Phase II Study of Perifosine and Sorafenib Dual-Targeted Therapy in Patients with Relapsed or Refractory Lymphoproliferative Diseases

Abstract

Purpose: To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases.Experimental Design: Patients with relapsed and refractory lymphoproliferative diseases received perifosine (50 mg twice daily) for 1 month. Patients achieving less than partial response (PR) after perifosine alone were administered the combination therapy [perifosine plus sorafenib (400 mg twice daily)] until progressive disease (PD) or unacceptable toxicity occurred. The pERK and pAKT in peripheral blood lymphocytes as well as serum cytokine levels were investigated as predictive biomarkers of response.Results: Forty patients enrolled in this study. After 1 month of perifosine alone, 36 who achieved less than PR went on to combination therapy, whereas four patients with chronic lymphocytic leukemia (CLL) who achieved PR continued with perifosine alone for a median of 10 months (range, 4-21). The most common drug-related toxicities were grade 1-2 anemia (17%), thrombocytopenia (9%), diarrhea (25%), joint pain (22%), and hand-foot skin reaction (25%). Three patients experienced grade 3 pneumonitis. Eight patients (22%) achieved PR, 15 (42%) achieved stable disease, and 13 (36%) experienced PD. A 28% PR rate was recorded for 25 patients with Hodgkin lymphoma. Among all patients, median overall survival and progression-free survival were 16 and 5 months, respectively. Early reductions in pERK and pAKT significantly correlated with the probability of clinical response.Conclusions: Perifosine and sorafenib combination therapy is feasible with manageable toxicity and demonstrates promising activity in patients with Hodgkin lymphoma. The predictive value of pERK and pAKT should be confirmed in a larger patient cohort.

Alkyl ether lipids, ion channels and lipid raft reorganization in cancer therapy

“…Nevertheless, additional combinations of perifosine with current therapeutic drugs are still in progress. In this regard, a phase II clinical trial using perifosine and sorafenib combination therapy showed some promising results with manageable toxicity in patients with Hodgkin lymphoma (Guidetti, et al, 2014). In addition, a phase II clinical trial of perifosine and Torisel (temsirolimus) in patients with recurrent/progressive malignant glioma to determine the induction of tumor shrinkage or stabilization and/or a delay in disease progression (NCT02238496) (Andrew Lassman, Columbia University; Pfizer; AEterna Zentaris) is underway.…”

Anti-tumor activities of lipids and lipid analogues and their development as potential anticancer drugs

“…In in vivo xenograft studies there was a reduction in tumor burden, increased survival, and enhanced tumor cell killing produced by this combination compared with single agents (Locatelli et al, 2013). A recent study also evaluated the combination in patients with lymphoproliferative diseases (Guidetti et al, 2014; Table 1). Patients who had received single-agent perifosine for relapsed and refractory lymphoproliferative diseases, and who achieved less than a partial response, received the combination therapy until the disease progressed or toxicity was unacceptable.…”

“…Initial results supported a clinical response in 7 of 25 patients with Hodgkin lymphoma. Also promising, 4 of 8 patients with chronic lymphocytic leukemia responded to perifosine alone (Guidetti et al, 2014). The clinical responses observed in the patients with relapsed and refractory Hodgkin lymphoma suggest that this subgroup could serve as target population for new studies (Guidetti et al, 2014).…”

Primary refractory and early‐relapsed Hodgkin's lymphoma: strategies for therapeutic targeting based on the tumour microenvironment

“…These findings were dependent on potent, early, time‐dependent ROS generation. Taken together, these data suggest that Givinostat/Sorafenib treatment warrants attention in refractory/relapsed HL patients .…”