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.
