investigational medicinal product code |
L03AA13
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Other name |
Neulasta
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
For R-CODOX-M: Day 13 Neulasta 6mg subcutaneous
For IVAC: Day 7 Neulasta 6mg subcutaneous
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Baseline characteristics reporting groups
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Reporting group title |
CODOX-M/IVAC with Rituximab
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Reporting group description |
A phase II single arm study of the use of CODOX-M/IVAC with rituximab (R-CODOX-M/IVAC) in the treatment of patients with diffuse large B-cell lymphoma DLBCL) or Burkitt's lymphoma (BL) of international Prognostic Index (PI) high or high intermediate risk. Efficacy, compliance and Baseline tables are given for eligible patients only (N=27 BL and N=111). Toxicity is given for all patients who started treatment (N=145) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
CODOX-M/IVAC with Rituximab
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Reporting group description |
A phase II single arm study of the use of CODOX-M/IVAC with rituximab (R-CODOX-M/IVAC) in the treatment of patients with diffuse large B-cell lymphoma DLBCL) or Burkitt's lymphoma (BL) of international Prognostic Index (PI) high or high intermediate risk. Efficacy, compliance and Baseline tables are given for eligible patients only (N=27 BL and N=111). Toxicity is given for all patients who started treatment (N=145) | ||
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End point title |
Progression-free survival (BL) [1] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
2 years from time of registration
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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: No statistical test for this endpoint, the historical rate was compared to the 2 year PFS found and its confidence interval. |
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Attachments |
PFS KM curve BL all |
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| Notes [2] - BL cohort only |
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression Free Survival (DLBCL) [3] | ||||||||
End point description |
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End point type |
Primary
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End point timeframe |
2 years from ranomisation
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| Notes [3] - 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: No statistical test for this endpoint, the historical rate was compared to the 2 year PFS found and its confidence interval. |
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Attachments |
PFS KM curve DLBCL all |
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| Notes [4] - DLBCL cohort only |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival (BL) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 years
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Attachments |
OS KM curve BL all |
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| Notes [5] - BL cohort only |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival (DLBCL) | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 years
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| Notes [6] - DLBCL cohort only |
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| No statistical analyses for this end point | |||||||||
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End point title |
Response (BL) | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
End of treatment
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| Notes [7] - BL cohort only |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Response (DLBCL) | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
end of treatment
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| Notes [8] - DLBCL who started treatment only |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Treatment compliance (BL) | ||||||||||||||
End point description |
Numbers of patients who were given cycles 1-4
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End point type |
Secondary
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End point timeframe |
End of treatment
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| Notes [9] - BL cohort only |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Treatment Compliance (DLBCL) | ||||||||||||||
End point description |
Number of patients who were given each cycle
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End point type |
Secondary
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End point timeframe |
End of treatment
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| Notes [10] - DLBCL patients who started treatment only |
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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 |
All adverse events (AEs) that occur between informed consent and 30 days post treatment.
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Adverse event reporting additional description |
Patients were assessed for adverse events prior to each treatment cycle. Pre-existing conditions did not qualify as adverse events unless they worsened. Relationships are to R-CODOX-M R-IVAC treatment (i.e. counted as related if possibly, probably or definitely related to any IMP in the regimen). 145 out of 145 patients experienced at least one AE.
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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 |
3.0
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Reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
AEs are reported including both cohorts (DLBCL and BL). Both groups were given the trial treatment as per protocol; alternating CODOX-M/IVAC x 2 cycles + G-CSF, + rituximab x 8 doses, + cytarabine (4/7 doses), + methotrexate (4/5 doses). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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04 Jul 2006 |
An amendment to the protocol containing the following changes:
• For each of the IVAC courses the Depocyte is given on day 5 not on day 1
• Consequently Dexamethasone is moved to day 5-10 instead of day 1-5
• The Depocyte will be given on day 5 as a part of treatment of patients with CNS disease
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19 Oct 2006 |
The protocol was amended as follows:
• International Prognostic Index has replaced the Age Adjusted IPI in Appendix 1 and reference made to this changed throughout the protocol
• The Declaration of Helsinki was added, appendix 11
• Reference to Rasburicase removed
• Information on who will be supplying what drugs was added
• Rituximab amended to be given on day 11 as opposed to day 10
• Section on safety reporting has had additions made to it, providing more comprehensive information to sites as well as a flow diagram on assessing and notifying the Lymphoma Trials Office of events
• A reference has been removed
• Appendix 3 addition of information prophylaxis has been added
• Patient Information Sheet, reference to ‘age adjusted’ has been removed as well as reference to Rasburicase
• Consent form part I and II, reference to ‘age adjusted’ has been removed
• GP letter, reference to ‘age adjusted’ has been removed.
• Contact details have changed for Cathy Burton.
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28 Aug 2007 |
The protocol, PIS, consent form and GP letter were amended as below:
• International Prognostic Index replaced the Age Adjusted IPI in Appendix 1 and reference made to this was changed throughout the protocol
• The Declaration of Helsinki was added, appendix 11
• Reference to Rasburicase was removed
• Information on who will be supplying what drugs was added
• Rituximab was amended to be given on day 11 as opposed to day 10
• Section on safety reporting had additions made to it, providing more comprehensive information to sites as well as a flow diagram on assessing and notifying the Lymphoma Trials Office of events
• Pg 42, a reference was removed
• Appendix 3 addition of information on prophylaxis was added
• Patient Information Sheet reference to ‘age adjusted’ was removed as well as reference to Rasburicase
• Consent form part I and II reference to ‘age adjusted’ was removed
• GP letter reference to ‘age adjusted’ was removed
• Contact details changed for Cathy Burton |
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20 Aug 2008 |
An Urgent Safety Measure (USM) led to an amendment to the protocol, PIS and consent form. This was following a decision to remove Depocyte (liposomal cytarabine) from the protocol treatment schedule due to safety concerns over it's use with high dose chemotherapy, Depocyte was replaced in the protocol amendment with a proven safe and effective option.
The PIS was also amended to include an update to the the number of times patients would receive intrathecal treatment. |
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19 May 2009 |
The title of the study and the protocol was amended to include Burkitt's Lymphoma (BL). The decision to include BL patients into the trial was based upon published data which suggested promising results had been reported using CODOX-M/IVAC in this group of patients at the time.
The protocol amendment included:
• Change of primary outcome measure and endpoint to progression free survival
• More information given on non-haematological toxicity & dose modification (section 8.2)
• Statistical Consideration section was changed to reflect the change in endpoint and inclusion of Burkitt’s lymphoma patients (section 13)
• Additional information added to Appendix 5, recommending that Septrin be stopped once week prior to the administration of high dose methotrexate to avoid any potential drug reactions
• Appendix 6 included an extensive list of toxicities expected with chemotherapy drugs
• PIS , consent form and GP letter removed as appendices and provided as stand alone documents
• The inclusion of BL patients was added to the PIS and GP letter, the title of the consent form was changed on the consent form, GP letter and the PIS. The PIS was also updated to include the advice by Roche over the concern of patients developing Progressive Leukoencephalopathy (PML) having been treated with rituximab.
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09 Aug 2010 |
The protocol was amended to include the following changes:
• Change of protocol cover page and authorisation signature page
• Additional information to the site selection section (section 3.0)
• Addition of a section on Informed consent (section 4.0)
• Change in the patient selection section; baseline investigations and eligibility criteria. Maximum age of inclusion was increased from 60 years as stated in the original application to 65 years of age. Echocardiogram or nuclear medicine scan (MUGA) was made mandatory for patients aged from 61 to 65 years. (sections 5.1 and 5.3.1)
• Addition of sections on pregnancy /birth control and long term infertility (sections 5.3.3 and 5.3.4)
• Additional sections on trial monitoring and oversight, withdrawal of patients and trial closure (sections 14.0, 15.0 & 16.0,)
• Additional information to the ethical and regulatory approvals section (section 18.0)
• Additional sections on sponsorship & indemnity, funding and publication policy (section 19.0, 20.0 and 21.0)
• Removal of the expected toxicities for each chemotherapy drug from the appendix, and the addition of expected adverse events for the treatment regimen. The expected adverse events for each drug will be based on the individual SmPCs (appendix 9)
The PIS and consent form were also updated to reflect the changes to the protocol. |
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28 Jan 2011 |
The protocol was amended following an urgent safety measure (USM) which lead to amending the treatment schedule so vincristine was no longer scheduled on the same day as the intrathecal drugs. |
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06 Jun 2011 |
The protocol was amended to include:
• Update of the Trial Synopsis to include patients with positive serology for HIV
• Inclusion of a section on the training requirements for site staff
• Additional information for patients pre-treated with steroids
• Addition of patients with positive serology for HIV with criteria to be satisfied in the ‘inclusion criteria’
• Addition of Neulasta to the list of IMPs as stated in the CT application
• Update of rituximab administration to fall in line with the information given in its SPC
• Update of the dose modification for renal impairment toxicity
• Update to the data management, pharmacovigilance, trial monitoring and oversight sections of the protocol
• Addition of a reference to the existing list
• Update to the appendix on Methotrexate administration and uroprotection
• Update to the appendix on protocol version history
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14 Oct 2015 |
The protocol was amended to clarify timelines for adverse event reporting. The wording was amended to state' adverse events that occur between informed consent and 30 days days post trial treatment must be recorded in the patient notes and the trial CRFs'. |
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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. | |||
| See 'general information about the trial' section. | |||
