Clinical Trial Results:
Reduced intensity conditioning with high-dose rituximab followed by allogeneic transplantation of hematopoietic cells for the treatment of relapsed/refractory B-cell non Hodgkin’s lymphomas
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Summary
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EudraCT number |
2007-003657-87 |
Trial protocol |
IT |
Global end of trial date |
02 Feb 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Dec 2021
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First version publication date |
13 Dec 2021
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Other versions |
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Summary report(s) |
Synopsis 3.0 |
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 |
BCNHL
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Additional study identifiers
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ISRCTN number |
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US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Fondazione IRCCS Istituto Nazionale Tumori
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Sponsor organisation address |
Via G. Venezian 1, Milano, Italy, 20133
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Public contact |
Anna Dodero MD, Fondazione IRCCS Istituto Nazionale dei Tumori, 0039 0223903146, anna.doder@istituttoumori.mi.it
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Scientific contact |
Anna Dodero MD, Fondazione IRCCS Istituto Nazionale dei Tumori, +39 0223902072, anna.dodero@istitutotumori.mi.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 |
03 Apr 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 Feb 2017
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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 |
Progression-free survival at one year
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Protection of trial subjects |
Not applicable to this patient's population
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Background therapy |
High-dose chemoradiotherapy and allogeneic stem cell transplantation (SCT)has been widely used for the treatment of several hematological tumors1. The procedure was originally proposed as a mean to escalate the doses of chemotherapy and radiation with bone marrow transplantation to restore hematopoiesis. Several lines of evidence indicate that conditioning regimen frequently does not eradicate the malignancy and an immune-mediated graft-versus-tumor effect is important to prevent disease relapse. The most direct demonstration of the graft-versus-leukemia (GVL) effect is the re-induction of complete remission (CR) by the infusion of donor lymphocytes (DLI) in patients who had relapsed after allogeneic stem cell transplantation. This GVL effect takes several weeks to occur after DLI and presumably requires the persistent engraftment of allogeneic effector cells. It has been shown that allogeneic SCT is an effective treatment for patients with relapsed/refractory lymphomas. Disease-free survivals (DFS) of 40-50% have been reported in relapsed low-grade lymphomas. A recent report describes the achievement of long-term clinical and molecular remissions after allogeneic SCT in patients with poor prognosis non-Hodgkin’s lymphoma. In addition, responses to donor lymphocyte infusions have been documented in patients with chronic lymphocytic leukemia and follicular lymphoma relapsing after allograft .This findings support the notion that allogeneic SCT is an effective salvage treatment and that immune-mediated killing of lymphoma cells is part of therapeutic effect . | ||
Evidence for comparator |
We previously evaluated a population of lymphoma patients transplanted form HLA matched sibling donors with the same conditioning regimen without Rituximab. In that old trial the incidence of acute was GVHD 35%, severe GVHD 14%, and of chronic was GVHD 49% (extensive GVHD 25%). | ||
Actual start date of recruitment |
31 Oct 2007
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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 |
Italy: 121
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Worldwide total number of subjects |
121
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EEA total number of subjects |
121
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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) |
121
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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 |
From Oct 2007 to Oct 2015, 121 patients were enrolled. The median age was 52 yrs. Diagnoses were de novo or transformed DLCBL, and indolent lymphomas. 67 out of 121 underwent tx form a related sibling and 54 received a graft from an unrelated donor. 12 patients had mismatches in class I and the rest in class II. Only 3/20 pts had mism. in locus C | ||||||
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Pre-assignment
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Screening details |
we excluded patients with diagnosis not included in the inclusion criteria | ||||||
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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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Single arm | ||||||
Arm description |
This is a single arm, prospective, phase II study investigating the effect of a single dose of rituximab in combination with a RIC regimen on PFS in refractory/relapsed B cell lymphomas. In addition, overall survival, incidence of acute and chronic GVHD, and GVHD-free relapse survival were evaluated. | ||||||
Arm type |
Experimental | ||||||
Investigational medicinal product name |
Rituximab
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Investigational medicinal product code |
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Other name |
Mabthera
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Pharmaceutical forms |
Solution for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Enrolled patients were treated with salvage rituximab chemotherapy at time of relapse. The choice of the salvage regimen was left to center preference. Then the patients received the folowing drug as conditioning regimen: rituximab (500 mg/m2, day -6), thiothepa (6 mg/kg every 12 hrs for 2 doses, day -5), cyclophophamide (30mg/kg, days -4 and -3), and fludarabine (30 mg/m2, days -4 and -3, administered 4 hrs after cyclophosphamide). The choice to administer one single dose of rituximab relies on the assumption that circulating CD20+ B cells of the recipient had already been depleted by rituximab-supplremented salvage chemo-immunotherapy, whereas pretransplantation rituximab will probably work largely by depleting the donor's alloreactive B cells.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
All patients
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Subject analysis set type |
Full analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
One hundred twenty-one patients with relapsed/refractory
lymphoma were enrolled in this multicenter, prospective,
phase II trial (refer to Table 1 for baseline characteristics of
patients). The median agewas 52 years (range, 24 to 65 years).
Diagnoses were de novo or transformed DLBCL (n = 35, of
which 2 transformed and 33 de novo), MCL (n = 22), and indolent
lymphomas (FL, n = 35; CLL/SLL, n = 29). Sixty-seven
out of 121 (55%) underwent transplantation from a relate dsibling (1 mismatched siblings in only 2 cases) and 54 (45%)
received a graft from an unrelated donor (34 matched, 20
mismatched). Twelve patients had mismatches in class I and
the rest had mismatches in class II. Interestingly, only 3 patients
out of 20 (15%) had antigenic mismatches at locus C.
It is important to note that most of the patients had a chemosensitive
disease (complete remission [CR], n = 48 [39%];
partial remission, n = 61 [51%]) at transplantation.
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End points reporting groups
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Reporting group title |
Single arm
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Reporting group description |
This is a single arm, prospective, phase II study investigating the effect of a single dose of rituximab in combination with a RIC regimen on PFS in refractory/relapsed B cell lymphomas. In addition, overall survival, incidence of acute and chronic GVHD, and GVHD-free relapse survival were evaluated. | ||
Subject analysis set title |
All patients
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
One hundred twenty-one patients with relapsed/refractory
lymphoma were enrolled in this multicenter, prospective,
phase II trial (refer to Table 1 for baseline characteristics of
patients). The median agewas 52 years (range, 24 to 65 years).
Diagnoses were de novo or transformed DLBCL (n = 35, of
which 2 transformed and 33 de novo), MCL (n = 22), and indolent
lymphomas (FL, n = 35; CLL/SLL, n = 29). Sixty-seven
out of 121 (55%) underwent transplantation from a relate dsibling (1 mismatched siblings in only 2 cases) and 54 (45%)
received a graft from an unrelated donor (34 matched, 20
mismatched). Twelve patients had mismatches in class I and
the rest had mismatches in class II. Interestingly, only 3 patients
out of 20 (15%) had antigenic mismatches at locus C.
It is important to note that most of the patients had a chemosensitive
disease (complete remission [CR], n = 48 [39%];
partial remission, n = 61 [51%]) at transplantation.
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End point title |
PFS | |||||||||
End point description |
Endpoint was 1 year progression free survival. We expected an improvement of 1 year PFS form 70% to 77%. To obtain this result, a total sample of 190 patients was required.
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End point type |
Primary
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End point timeframe |
at 3 years post transplant
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Statistical analysis title |
Statistical analysis plan | |||||||||
Statistical analysis description |
The incidence of NRM, relapse, and acute and chronic GVHD were estimated in a competing risks setting using cumulative incidence estimates and the curves were compared by means of the Gray test. In the estimation of GVHD, death without GVHD was evaluated as a competing event. NRM and relapse werecompeting events for each other [Gray RJ. A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141-1154]
We also tested the composite endpoint GRFS [
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Comparison groups |
Single arm v All patients
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Number of subjects included in analysis |
242
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | |||||||||
P-value |
> 0.05 [2] | |||||||||
Method |
t-test, 1-sided | |||||||||
Parameter type |
difference in PFS | |||||||||
Point estimate |
190
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Confidence interval |
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80% | |||||||||
sides |
1-sided
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lower limit |
70 | |||||||||
upper limit |
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Variability estimate |
Standard error of the mean
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| Notes [1] - no treatment effect on NRM and a 35% relative improvement of relapse rate (from 20% to 13%), at a significance level of 10% (1-sided test) a sample size of 190 assessable patients ensured a 80% probability of detecting a 70% to 77% increase in 1-year PFS. However, because of the expansion of trials incorporating novel agents and an increase of haploidentical donor use, the accrual rate decreased in the last 2 years and the data safety and monitoring committee suggested to stop [2] - no treatment effect on NRM and a 35% relative improvement of relapse rate (from 20% to 13%), at a significance level of 10% (1-sided test) a sample size of 190 assessable patients ensured a 80% probability of detecting a 70% to 77% increase in 1-y |
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End point title |
Incidence of acute graft-versus-host disease (aGVHD) within 100 days | ||||||
End point description |
Acute GVHD were estimated in a competing risks setting using cumulative incidence estimates and the curves were compared by means of the Gray test
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End point type |
Secondary
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End point timeframe |
100 days
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End point title |
Incidence of chronic graft-versus-host disease (cGVHD) within 100 days | |||||||||
End point description |
Chronic GVHD were estimated in a competing risks setting using cumulative incidence estimates and the curves were compared by means of the Gray test
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End point type |
Secondary
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End point timeframe |
Between 101 days and 3 years from allogenic transplantation
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End point title |
Nonrelapse mortality at one year | |||||||||
End point description |
The incidence of NRM was estimated in a competing risks setting using cumulative incidence estimates and the curves were compared by means of
the Gray test. Relapse was competing event for NRM.
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End point type |
Secondary
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End point timeframe |
One year from allogenic transplantation
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Adverse events information
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Timeframe for reporting adverse events |
Post transplantation toxicities were reported as infections or complications after engraftment.
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Assessment type |
Non-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 |
all patients
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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09 Feb 2009 |
Text changes
(New text in bold; deleted text in italics)
Synopsis “ IC”:pag.6 for identical sibling and age ≥ 18 ≤ 60 years in case of matched
unrelated donor;
Synopsis” IC” pag.6 Unrelated donor fully HLA matched at locus HLA-A, HLA-B, HLAC,
HLA-DRB1, HLA-DQB1 as evaluated by high resolution typing
Synopsis “TP” pag.7 Conditioning regimen for identical sibling or unrelated donor
Synopsis “TP”pag.7 Patients with related sibling with a class I antigen mismatch or
with unrelated donor will receive rabbit anti-thymocyte
globulin.(Thymoglobuline 3.5 mg/kg daily on days – 4 and – 3)
“Rationale ” pag.9 Treatment-related mortality and survival, for recipients of unrelated grafts, has declined significantly over the years.
Improvements in HLA matching, better supportive care particularly in infection management, and better GVHD prophylaxis and treatment, and the recent introduction of RIC have probably played roles in the reduction of NRM. In fact, for patients who received myeloablative unrelated donor transplants as a first transplant, there was a significant improvement in NRM from earlier period (1990-2002) to recent period (2003-2006) [1-year NRM 48% versus 32% versus 20% for patients receiving myeloablative conditioning in earlier period versus recent period versus RIC in recent period, respectively]. For this reason, we have decided to include also patients having a matched unrelated donor (in
absence of HLA identical sibling)
Inclusion criteria 1) Age ≥ 18 ≤ 65 years in case of identical sibling donor
2) Age ≥ 18 ≤ 60 years in case of matched unrelated donor
6)Unrelated donor fully HLA matched at locus HLA-A, HLAB,
HLA-C, HLA-DRB1, HLA- DQB1 as evaluated by high
resolution typing (it is acceptable one allelic mismatched at
class I)
“TP” pag 11. Conditionin |
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18 Jul 2012 |
This amendment involved the following sections:
1) Extension of enrollment period: given the enrollment rate below planned numbers, it was decided to enroll 40 more patient in the following 2 years. Afted the next IMDC it will be decided to prolong enrollment period. protocol page 4, synopsis page 1 and IC were modified.
2) insurance coverage extension: since at first protocol approval insurance was not required, principal investigator decided to implement insurance coverage as for Ministerial decree 14.07.2009.
3) Informed consent for personal data protection: it was included a specific section for personal data protection as per decree dated 24/07/2008. Informed consent was modified.
4) Inclusion of patients with indolent lymphoma (lymphocytic lymphoma/CLL, FL, Marginal Nodal Lymphoma) having PD at allo-TX: latest available data proved benefits from allo-Tx in patients with indolent lymphoma. The following IC were edited as indicated: 2c) FCL and MZL lymphoma relapsing after 2 lines or relapsing afeter auto-SCT; 2d) Primary refractory MCL e MZL; 2g) CLL, FCL, MCL, MZL and DLBCL considered eligible for high-dose chemotherapy, with a positive bone marrow biopsy or collecting PCR positive harvests before the autografting phase.
5) Minimum criteria for unrelated mismatched donors. Protocol was amended to include patients with HLA as per IBMDR.
6) Inclusion of patients with age up to 65yrs with HLA matched unrelated donor.
7) ATG administration: considering better tolerability of ATG in terms of reduction of IRR, administration was started since day 4. Dosage: 0.5mg/kg day -4, 3 mg/kg day -3 and 3.5mg/kg day -2. Total dosage remains unchanged.
8) Modification of partecipant centers.
9) Integration in the ICF of informations contained in the paragraph "Cautions required by being a trial partecipant"
10) It is specified that administrative management and monitoring o the study is done by Clinical Trial Center ad "Fondazione IRCCS Istituto Nazionale dei Tumori" |
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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. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/28390983 |
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