Phase 1 Single Agent Antitumor Activity of Twice Weekly Consecutive Day Dosing of the Proteasome Inhibitor Carfilzomib (PR-171) in Hematologic Malignancies.

Abstract Carfilzomib (CFZ) is a structurally- and mechanistically-novel proteasome inhibitor of peptide epoxyketone class that exhibits a high level of selectivity for the unique N-terminal threonine active sites within the proteasome. CFZ is similar to bortezomib (BTZ,Velcade®), in that it is a potent inhibitor of the proteasome chymotrypsin-like activity, but unlike BTZ, CFZ has shown minimal cross-reactivity with the other catalytic sites within the proteasome or across other protease classes. Preclinical human tumor xenograft models indicated that consecutive day (D1, D2) dosing resulting in 48 hours of proteasome suppression was superior to split dosing (D1, D4). This phase 1 sequential dose escalation trial tested twice weekly consecutive day dosing (48 hour proteasome inhibition) with carfilzomib. Carfilzomib was administered as an IVP on a 28 day cycle (D1, 2, 8, 9, 15 and 16 with 12 days rest) at doses from 1.2 mg/m2 to 27 mg/m2. Patients with Multiple myeloma (MM), non-Hodgkin’s Lymphoma (NHL) that included mantle cell lymphoma (MCL), Hodgkin’s disease (HD), or Waldenström’s macroglobulinemia (WM) were eligible if they had relapsed after at least 2 prior therapies. A total of 37 subjects have been treated. The minimal effective dose (MED) was 15 mg/m2, and maximum (80%) proteasome inhibition was achieved in peripheral blood and mononuclear cells at this dose. Five objective responses have occurred in 16 patients (13 MM, 3 MCL) enrolled at ≥ the MED: 4 MM partial response (PR), 1 MM minimal responses (MR). The responses have been durable (134 to 392 days) and occurred in patients who had failed bortezomib, immunomodulatory agents and stem cell transplant. Six additional patients have had stable disease (SD): 2 MM, 1 T NHL, 2 MCL, 1 B NHL. Dose limiting toxicity reported at 27 mg/m2 included a hypoxic event and Grade 2 thrombocytopenia increasing to Grade 4. A reversible Grade 2 creatinine D2 was reported in 3/5 MM patients treated at 27 mg/m2 and was associated with a rapid decline in M-protein without evidence of tumor lysis syndrome and the event did not occur on rechallenge. Cyclic thrombocytopenia was rapidly reversible and painful peripheral neuropathy was not reported. This study demonstrates that consecutive CFZ dosing leading to sustained proteasome inhibition is well tolerated on a weekly basis. The selectivity of epoxyketone class of proteasome inhibitors may provide a wide therapeutic index. Patients have remained on therapy for over a year, and furthermore, antitumor responses in heavily pretreated MM patients suggest non-cross resistant activity. Phase 2 trials in relapse and refractory MM and relapse solid tumors are proceeding with this schedule.

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