Clinical Trial Results:
Bendamustine and Rituximab for the treatment of Splenic Marginal Zone Lymphoma. The IELSG-36 phase II prospective study.
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Summary
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EudraCT number |
2011-000880-28 |
Trial protocol |
IT |
Global end of trial date |
30 Dec 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
11 Jan 2022
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First version publication date |
11 Jan 2022
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Other versions |
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Summary report(s) |
Synopsis IELSG36 |
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 |
IELSG36
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02853370 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
International Extranodal Lymphoma Study Group (IELSG)
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Sponsor organisation address |
Ospedale Regionale di Bellinzona e Valli, Via A. Gallino, Bellinzona, Switzerland, 6500
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Public contact |
Segreteria Amministrativa, Fondazione Italiana Linfomi ONLUS, +39 0131/206071, segreteria@filinf.it
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Scientific contact |
Segreteria Amministrativa, Fondazione Italiana Linfomi ONLUS, +39 0131/206071, segreteria@filinf.it
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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 |
20 Sep 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Dec 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Dec 2020
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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 |
Evaluation of the efficacy of Rituximab-Bendamustine measured by Complete Response rate in symptomatic splenic marginal zone lymphoma patients.
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Protection of trial subjects |
Guidelines for dose modifications, treatment delays and restart were included in the study protocol, in order to minimize any possible risks for the patients
All supportive therapies other than anti-cancer treatment needed for the management of patients enrolled in this study were permitted.
The following medications and support therapies may be used if needed during this study:
- Prophylaxis with levofloxacine or ciprofloxacine and fluconazole/itraconazole in case of neutropenia <1.000/mm3.
- Platelets and red blood cell transfusion were allowed, if needed, in case of Hb <8 g/dl or Plt <10.000/mm3.
-Erytropoietin therapy was allowed according to ASH/ASCO guidelines.
- G-CSF or PegG-CSF was allowed according to primary physician decision.
- Immunoglobulin assay was advised during induction therapy and follow-up; immunoglobulin replacement therapy was advised in case of IgG level <0.3-0.5 gr/dl and frequent infectious events.
-Premedication for rituximab infusion with paracetamol and diphenhydramine was suggested before each infusion of rituximab, because it might reduce infusion reactions.
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Background therapy |
Patients received prophylactic treatment with valciclovir 500 mg/d and trimetroprim/Cotrimoxazole double strengths (one tablet twice daily, given three times per week ) until completion of the last Rituximab-Bendamustine cycle. In patients HBcAb+, prophylaxis against hepatitis B reactivation with Lamivudine 100 mg/die from the start of the treatment to one year after the end of the treatment. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Dec 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
France: 27
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Country: Number of subjects enrolled |
Italy: 51
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Worldwide total number of subjects |
78
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EEA total number of subjects |
78
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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) |
30
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From 65 to 84 years |
47
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85 years and over |
1
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Recruitment
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Recruitment details |
Recruitment lasted from 03 December 2021 to 13 November 2014 | ||||||||||||||||||
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Pre-assignment
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Screening details |
78 patients were screened and 56 patients were eligible: 16 patients were uneligible for unconfirmed diagnosis of SMZL, 3 for age >80 years, 1 for withdrawal of the Informed Consent, 1 for treatment not started and 1 urgent treatment needed. | ||||||||||||||||||
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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 | ||||||||||||||||||
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Arms
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Arm title
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Arm 1 | ||||||||||||||||||
Arm description |
All patients treated with Rituximab and Bendamustine | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Rituximab
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Investigational medicinal product code |
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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 |
Patients were treted with 375 mg/sqm on day 1 of 28 days cycles .
Patients were treated with 3 cycles of Rituximab-Bendamustine (R-B) and then restaged.
If in PR patients proceeded to the next extended phase with 3 more R-B cycles. If in CR only one more R-B cycle was be delivered.
Patients with clinical response less than PR went go off the study.
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Investigational medicinal product name |
Bendamustine Hydrochloride
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients were treted with Bendamustine 90 mg/sqm on days 1-2 or days 2-3 of 28 days cycles .
Patients were treated with 3 cycles of Rituximab-Bendamustine (R-B) and then restaged.
If in PR patients proceeded to the next extended phase with 3 more R-B cycles. If in CR only one more R-B cycle was delivered.
Patients with clinical response less than PR went off the study.
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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: Seventy-eight patients were enrolled in the trial, but only 56 were eligible. |
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Baseline characteristics reporting groups
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Reporting group title |
Arm 1
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Reporting group description |
All patients treated with Rituximab and Bendamustine | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm 1
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Reporting group description |
All patients treated with Rituximab and Bendamustine | ||
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End point title |
Complete Response Rate [1] | ||||||||
End point description |
Complete response rate to be be assessed by means of CT-scan, Immunophenotype in blood and bone marrow (PET-scan optional)
Complete response (CR) requires the disappearance of all evidence of disease
a. Regression to normal size on CT of organomegaly (splenomegaly, hepatomegaly and lymphoadenopathies)
b. Normalization of the blood counts (Hb >12 g/dl; platelets >100.000/mm3; neutrophils >1.500/mm3 and no evidence of circulating clonal B-cells)
c. No evidence or minor (<5%) BM infiltration detected by immunohistochemistry
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End point type |
Primary
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End point timeframe |
After Cycle 3 and at the end of treatment
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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: Sample size was calculated with a reference CRR of 60% (p0) and an alternative CRR of 80% (p1), an alpha error of 0.05 (two sided) and a power of 0.9. A sample size of 53 evaluable patients was needed. According to Simon’s optimal two-stage design, the alternative hypothesis would have been considered not reached if ≤12 CR were observed in the first 19 cases (stage1) or ≤37 CR were observed in the 53 evaluable cases (stage 2). |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Response rate (ORR) | ||||||||
End point description |
Complete response + Partial Response
Partial response (PR) requires regression of 50% or greater in the measurable disease manifestations and no new sites of disease. This should include: resolution or decrease in spleen size, improvement on cytopenias and resolution or decrease in lymphadenopathy if present. Bone Marrow should show a decrease in the level of lymphoid infiltration and improvement of the haemopoietic reserve
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End point type |
Secondary
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End point timeframe |
After cycle 3 and at the end of treatment
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| No statistical analyses for this end point | |||||||||
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End point title |
3-year Progression Free Survival (PFS) | ||||||||
End point description |
PFS was measured from time of study entry until lymphoma relapse/progression, or death from any cause
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End point type |
Secondary
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End point timeframe |
From study entry until 3 years after
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| No statistical analyses for this end point | |||||||||
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End point title |
3-years Duration of Response (DOR) | ||||||||
End point description |
DOR was measured from time of documentation of tumour response to disease progression
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End point type |
Secondary
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End point timeframe |
From the first documented response to the first documented progression/relapse until 3 years from study entry
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| No statistical analyses for this end point | |||||||||
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End point title |
3-years Event Free Survival (EFS) | ||||||||
End point description |
EFS is measured from time of study entry until any treatment failure, including disease progression/relapse, histological transformation or initiation of new anti-lymphoma therapy or death from any cause
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End point type |
Secondary
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End point timeframe |
From study entry until 3 years after
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| No statistical analyses for this end point | |||||||||
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End point title |
3-years Overall Survival Rate | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3 years from treatment start
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| No statistical analyses for this end point | |||||||||
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End point title |
5 years Progression Free Survival (PFS) | ||||||||
End point description |
PFS was measured from time of study entry until lymphoma relapse/progression, or death from any cause
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End point type |
Secondary
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End point timeframe |
From study entryt until five years after
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| No statistical analyses for this end point | |||||||||
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End point title |
5 years Overall Survival (OS) | ||||||||
End point description |
OS was measured from the date of protocol treatment start until date of death irrespective of cause
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End point type |
Secondary
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End point timeframe |
From the date of protocol treatment start until five years after
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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 |
From the date of informed consent signature until 30 days after end of treatment
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
5.1
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Reporting groups
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Reporting group title |
Safety Population
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Reporting group description |
All patients who have received at least one dose of treatment will be considered as Safety Population | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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15 May 2012 |
This was an administrative amendment and its main purpose was to include the cooperative group LYSA, born in February 2012 from the fusion of two research groups that had already been working for several decades, the GELA (the Adult Lymphoma Study Group) and the GOELAMS (Groupe Ouest-Est d’etudes des Leucémies Aigues et autres Maladies du Sang |
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04 Jul 2012 |
The main purpose of this amendment was to add :
- adequate methods of contraception in the inclusion criteria;
- major surgery and renal impairement in the exclusion criteria;
- allopurinol and vaccination against yellow fever as prohibited concomitant medications; |
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06 Jun 2013 |
This amendment was issued to implement several changes:
1. Inclusion of additional tests (blood and bone marrow samples) after cycle 3, 4, 6 and during follow-up for MRD assessment.
2. Detailed description of the central review of the diagnosis
3. Change of contact of safety officer and inclusion of an appendix on procedures for reporting SAE/AE/SUSAR.
4. Additional Appendix detailing the management of AEs related to progressive multifocal leukoencephalopathy (PML) occurring in patients treated with anti-CD20 including rituximab.
5. Appendix containing guidelines for the use of granulocyte colony-stimulating factor.
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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. | |||
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