The primary objective is to describe the effect of optimized retreatment with bortezomib in combination with dexamethasone followed by prolonged therapy with bortezomib versus standard retreatment with bortezomib in combination with dexamethasone on…
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
Disease status and response to therapy will be assessed by investigators based
on the IMWG 2011 response criteria.
Response rates, TTP, DOR, TTNT, ECOG performance status, QoL measures, and MRU
data will also be
assessed. Overall survival and details of the first alternative multiple
myeloma therapy will be evaluated.
Secondary outcome
Response to therapy will be measured based on changes in the M protein in serum
and urine, as determined by SPEP and UPEP. Confirmation by immunofixation and
bone marrow assessments will be done in CR.
Response and progression will be determined according to the criteria IMWG.
Duration of response will be measured.
Time to progression, overall survival, time to new therapy will be measured.
Difference in ECOG performance status will be determined relative to
randomization and compared screening
Quality of life will be determined on the basis of EORTC QLQ-C30 questionnaire
and the EQ-5D questionnaire 5SL.
Background summary
A Randomized, Controlled, Phase 3 Study to Evaluate Optimized Retreatment and
Prolonged Therapy With Bortezomib (VELCADE®) in Patients With Multiple Myeloma
in First or Second Relapse (OPTIMIZED-RETREAT)
VELCADE® (bortezomib for injection) is a small molecule proteasome inhibitor,
which has been approved for the treatment of multiple myeloma. It is thought to
be efficacious in multiple myeloma via its inhibition of nuclear factor *B
(NF-*B) activation, its attenuation of interleukin-6 (IL-6)-mediated cell
growth, a direct apoptotic effect, and possibly antiangiogenic and other
effects.
This study is designed to examine whether optimized retreatment with bortezomib
in combination with dexamethasone followed by prolonged therapy with bortezomib
could improve progression free survival (PFS), and consequently overall
survival (OS) of patients with multiple myeloma in first or second relapse.The
baseline assumption is that standard retreatment with bortezomib in relapsed
multiple myeloma will result in a median PFS of 11 months. The hypothesis is
that optimized retreatment with bortezomib followed by prolonged therapy with
bortezomib will provide a median PFS of 17 months. Due to the lower than
planned total enrollment for this study, the number of evaluable subjects will
be inadequate for formal testing of the hypothesis and descriptive analysis
only will be performed.
Due to a reduced commitment towards enrollment of subjects, influenced by
competitive recruitment for other studies, other new/developmental treatment
options for relapsed/refractory patients, and expansion of the bortezomib label
to include bortezomib-dexamethasone combination treatment and single-agent
bortezomib retreatment options, the number of subjects needed for statistically
meaningful analysis of the data will not be reached within an acceptable
timeframe. Consequently, enrollment for this study will be stopped, effective
20 June 2014, and no further patients will be allowed to provide their consent
or be screened for eligibility after that date. Eligible subjects who were
screened before or are ongoing in the study as of that date will be randomized,
treated and clinically managed per the protocol for a maximum of 18 months
after enrollment of the last subject in the study.
Study objective
The primary objective is to describe the effect of optimized retreatment with
bortezomib in combination with dexamethasone followed by prolonged therapy with
bortezomib versus standard retreatment with bortezomib in combination with
dexamethasone on PFS.
The secondary objectives are to describe:
* Overall response rate (ORR)
* Time to progression (TTP)
* Duration of response (DOR)
* Time to next myeloma therapy (TTNT)
* Overall survival (OS)
* Eastern Cooperative Oncology Group (ECOG) Performance Status
* Quality of life (QoL: European Organisation for Research and Treatment of
Cancer Quality of Life
Questionnaire-C30 [EORTC QLQ-C30] and European Quality of Life-5 Dimensions
Questionnaire
[EQ-5D])
* Safety
The exploratory objectives are:
* To explore the efficacy and safety of 2 different schedules of prolonged
therapy with bortezomib (once a week for first 4 weeks in 35-day cycles versus
once every other week).
* To collect medical resource utilization (MRU) data to evaluate the impact of
optimized retreatment with bortezomib followed by prolonged therapy with
bortezomib on resource use items other than
drug costs.
Study design
This is an interventional, randomized, open-label, parallel-group,
event-driven, international, multicenter, Phase 3 study to evaluate an
optimized retreatment schedule of bortezomib used in combination with
dexamethasone followed by prolonged therapy with single-agent bortezomib in
subjects with multiple myeloma at the time of first or second relapse. The
study consists of a pretreatment phase, a treatment
phase (which consists of an optimized retreatment period followed by a
prolonged therapy period or a standard retreatment period followed by a
posttreatment period), and a long-term follow-up phase for survival up to the
end of the study. Before the premature stopping of enrollment, the end of the
study iswas event-driven and is, defined as 1 year after 186 events (an *event*
being defined as disease progression or death) occur. Following the premature
stopping of enrollment, effective 20 June 2014, the end of the study is defined
as a maximum of 18 months after enrollment of the last subject in the study.
Intervention
There will be 2 randomizations in this study, the first will randomly assign
subjects to either optimized or standard bortezomib and dexamethasone
retreatment in a 2:1 ratio and the second will randomly assign eligible
subjects who complete optimized bortezomib and dexamethasone retreatment to 1
of 2 prolonged single-agent bortezomib therapy groups in a 1:1 ratio. The first
randomization will be stratified according to whether a subject had 1 or 2
previous lines of therapy. Before the premature stopping of enrollment, it was
planned to enroll a target of 240 in this study (160 subjects in the optimized
retreatment group and 80 subjects in the standard retreatment group); due to a
reduced commitment towards enrollment of subjects, this number will not be
reached within an acceptable timeframe.
After providing written informed consent, subjects will be evaluated for
eligibility during a 14-day screening period. Baseline efficacy and safety
assessments should be available on Day 1 of Cycle 1 prior to administration of
study medication.
All eligible subjects will be randomly assigned to 1 of 2 different bortezomib
retreatment schedules:
* Group A: optimized retreatment followed by prolonged therapy starting with
retreatment with 6 cycles of bortezomib and dexamethasone (two 21-day cycles
followed by four 35-day cycles) followed by a second randomization to 1 of 2
prolonged therapy schedules with single-agent
bortezomib (Group A1: once weekly for first 4 weeks in 35-day cycles; or Group
A2: once every other week).
* Group B: standard retreatment with eight 21-day bortezomib and dexamethasone
cycles, followed by posttreatment follow-up every 6 weeks.
Disease status and response to therapy will be evaluated on Day 1 of each cycle
during optimized/standard retreatment with bortezomib and dexamethasone (Group
A and Group B). Treatment will continue until completion of the retreatment
period or until confirmed disease progression, unacceptable toxicity despite
dose modification or delays, start of alternative multiple myeloma therapy,
withdrawal from the study, death, or the end of study (a maximum of 18 months
after the last subject is enrolled in the study), , whichever occurs first.
Subjects who complete optimized retreatment in Group A (6 cycles) and standard
retreatment in Group B (8 cycles) and have responded to treatment (minimal
response [MR], partial response [PR], very good partial response [VGPR], or
complete response [CR]) or have stable disease (SD), and have not had disease
progression, have not discontinued bortezomib early, or have started an
alternative multiple myeloma
therapy, will enter the prolonged therapy period (Group A1 or Group A2) or
posttreatment period (Group B) for up to a maximum of 18 months after the last
subject is enrolled in the study), .
During prolonged therapy with single-agent bortezomib, disease status and
response to therapy will be evaluated every 6 weeks in both Group A1 and Group
A2. Treatment in the prolonged therapy period will continue until confirmed
disease progression, unacceptable toxicity despite dose modification or delays,
start of alternative multiple myeloma therapy, withdrawal from the study,
death, or the end of the study (a maximum of 18 months after the last subject
is enrolled in the study), whichever occurs first.
During the posttreatment period, subjects in Group B will continue to be
evaluated for disease status every 6 weeks (after the end-of-treatment [EOT]
visit in Week 28 [ie, 30 to 35 days after last bortezomib dose in the
retreatment period]) until confirmed disease progression, start of alternative
multiple myeloma treatment, withdrawal of consent for study participation,
death, or the end of study, whichever occurs first.
Any subject who discontinues bortezomib before disease progression during the
treatment phase (eg, unacceptable toxicity despite dose modification or delays)
will continue to be evaluated for disease status after the EOT visit at a
posttreatment visit every 6 weeks until confirmed disease progression, start of
alternative multiple myeloma treatment, withdrawal of consent for study
participation, death, or the
end of study, whichever occurs first. For a complete list of efficacy
assessments and ongoing patient assessments to be performed at each
posttreatment visit, and other procedures that should be performed at these
visits if clinically indicated, see the Time and Events Schedule - Prolonged
Therapy/Posttreatment Period.
All subjects will have an EOT visit performed 30 to 35 days after the last
administration of bortezomib, or as soon as possible after bortezomib treatment
discontinuation in subjects receiving alternative multiple myeloma therapy.
After confirmed disease progression or start of the first alternative multiple
myeloma treatment, whichever occurs first, subjects will enter the long-term
follow-up phase of the study for up to a maximum of 18 months after the last
subject is enrolled in the study. During this phase,
subjects will be contacted by at least a telephone call every other month to be
followed up for the first alternative multiple myeloma therapy and survival.
The final analysis will be performed at the end of the study (a maximum of 18
months after the last subject is enrolled) and will include all efficacy and
safety parameters, including OS where possible.
From the end of the study in countries where bortezomib is not commercially
available for prolonged
therapy or is not accessible (via a national program or access program) at that
time, subjects who in the opinion of the investigator would continue to benefit
from prolonged therapy with bortezomib, will continue to be supplied with
bortezomib until it is accessible in that particular country or for a period of
2 years, whichever occurs first.
Study burden and risks
The risks of treatment and procedures for this study are included in the
patient information. Treatment with Velcade is a standard treatment for
multiple myeloma. The study was designed to simulate normal practice. Every
effort is made withiin this study **to decrease further risks and
inconveniences to the minimum.
Antwerpseweg 17-19
Beerse 2340
BE
Antwerpseweg 17-19
Beerse 2340
BE
Listed location countries
Age
Inclusion criteria
Have received a bortezomib containing regimen in one of the previous line(s) of therapy and have shown at least PR to the previous bortezomib therapy.;Have relapsed / progressed multiple myeloma following 1 or 2 previous lines of therapy as defined in the protocol.;Have measurable secretory multiple myeloma: measurable disease for secretory multiple myeloma is defined by at least one of the following measurements: serum M protein greater than or equal to 1 g/dL (>=10g/L], urine M-protein of >=200 mg/24 hours.;Have an ECOG performance status of <=2. ;Have a life expectancy estimated at screening of >=6 months.
Exclusion criteria
Has received more than 2 previous lines of therapy for multiple myeloma or has received no previous bortezomib-containing regimen.;Has been refractory to bortezomib, defined as either having progressed during bortezomib therapy or relapsed/progressed within 6 months after the last dose of bortezomib.;Has oligosecretory or nonsecretory multiple myeloma.;Has a history of a myocardial infarction within 6 months of enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.;Has peripheral neuropathy or neuropathic pain of grade 2 or greater intensity, as defined by the National Cancer Institute Common Terminology Criteria of Adverse Events (NCI CTCAE), version 4.0.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
EudraCT | EUCTR2011-004795-11-NL |
CCMO | NL43247.008.13 |