Clinical Trial Results:
Phase II study of age‐adjusted R‐BAC (Rituximab, Bendamustine, Cytarabine) as induction therapy in older patients with Mantle Cell Lymphoma (MCL)
|
Summary
|
|
EudraCT number |
2011-005739-23 |
Trial protocol |
IT |
Global end of trial date |
11 Sep 2017
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
25 Aug 2022
|
First version publication date |
25 Aug 2022
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
FIL-RBAC500
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT01662050 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Fondazione Italiana Linfomi (FIL) ONLUS
|
||
Sponsor organisation address |
Piazza Turati 5, Alessandria, Italy,
|
||
Public contact |
Segreteria, Fondazione Italiana Linfomi ONLUS, +39 0131/033151, segreteriadirezione@filinf.it
|
||
Scientific contact |
Segreteria, Fondazione Italiana Linfomi ONLUS, +39 0131/033151, segreteriadirezione@filinf.it
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
15 Jan 2019
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
29 Aug 2014
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
11 Sep 2017
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The primary objective is to determine the activity (complete remission rate according to Cheson 2007 criteria) and safety of age‐adjusted Rituximab‐Bendamustine‐Cytarabine (RBAC500) regimen at the end of treatment in older untreated patients with MCL.
|
||
Protection of trial subjects |
1) Occurrence of relevant toxicity for two subsequent or consecutive cycles (the protocol allows for a 25% reduction of drugs dosage when an episode of relevant toxicity occurs for the first time)
2) Grade 3-4 hematological or non‐hematological toxicity on day +28 of a cycle not resolving within two weeks (+28 days+14 days since last cycle)
3) Grade 3-4 hematological or non‐hematological toxicity on day +28 of a cycle after the 25% dose reduction
4) Patient refusal to procede with further cycles due to perceived excessive toxicity
5) Any unpredictable drug related event that suggests against study continuation
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
20 Mar 2012
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Italy: 57
|
||
Worldwide total number of subjects |
57
|
||
EEA total number of subjects |
57
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
5
|
||
From 65 to 84 years |
52
|
||
85 years and over |
0
|
||
|
|||||||||||||||
|
Recruitment
|
|||||||||||||||
Recruitment details |
Fifty-seven patients recruited in Italy from 03/20/2012 , with date of last completed at 09/11/2017. We adopted the Bryant and Day two-stage design for calculating the sample size. At the end of the first stage, 19 pts, the trial will be stopped if there are <= 8/19 responses and >=7/19 toxicities. Otherwise, further 38 pts will be enrolled. | ||||||||||||||
|
Pre-assignment
|
|||||||||||||||
Screening details |
Patients with an established histological diagnosis of MCL on lymph-node biopsy, bone marrow biopsy, or extranodal tissue are eligible for entry into the study. All patients must satisfy all the inclusion criteria and none of exclusion criteria. | ||||||||||||||
|
Period 1
|
|||||||||||||||
Period 1 title |
Baseline (overall period)
|
||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Non-randomised - controlled
|
||||||||||||||
Blinding used |
Not blinded | ||||||||||||||
|
Arms
|
|||||||||||||||
|
Arm title
|
Single arm | ||||||||||||||
Arm description |
Patients will be treated with at least two cycles of RBAC500, recycling every 28 days. Patients with PD after 2 cycles will stop treatment, while all other patients will continue treatment. After 4 cycles patients that had SD after 2 cycles will be reevaluated for response and they will stop treatment if still in SD or PD. Responsive patients (CR, CRu, PR after 2 cycles; SD after 2 cycles that improved their response at the end of cycle 4) will receive a total of 6 cycles. Patients experiencing at least one episode of relevant toxicity during any of the first 4 cycles will be treated with a total of four cycles (end of treatment after 4 cycles) regardless of response to treatment. | ||||||||||||||
Arm type |
Single arm study | ||||||||||||||
Investigational medicinal product name |
Rituximab
|
||||||||||||||
Investigational medicinal product code |
|||||||||||||||
Other name |
|||||||||||||||
Pharmaceutical forms |
Infusion
|
||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||
Dosage and administration details |
Dose administered: 375 mg/m2
The amount (in mg) of Rituximab to be administered will be determined based on body surface area (BSA) using a standard calculation.
Patients presenting with high lymphocyte count in the peripheral blood, defined as total lymphocytes >20000/mmc will receive the dose of Rituximab postponed after chemotherapy, 4 days after the completion of the last dose of Ara-C (+8 from the start of therapy). Patients that still have elevated lymphocyte count at that time point will avoid Rituximab for the first cycle, maintaining the same measures for subsequent cycles.
|
||||||||||||||
Investigational medicinal product name |
Bendamustine
|
||||||||||||||
Investigational medicinal product code |
|||||||||||||||
Other name |
|||||||||||||||
Pharmaceutical forms |
Powder for injection
|
||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||
Dosage and administration details |
Bendamustine will be administered intravenously at a dose of 70 mg/m2 and as a 30-60 minute infusion on Days 2 and 3.
Following the first cycle, if no major complication has followed rituximab infusion, bendamustine and ara-C will be administered on day 1 following rituximab, and the complete cycle will last for 3 days, in order to facilitate an outpatient approach.
|
||||||||||||||
Investigational medicinal product name |
Cytarabine
|
||||||||||||||
Investigational medicinal product code |
|||||||||||||||
Other name |
Ara-C
|
||||||||||||||
Pharmaceutical forms |
Injection
|
||||||||||||||
Routes of administration |
Intravenous use
|
||||||||||||||
Dosage and administration details |
Ara-C will be administered intravenously at the dose of 500 mg/m2 as a 2-hour infusion, 2 hours after Bendamustine on Day 2 and 3, and once on Day 4.
Following the first cycle, if no major complication has followed rituximab infusion, bendamustine and ara-C will be administered on day 1 following rituximab, and the complete cycle will last for 3 days, in order to facilitate an outpatient approach.
|
||||||||||||||
|
|||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Baseline
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Fifty-seven patients recruited in Italy from 03/20/2012 , with date of last completed (last follow-up) at 09/11/2017. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
Single arm
|
||
Reporting group description |
Patients will be treated with at least two cycles of RBAC500, recycling every 28 days. Patients with PD after 2 cycles will stop treatment, while all other patients will continue treatment. After 4 cycles patients that had SD after 2 cycles will be reevaluated for response and they will stop treatment if still in SD or PD. Responsive patients (CR, CRu, PR after 2 cycles; SD after 2 cycles that improved their response at the end of cycle 4) will receive a total of 6 cycles. Patients experiencing at least one episode of relevant toxicity during any of the first 4 cycles will be treated with a total of four cycles (end of treatment after 4 cycles) regardless of response to treatment. | ||
Subject analysis set title |
Subject analyzed
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Fifty-seven patients recruited in Italy from 03/20/2012 , with date of last completed (last follow-up) at 09/11/2017.
|
||
|
|||||||||||||
End point title |
Complete response rate (CR) | ||||||||||||
End point description |
Primary efficacy end point of the study is the proportion of CR defined according to Cheson criteria (2007) at the end of treatment (6 or 4 cycles)
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
At the end of treatment (6 or 4 cycles)
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Complete Response (CR) Rate | ||||||||||||
Comparison groups |
Single arm v Subject analyzed
|
||||||||||||
Number of subjects included in analysis |
114
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
CR proportion | ||||||||||||
Point estimate |
91
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
1-sided
|
||||||||||||
lower limit |
85 | ||||||||||||
upper limit |
- | ||||||||||||
|
|||||||||||||
End point title |
Patients with at least a relevant one episode of relevant toxicities | ||||||||||||
End point description |
Relevant toxicity was defined as grade 4 cytopenia lasting for more than 6 days, grade 3–4 non haematological toxicity, or febrile neutropenia lasting for more than 3 consecutive days.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
6 months
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Patients with relevant toxicities | ||||||||||||
Comparison groups |
Single arm v Subject analyzed
|
||||||||||||
Number of subjects included in analysis |
114
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
Method |
|||||||||||||
Parameter type |
Proportion | ||||||||||||
Point estimate |
40
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
1-sided
|
||||||||||||
lower limit |
- | ||||||||||||
upper limit |
53 | ||||||||||||
|
|||||||||||||
End point title |
Progression Free Survival (PFS) | ||||||||||||
End point description |
PFS is measured from the time of enrollment until disease progression, relapse or death from any cause.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
30 months. The reported value corresponds to PFS% at 2-years.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Overall Survival (OS) | ||||||||||||
End point description |
OS is measured from enrollment until death from any cause.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
30 months. The reported value corresponds to OS% at 2-years.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
End point title |
Duration of responses (DOR) | ||||||||||||
End point description |
DOR is measured from the first assessment that documents response (CR or PR) to the date of disease relapse or progression.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
30 months. The reported value corresponds to DOR% at 2-years.
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||
End point title |
Rate of molecular response | |||||||||||||||
End point description |
Molecular response is the proportion of patients with molecular rearrangements at baseline that become negative during treatment, measured by qualitative and quantitative PCR.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
6 months
|
|||||||||||||||
|
||||||||||||||||
| Notes [1] - Of 57 patients, 45 (79%) had a molecular marker [2] - Of 57 patients, 45 (79%) had a molecular marker |
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
30 months
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
All subjects will be monitored for adverse events throughout the study and for 30 days after the end of treatment.
During the follow-up, patients will be monitored for adverse events every 3 months.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Single arm
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Patients will be treated with at least two cycles of RBAC500, recycling every 28 days. Patients with PD after 2 cycles will stop treatment, while all other patients will continue treatment. After 4 cycles patients that had SD after 2 cycles will be reevaluated for response and they will stop treatment if still in SD or PD. Responsive patients (CR, CRu, PR after 2 cycles; SD after 2 cycles that improved their response at the end of cycle 4) will receive a total of 6 cycles. Patients experiencing at least one episode of relevant toxicity during any of the first 4 cycles will be treated with a total of four cycles (end of treatment after 4 cycles) regardless of response to treatment. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
|||
| http://www.ncbi.nlm.nih.gov/pubmed/27927586 |
|||
