A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of the Novel Proteasome Inhibitor Carfilzomib (PR-171) in Patients with Hematologic Malignancies

Abstract

Purpose Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib. Experimental Design In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles. Results Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patients—mostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses ≥11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenström’s macroglobulinemia). Conclusion This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing.

Marizomib irreversibly inhibits proteasome to overcome compensatory hyperactivation in multiple myeloma and solid tumour patients

“…The irreversible mode of action of MRZ, also seen with CFZ (O'Connor et al , 2009), resulted in similar efficacy in PBMCs and erythrocytes (i.e. whole blood), suggesting that the irreversible binding mode of these two newer drugs is able to overcome the re‐synthesis of proteasome subunits that occurs in nucleated cells.…”

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

“…In phase I and II trials, only the LLVY‐AMC assay was used in a limited number of patient samples to measure CT‐L activity alone (O'Connor et al , 2009; Badros et al , 2013; Niesvizky et al , 2013; Papadopoulos et al , 2013). To obtain the full active‐site inhibition profile of carfilzomib, we utilized ProCISE to quantify active site activity and occupancy in whole blood and PBMC samples from patients in multiple studies ( n  =   41 ST and n  =   73 MM) 1 h after the first dose of carfilzomib (15–45 mg/m 2 ) was administered.…”

“…Minimal recovery of proteasome activity was observed 24 h after the first dose, and incomplete recovery was seen after the 5‐day non‐dosing period during the first week of treatment. This effect is unlikely to be due to prolonged exposure, because carfilzomib is rapidly cleared from the plasma (O'Connor et al , 2009). Rather, these data demonstrate that carfilzomib results in proteasome inhibition that lasts at least 48 h and suggests that PBMCs have an altered rate of proteasome recovery relative to other cell types.…”

BRAF V600E Is a Determinant of Sensitivity to Proteasome Inhibitors

“…It showed antitumor activity on xenografted cancer cell lines originating from solid tumors (42). A phase 1 study of carfilzomib has shown that it is well tolerated with consecutive day dosing (43), and a phase 1b/2 study on relapsed solid tumors is ongoing [http://www.clinicaltrials.gov].…”