The study will evaluate if the N-methyl-pyrrolidone (NMP) can be safely administered to humans at doses, which induce measurable immunological and anti-tumour effects in patients with myeloma who are resistant to or intolerant of lenalidomide and bortezomib.
N-Methyl-2-pyrrolidone (NMP) is a small molecule acetyl-lysine mimetic compound with potent (low micromolar range) immunomodulatory and direct anti-myeloma activity attributable to BETbromodomain inhibition at higher concentrations. NMP is nontoxic, stable and already in use as a solvent in biomedical applications. It has been the subject of numerous toxicity studies in humans and been demonstrated to have few adverse effects. The study is proposing an empiric starting dose of 50mg daily, 50% of that seen in healthy volunteers with no observable toxicity. Dose escalation will follow a rule based on accelerated trial design in order to minimise the number of patients treated at sub-therapeutic doses and minimise the length of the study. During the accelerated dose-escalation phase, one patient will be entered per cohort with a dose escalation increment of 100%, with up to 6 dose escalation and up to two dose de-escalation levels.The accelerated phase ends when one patient experiences DLT during the first cycle of treatment or when a total of two patients have experienced moderate toxicity during the first cycle of treatment regardless of the dose level; or the most recent patient has been treated at the highest dose level in the first cycle. If 1 patient experiences a DLT in the first cycle at any dose level, the cohort will be further expanded to a total of 6 patients treated at the same dose level. The maximum tolerated dose (MTD) in the study will be defined as the highest dose in which the incidence of DLT was less than 33%.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
13
NMP will be taken each morning as a single daily dose of oral suspension at a concentration of 50mg/ml on an empty stomach at least 30 minutes prior to food.
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia
Adverse events to establish the Maximum Tolerated Dose (MTD)
Each patient will be monitored for adverse events during the first cycle of NMP treatment (28 days) to establish the maximum tolerated dose
Time frame: 28 days
Optimum biological dose (OBD)
The maximum changes in correlative biomarkers will be tested at the specific time-points. Descriptive statistics will be used to analyse data from correlative studies and summarized in graphical or tabular formats as appropriate.
Time frame: 6 months
Safety of the repeated dosing of NMP by oral administration - possible toxicities
To assess safety, the numbers and rates (with confidence intervals) of patients experiencing any haematological and non-haematological and specific grade 3+ adverse events experienced at each given dose level and schedule of NMP will be calculated, over the full treatment period and by cycle
Time frame: 6 months
Pharmacokinetic properties of NMP after oral administration
Pick plasma concentrations (Cmax) of NMP
Time frame: Predose,0.5,1,2,4,8, 24 hours post dose
Response rate measured using IMWG criteria
Patients will be evaluated for response after every 28 day cycle for the first 6 cycles of treatment and thereafter every 2 months in follow up using the IMWG criteria for multiple myeloma.
Time frame: 6 months up to 2 years
Time to progression from start of treatment
Patients will be assessed for disease progression weekly in Cycle 1, then monthly on D1 of each cycle during treatment for the first 6 months and then monthly until disease progression, next anti-cancer treatment or death. Time to progression from start of treatment will be estimated using Kaplan Meier survival curves.
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Time frame: up to 3.5 years