Study design
diarrhoea, nausea, DLTs, neutropenia, MM, toxicity, thrombocytopenia
ADVERSE EVENT, DISEASE PROGRESSION, PLASMA CELL MYELOMA, NEUTROPENIA, FEBRILE NEUTROPENIA, ADVERSE EVENT, DISEASE, THROMBOCYTOPENIA, RELAPSED/REFRACTORY MULTIPLE MYELOMA, PLASMACYTOMA, STERILE, ONCOLOGY
This was a phase 1, open-label dose-escalation trial of orally administered NMP in patients with relapsed/refractory multiple myeloma (RR–MM). Eligible patients were ≥ 18 years old with Eastern Cooperative Oncology Group (ECOG) < 2 and histologically confirmed plasma cell myeloma defined by WHO 2008 criteria with measurable disease (defined by serum M-protein > 5 g/L, urine M-protein > 200 mg/24 h, involved serum free light chain > 100 mg/L or measurable soft tissue plasmacytoma) [The primary study endpoint was to determine the MTD of orally administered NMP in patients with RR–MM. Secondary endpoints included safety, PK analyses, IMWG defined response rate and exploratory immunological biomarkers. Adverse events were defined according to Common Terminology Criteria for Adverse Events (CTCAE version 4.03). Haematological DLTs were defined as grade 4 neutropenia unresponsive to G-CSF, grade 4 thrombocytopenia and febrile neutropenia. Non-haematological DLTs were grade 3 or higher and considered probably related to study drug and not attributable to disease progression and those resulting treatment delays greater than two weeks due to drug-related toxicity. Self-limited (< 24 h) gastrointestinal side effects (e.g. nausea, diarrhoea) responding to supportive measures were not classified as DLTs.Pharmaceutical grade NMP stock solution (Ashland, Columbus, OH, USA) was diluted in ORA SWEET® SF (Medical Flavouring Systems, Vic, Australia) oral syrup vehicle and sterile water to a final concentration of 50 mg/mL and dispensed weekly in amber glass bottles for storage a room temperature. NMP was administered as a single morning dose on an empty stomach at least 30 min prior to food. Patients were dosed according to an ‘accelerated’ escalation schedule (one patient per dose level) in the absence of significant toxicity until a DLT was experienced and then in a 3 × 3 ‘standard’ dose-escalation phase. Intra-patient dose escalation at 100 mg increments was also permitted whereby the MTD had not been determined and the patient tolerated two consecutive cycles without DLT or an objective disease response. Treatment was administered daily for 28-day cycles until withdrawal from protocol due to toxicity or disease progression.