A phase 1 study of daily oral perifosine (P) with weekly paclitaxel (T)

Abstract

13117 Background: P is an oral signal transduction modulator with limited toxicity. P combined with 3-weekly T led to no toxicity beyond that expected with each drug alone. Weekly T is more effective than 3-weekly T in some settings (Seidman, ASCO 2004:512), so this study evaluated whether weekly T altered the tolerance to P. Methods: Twelve patients (pts) were enrolled. T was given at 80 mg/m2 on days 1, 8 and 15 of a 28 day cycle. P, 50 mg, was given 1, 2 or 3 times a day on days 1–21 of each cycle. Results: Tumor types were lung 2, breast 4, endometrium 3 and other 3. Median age was 55 (range 41–82). All pts had received prior chemotherapy (median 2.5, range 1–3 regimens) and 6 a prior taxane. Three pts were entered at each dose and the cohort expanded to 6 pts if 2 or more experienced a grade 3/4 non-hematologic toxicity (DLT) during cycle 1. A dose was toxic if 4 or more pts experienced a DLT during cycle 1. Since toxicity was not dose limiting in any cohort, the 150 dose was expanded to 6 pts. There were no grade 3/4 hematologic toxicities. The grade 3/4 non-hematologic toxicities at least possibly related to perifosine are given in the table below: The high glucose values were 276 and 277. A total of 38 cycles and a median of 2.5 cycles per pt (range 1–10+) were delivered. Full dose T was given in 85% of cycles (50 mg–100%, 100 mg–85%, 150 mg–86%). Dose reductions of T in 3 pts were related to neuropathy, suspected bronchitis and fatigue. One pt treated at 100 mg requested T be stopped after 6 cycles due to neurotoxicity and has received 6 additional cycles of perifosine alone. Perifosine dose reductions were required in 13% of cycles (50 mg - 0%, 100 mg - 21%, 150 mg - 9%). One pt each was reduced due to constipation, nausea and diarrhea. Five of 7 evaluable pts had stable disease (breast 2, cervix, endometrium, thyroid) for at least 3 months. Four remain stable at 3+ to 10+ months. Conclusions: The single agent doses of P (150 mg daily) & T (80 mg/m2 weekly) were given without increasing the toxicities expected from using each drug alone. Phase II studies are warranted to define the 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

“…Furthermore, the maximum tolerated dose for the weekly perifosine was 1200 mg. 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.…”

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

“…A number of phase I trials have investigated the toxicity of combining the AKT inhibitor perifosine with traditional chemotherapeutic agents, such as docetaxel, paclitaxel, and gemcitabine [Cervera et al . 2006; Ebrahimi et al . 2006; Goggins et al .…”