Phase I dose escalation trial of the novel proteasome inhibitor carfilzomib in patients with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma

Abstract

The proteasome complex degrades proteins involved in a variety of cellular processes and is a powerful therapeutic target in several malignancies. Carfilzomib is a potent proteasome inhibitor which induces rapid CLL cell apoptosis in vitro. We conducted a phase I dose-escalation trial to determine safety and tolerability of carfilzomib in relapsed/refractory CLL or small lymphocytic lymphoma (SLL). Nineteen patients were treated with carfilzomib initially at 20 mg/m2, then escalated in 4 cohorts (27, 36, 45 and 56 mg/m2) on days 1, 2, 8, 9, 15, and 16 of 28-day cycles. Therapy was generally well-tolerated, and no dose-limiting-toxicities were observed. The most common hematologic toxicities were thrombocytopenia and neutropenia. All patients evaluable for response had stable disease, including patients with del17p13 and fludarabine-resistant disease. This trial shows acceptable tolerability and limited preliminary efficacy of carfilzomib in CLL and SLL.

Carfilzomib Triggers Cell Death in Chronic Lymphocytic Leukemia by Inducing Proapoptotic and Endoplasmic Reticulum Stress Responses

“…Recently, we showed that carfilzomib, a selective and irreversible proteasome inhibitor, is a potent cytotoxic agent in CLL samples isolated from patients treated with ibrutinib, a well-tolerated, orally bioavailable Bruton’s tyrosine kinase inhibitor (10). While our present manuscript was under preparation a phase I trial conducted in a group of 19 patients with relapsed/refractory CLL showed modest activity of carfilzomib (43). In this study, the patient population was high risk with very unfavorable clinical and prognostic factors (i.e., 84% had a Rai stage between 3 and 4, 85% were IgVH unmutated, 47% had del(17p), 21% had del(11q), 68% were refractory to fludarabine and 70% had complex karyotype), which probably contributed to the poor response observed with carfilzomib.…”

“…However, our report could not illustrate a correlation between the cytotoxic effect of carfilzomib and del (11q), which is associated with loss of ATM and progressive disease, or del (17p) because only 13% and 10% of the patients, respectively, presented these unfavorable genetic abnormalities. Furthermore, the authors of the phase I trial with carfilzomib did not investigate the cytotoxic effect of carfilzomib ex vivo at baseline to assess any correlation between the carfilzomib-induced cytotoxic effects ex vivo versus in vivo (43). This is particularly relevant since here we used 30 CLL patient samples and showed high interpatient variability in response to the cytotoxic effect of carfilzomib.…”

Changing treatment paradigms in lymphoma: new targets and new drugs

“…Bortezomib and, only recently, also carfilzomib were initially used for the treatment of multiple myeloma but several prospective trials proved their efficacy in lymphoproliferative disorders too, especially in MCL [31]. Instead, many trials investigating the impact of carfilzomib are ongoing (e.g., NCT02187133, NCT01959698, NCT01926665) or about to be designed while published phase I data is only available for chronic lymphocytic leukemia [32].…”

Idelalisib for the treatment of non-Hodgkin lymphoma

“…The proteasome inhibitor (PI) bortezomib has demonstrated activity in FL in combination with rituximab and bendamustine [12, 13], alone and in combination with rituximab in lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia LPL/WM [14, 15], and is FDA approved for use in relapsed MCL. Investigations of other PIs including carfilzomib and ixazomib are underway to identify active agents in the class with less neurotoxicity and improved ease of administration [16, 17]. …”