Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03141203 |
| Other study ID # |
RG_13-107 |
| Secondary ID |
2013-001879-20 |
| Status |
Completed |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
July 13, 2015 |
| Est. completion date |
September 23, 2021 |
Study information
| Verified date |
May 2022 |
| Source |
University of Birmingham |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This is a multicentre phase I/II trial looking at the combination of romidepsin and
carfilzomib.
The aim of the phase I part is to determine the maximum tolerated dose (MTD) of the
combination. This part will recruit up to 27 patients, plus possibly an additional 3 patients
at the MTD.
The aim of the phase II part is to assess the activity of the combination at the maximum
tolerated dose in 28 patients (including at least 6 patients treated at the MTD from phase
I).
Patients will receive 8 cycles of romidepsin with carfilzomib and response will be assessed
every second cycle. Patients will be followed up for progression and survival until the end
of the trial.
Description:
This is a prospective, single arm, phase I/II, multicentre, dose finding study of romidepsin
in combination with carfilzomib.
The aim of the phase I is to establish the MTD of the combination using a restricted
two-stage CRM. The MTD is defined as the dose level that is closest to the level at which 25%
of patients experience a DLT over the first cycle of treatment.
The intention in phase I is to evaluate the DLT-inducing effects of doses in cohorts of
patients. Patients will be treated in cohorts at a dose level and each patient will be
evaluated for presence or absence of DLT. In stage I, the first cohort of 3 patients will be
enrolled at the starting dose, i.e. dose level 2. If none experiences a DLT, the next cohort
of 3 patients will be recruited at the next higher level, i.e. dose level 3. This escalation
routine will continue until the first DLT is observed or the maximum recruitment for stage I
is reached. As soon as the first DLT is observed, dose escalation and de-escalation will be
guided by the CRM design that will recommend the dose believed to have associated DLT-rate
closest to 25%. If the trial escalates, each dose below the newly tested dose is regarded as
being tolerable.
In stage II, we will consider variable cohort sizes of up to eight patients. Patients are
screened for eligibility before they are formally registered. During screening, we expect it
to transpire that some patients will be ineligible. To maximise recruitment and reduce trial
suspension period between cohorts in this rare disease, we will allow for the flexibility of
variable cohort sizes by screening cohorts of up to eight patients. We will allocate
screening slots so that the sum of: a) the number of patients already receiving treatment in
the current cohort; and (b) the number of patients in screening; does not exceed eight. If a
patient is screened and proves to be eligible, they will be recruited to the trial. The first
three patients in a cohort will receive the dose-level allocated to the cohort. Patients who
are inevaluable, as described immediately above, can be replaced. If the fourth to eighth
patients are recruited to a cohort and the dose allocated to the cohort is not yet regarded
as tolerable, the fourth to eighth patients will receive the next dose-level below.
Otherwise, they will receive the same dose level as the previous patients in the cohort. The
aim of the described strategy is to maximise recruitment but not expose more than three
patients to a dose that has not yet been demonstrated tolerable. The model will be updated
regularly and subsequent recommended doses will be assigned to patients iteratively until the
maximum sample size is reached, or the trial is stopped early because there is a high chance
that the lowest dose is too toxic. It is expected that the CRM will likely allocate patients
to the eventual MTD at the later stage of the trial as more data accumulate. Recruitment will
be permitted to continue seamlessly to the Phase II component at the latest recommended MTD
dose, in consultation with the Trial Safety Committee, unless it is considered necessary to
halt recruitment The initial guess of MTD is at dose combination level 4, however to exercise
caution, dose level 2 is defined as the starting dose level.
Dose Levels
1. 8mg/m2 Romidepsin (days 1, 8, 15), 20/36mg/m2 Carfilzomib (days 1, 2, 8, 9, 15, 16)
2. (Starting dose) 10mg/m2 Romidepsin (days 1, 8, 15), 20/36mg/m2 Carfilzomib (days 1, 2,
8, 9, 15, 16)
3. 10mg/m2 Romidepsin (days 1, 8, 15), 20/45mg/m2 Carfilzomib (days 1, 2, 8, 9, 15, 16)
4. 12mg/m2 Romidepsin (days 1, 8, 15), 20/45mg/m2 Carfilzomib (days 1, 2, 8, 9, 15, 16)
5. 12mg/m2 Romidepsin (days 1, 8, 15), 20/56mg/m2 Carfilzomib (days 1, 2, 8, 9, 15, 16)
6. 14mg/m2 Romidepsin (days 1, 8, 15), 20/56mg/m2 Carfilzomib (days 1, 2, 8, 9, 15, 16) For
all dose levels, the carfilzomib dose will be 20mg/m2 for the first 2 doses (i.e. day 1
and 2 of cycle 1), rising to the target dose for subsequent doses and cycles.
Once the MTD is defined, patients recruited at a lower dose may receive the MTD for any
subsequent cycles of treatment at the discretion of the treating Investigator and the Chief
Investigator.
The phase II component will aim to provide a preliminary estimate of activity in 28 patients
at the MTD combination established in phase I. The phase II component is based on A'Hern's
single arm, single stage design and would utilise patients allocated to the MTD in phase I.
Patients will be recruited over a 36-month period and will receive a minimum of 8 cycles of
treatment. Patients will continue to be followed up for progression and survival until the
end of the trial.
