Clinical Activity and Safety of the Combined Therapy with the AKT Inhibitor Perifosine and the Multikinase Inhibitor Sorafenib In Heavily Pretreated Patients with Relapsed/Refractory Lymphomas: Preliminary Results of a Phase II Trial

The AKT inhibitor Perifosine (Æterna Zentaris GmBH, Germany) has been shown in phase II studies to induce partial responses in a variety of solid tumors. Sorafenib (Nexavar, Bayer) is an oral multikinase inhibitor exerting in vitro and in vivo antiproliferative, antiangiogenic, and proapoptotic effects in a variety of hematological and nonhematological tumors. Our preclinical data demonstrating that the combination of Perifosine and Sorafenib induces gene expression profiling and signaling changes associated with a synergistic cytotoxic activity against lymphoma cell lines in vitro and in vivo, established the rationale for this ongoing phase II study aimed to determine safety and activity of Perifosine/Sorafenib combination therapy in relapsed/refractory non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL).

Between July 2008 and July 2010, 26 out of 36 planned patients (18 males and 8 females; median age, 42 years; range, 19–73 years) with relapsed/refractory diffuse large B cell lymphoma (DLBCL, n = 3), follicular lymphoma (FL, n = 3), Waldenstrom macroglobulinemia (WM, n = 1), chronic lymphocytic leukemia (CLL, n = 4), and HL (n = 15) who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled in this trial. Prior to study entry, patients received a median of 5 (range 2 – 11) lines of treatment with autologous SCT performed in 19 (73%) and an additional allogeneic SCT in 10 (38%) patients. At study entry, 7 patients had relapsed and 19 refractory lymphoma. Perifosine (50 mg BID, per os) was initially administered as single agent for 4 weeks to assess tolerability and tumor response. Patients achieving less than partial remission (PR) were given the combination therapy, i.e., Perifosine (50 mg BID, per os) plus Sorafenib (400 mg BID, per os) until disease progression or clinical significant toxicity. Patients achieving ≥PR went off-study and continued with Perifosine (50 mg BID, per os) alone until disease progression or clinical significant toxicity. Tumor responses were assessed according to the revised response criteria for malignant lymphoma of the International Working Group. NCI CTCAE v3.0 was used for toxicity assessment. The study was approved by the Institutional Ethical Committee.

After a 4-week treatment with Perifosine alone, 22 out of 26 patients achieved <PR and were started on Perifosine/Sorafenib combination therapy. As of July 2010, a median of 5 months (range, 2 – 18) combination therapy have been administered, and 22 patients are evaluable for toxicity and response. In contrast, 4 patients who achieved ≥PR went off-study and continued therapy with Perifosine single agent. Combination therapy was well tolerated without significant adverse events. No patients interrupted the treatment due to toxicity. The most common drug-related hematological toxicities included grade 1–2 anemia (5%), neutropenia (5%), and thrombocytopenia (18%). Non-hematological toxicities included grade 1–2 diarrhea (27%) and hand-foot syndrome (27%). Three patients (14%) experienced grade 3 infections [pneumonia (n = 2), skin infection (n = 1)]. Best response to Perifosine/Sorafenib therapy included 5 (23%) PR with median response duration of 9 months (range, 1– 12) with 2 of 5 patients having received an allogeneic SCT. Eleven patients (50%) achieved stable disease (SD) with 7 patients (32%) achieving SD for ≥4 months, while 6 patients (27%) progressed. Interestingly, all responding patients had a diagnosis of HL, thus raising to 33% the PR rate in this histological subgroup. At a median follow-up of 11 months (range, 5 – 25), study patients (n = 22) have a median overall survival (OS) of 15 months and a projected 2-year OS of 42% (95% CI: 20% - 66%), with a median time to progression (TTP) for patients achieving PR or SD (n = 16) of 7 months. The subgroup of HL patients (n =15) has a median OS of 16 months and a projected 2-year OS of 42% (95% CI: 12% - 72%), with a median TTP for patients achieving PR or SD (n = 11) of 10 months.

Perifosine/Sorafenib combination therapy has a good toxicity profile and is well tolerated by heavily pretreated, refractory/relapsed lymphoma patients. Preliminary results from this phase II trial suggest that Perifosine/Sorafenib combination therapy exerts significant anti-lymphoma activity in at least one third of relapsed/refractory HL patients, whereas no response other than SD was observed in NHL patients.

Off Label Use: Sorafenib for lymphoma.