Aeterna Zentaris Inc. (NASDAQ: AEZS) (TSX: AEZ) today announced that final Phase 2 data demonstrated that the combination of perifosine, its oral AKT inhibitor, and sorafenib, was well tolerated by heavily pretreated patients with relapsed/refractory lymphomas. Furthermore, promising clinical response activity was observed in patients with classical Hodgkin Lymphoma ("HL"), suggesting that this subgroup could represent the target population for future studies. Data were presented yesterday by Anna Guidetti, MD, of the Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, during a poster session at the American Society of Hematology annual meeting in Atlanta, Georgia.
This investigator-driven Phase 2 trial sponsored by the Fondazione IRCCS Istituto Nazionale Tumori, involved 40 patients with relapsed/refractory lymphomas who had failed second or subsequent-line salvage chemotherapy: there were 3 patients with diffuse large B-cell lymphoma, 3 with follicular lymphoma, 1 with Waldenstrom macroglobulinemia, 8 with chronic lymphocytic leukemia ("CLL") and 25 with classical Hodgkin lymphoma ("HL"). At study entry, 12 patients (30%) had relapsed and 28 (70%) refractory disease. Treatment plan included an initial 4 week treatment with perifosine (50 mg BID, per os) to assess tolerability and tumor response. Subsequently, patients achieving less than partial response ("PR") were given perifosine (50 mg BID, per os) combined with sorafenib (400 mg BID, per os) until progression of disease ("PD") or significant clinical toxicity. Patients achieving at least a PR went off-study and continued with perifosine (50 mg BID, per os) alone until PD or clinical toxicity. Tumor response was assessed according to the revised response criteria for malignant lymphoma of the International Working Group.
Based on tumor response to the initial 4 week perifosine therapy, 36 of 40 patients who achieved less than PR were subsequently administered the perifosine/sorafenib combination therapy. Median duration of combination therapy was 4 months (range: 2-18). Four CLL patients who achieved at least a PR with perifosine alone, went off-study and continued with single-agent therapy with a median duration of response of 10 months (range 4-21). The most common drug-related toxicities were grade 1-2 diarrhea (25%), joint pain (22%), weight loss (19%), anemia (17%), and thrombocytopenia (9%). Hand-foot skin reaction was observed in 25% (grade 2) and 14% (grade 3) of patients. Grade 4 neutropenia was observed in only 1 patient. Two responding patients experiencing grade 3 pneumonitis discontinued treatment.
For the 36 patients treated with combination therapy, 8 (22%) PR, 15 (42%) stable disease ("SD") and 13 (36%) PD were observed. Median time to achieve PR was 4 months (range 1-8) and median duration of response was 4 months (range 1-12). Median overall survival ("OS") and progression free survival ("PFS") for all patients were 16 and 5 months, respectively.
For the 25 patients in the HL subgroup also receiving combination therapy, the overall response-rate was 28%, with 7 PR; for HL patients, median OS and PFS were 16 and 5 months respectively, as it was for all patients.
A significant correlation between pErk and pAkt reduction during the first 2 months of therapy and clinical response was demonstrated by logistic regression model. The reduction of pErk and pAkt values (i.e difference between baseline values vs 60 day values) was related to a highly significant probability to observe a clinical response (p = 0.0003 and p = 0.005 for pErk and pAkt, respectively).
Combination of perifosine and sorafenib was well tolerated by heavily pretreated lymphoma patients. Promising clinical response activity was observed in relapsed/refractory HL patients, suggesting that this subgroup could represent the target population for future studies. Early reduction of pERK and pAK has a significant predictive value of clinical response.