A phase 1 study of daily oral perifosine (P) with every 3-week paclitaxel (T)

Abstract

13134 Background: Perifosine is a novel alkylphospholipid that has been shown to affect multiple signal transduction pathways including Akt, MAPK and JNK (Kondapaka, Mol. Canc. Ther 2: 1093–1103. 2003). Treatment with a taxane initially activates Akt, and persistent activation increases resistance to the drug (Vanderweele, Mol. Canc. Ther. 3: 1605–13, 2004). Methods: Twelve patients (pts) were enrolled on this study. T was given at a dose of 175 mg/m2 on day 8 (after 7 days of perifosine) of a 21 day cycle; this was to obtain a steady state level of P at the tumor before exposure to T. The intent of the protocol was to determine if full dose P could be delivered with 50 mg of perifosine given orally 1, 2 or 3 times a day on days 1–14 of each cycle. Results: Disease sites included lung 3, thyroid 3, breast 1, esophagus 1 and other 4, Median age was 66 (range 45 - 83); 6 pts were male and median ECOG performance status was 1 (range 0–2). All pts had received prior chemotherapy (median 2 regimens); 3 had prior treatment with a taxane. Three pts were entered at each dose level and the cohort expanded to 6 pts if 2 or more pts experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose level was toxic if 4 or more pts experienced a DLT during cycle 1. A total of 30 cycles and a median of 2 cycles (range 1–11) per patient were delivered. There were no grade 3/4 hematologic toxicities. Full dose T was given in all treatment cycles. P dose reductions were required in 6% of cycles (50 mg - 7%, 100 mg - 0%, 150 mg - 7%). One patient missed one dose due to nausea and one pt was stopped due to diarrhea. The grade 3 toxicities for each cohort are given in the table below. The elevated glucose value was 321. Nine pts were evaluable for response; two pts with thyroid cancer had stable disease by the RECIST criteria for 9 and 10+ months. Conclusions: In this study the usual single agent doses of P (150 mg daily) & T (175 mg/m2 q 3 weeks) were given together without increasing the toxicities that would be expected from using each drug alone. Phase II studies are warranted to define activity of the combination. [Table: see text] [Table: see text]

Targeting the PI3K/Akt/mTOR pathway: Effective combinations and clinical considerations

“…A phase I trial combining perifosine and radiotherapy in advanced solid tumors demonstrated that perifosine could be safely utilized as a radiation sensitizer, and phase II trials with this strategy are in development (Vink et al, 2006b). In addition, preliminary reports from a number of phase I trials investigating the combination of perifosine with traditional cytotoxic chemotherapeutic agents such as taxanes and gemcitabine indicate that these combinations can be safely administered (Cervera et al, 2006;Ebrahimi et al, 2006;Goggins et al, 2006;Weiss et al, 2006).…”

“…In trials combining mTOR inhibitors with conventional chemotherapy, unexpected toxicities in two trials lead to early discontinuation of the studies (Punt et al, 2003;Pacey et al, 2004). However, overlapping toxicities were not observed in preliminary data from trials combining perifosine with conventional chemotherapy (Cervera et al, 2006;Ebrahimi et al, 2006;Goggins et al, 2006;Weiss et al, 2006). Nevertheless, combining pathway inhibitors with conventional cytotoxic chemotherapy could result in more toxicity than when combining inhibitors with molecularly targeted agents.…”

Role of Akt signaling in resistance to DNA-targeted therapy

“…In the second trial (NCT00431054)[ 173 ] the safety and efficacy of the combination of docetaxel and perifosine were studied on 22 patients with epithelial cancer of the ovary, fallopian tube cancer or gynecologic primary peritoneal cancer, which were platinum resistant or refractory. The third phase I trial (NCT00399126)[ 174 ] studied the gastrointestinal toxicity and cancer progression on the combination of daily perifosine with weekly or every 3-wk paclitaxel in 12 cancer patients. The preliminary results showed that the combination was well tolerated without increasing the toxicities being expected from using each drug alone.…”

Therapeutic targeting of the phosphatidylinositol 3-kinase signaling pathway: novel targeted therapies and advances in the treatment of colorectal cancer

“…The PI3K/AKT pathway mediates major survival signals that protect cells from undergoing apoptosis. Thus, it is possible that in primary CRC conventional cytotoxic chemotherapeutic agents could induce PI3K/AKT activity in cancer cells [Goggins et al 2006], which could confer chemoresistance [Huang and Hung, 2009]. Thus, inhibiting PI3K signaling has the potential to improve the sensitivity of CRCs to the cytotoxic effects of standard chemotherapy.…”