An important target in cancer treatment is the serine/threonine specific protein kinase Akt, or protein kinase B. This kinase is involved in the pathway that prevents cell death, inhibiting apoptosis, and therefore inhibiting Akt may lead to cancer cell death.
One such compound is perifosine, discovered by Aeterna Zentaris and being developed by Keryx Biopharmaceuticals.1 Numerous clinical trials have been carried out in solid tumours, with varying success, and it failed a Phase III trial in colorectal cancer in 2012. However, it continues in trials for blood cancers such as lymphomas, where it shows promise.
In one Phase I/II trial, it was evaluated in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma who had previously received bortezomib therapy.2 A total of 84 patients, three-quarters of whom were refractory to bortezomib, and half to both bortezomib and dexamethasone, were given 50mg/day of perifosine, plus 1.3mg/m2 bortezomib, and 20mg dexamethasone added if progression occurred. The overall response rate was 43% in the 73 evaluable patients – 65% in the bortezomib-relapsed group and 32% in bortezomib-refractory patients. It was generally well tolerated, with manageable gastrointestinal events and fatigue. The median progression-free survival was 6.4 months, and a median overall survival of 25 months – 22.5 months in those refractory to bortezomib.
It has also been investigated in a Phase I trial in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma.3 A total of 32 subjects in four dose cohorts were given daily escalating doses of 50 to 100mg of perifosine alongside 15–25mg/day of lenalidomide for the first 21 days of a 28 day cycle, plus 20–40mg/day of dexamethasone weekly after this. All bar one subject was evaluable, and the maximum tolerated dose was not reached. The most frequently observed adverse events were fatigue and diarrhoea, which each occurred in nearly half of the patients, plus neutropoenia, hypophosphataemia, thrombocyto-poenia and leucopoenia. At least a minimal response was achieved by 22 patients, and 15 achieved at least a partial response. The median progression-free survival was 10.8 months, and median overall survival 30.6 months.
It is also being investigated in patients with heavily pretreated relapsed or refractory lymphomas.4 A total of 40 patients with various lymphomas – 25 of whom had classical Hodgkin’s lymphoma – were enrolled in the study; 12 had relapsed and 28 refractory disease. An initial four-week treatment with twice-daily 50mg doses of perifosine to determine tolerability and tumour response was followed by the 36 patients who achieved less than a partial response being given twice-daily doses of sorafenib as well as the perifosine.
The four subjects who achieved a partial response, all of whom had chronic lymphocytic leukaemia, continued on perifosine alone until disease progression or clinical toxicity occurred, with a median duration of response of 10 months. Eight patients achieved a partial response on the combination therapy, along with 15 stable disease, while 13 had disease progression. The partial response rate was slightly higher in the Hodgkin’s lymphoma group, at 28%. Trials continue.
References
1. P. Hilgard et al. Eur. J. Cancer, 1997, 33, 442
2. P.G. Richardson et al. J. Clin. Oncol. 2011, 29, 4243
3. A.J. Jakubowiak et al. Br. J. Haematol. 2012, 158, 472
4. A. Guidetti et al. Amer. Soc. Hematol. 2012 (8-11 Dec, Atlanta), Abst. 3679
