Publikationsdatum:
2007-11-16
Beschreibung:
INTRODUCTION: Perifosine (peri) is an oral, novel synthetic alkylphospholipid, with multiple effects on signal transduction pathways, including inhibition of Akt and activation of JNK. In vitro studies showed that peri induces cytotoxicity in both MM cell lines and patient (pt) MM cells resistant to conventional therapies, and augments dexamethasone (dex) and bortezomib-induced MM cell cytotoxicity (Hideshima T. et. al. BLOOD 2006). In vivo studies showed antitumor activity in a human plasmacytoma mouse model. Here we report the results of a phase II trial of peri, alone and + dex, in pts with relapsed or relapsed / refractory MM. METHODS: Pts received 150 mg of peri daily for a 21 day (d) cycle, and were assessed every cycle by serum- and/or urine-electrophoresis. Eligible pts had symptomatic relapsed or relapsed / refractory MM. Pts were permitted to receive bisphosphonate treatment. Concomitant steroids (prednisone 〉 10 mg/d), creatinine of 〉 3.0 mg/dL, and hemoglobin 〈 8.0 g/dL within 14 d of enrollment were exclusion criteria. Progressing pts, documented on 2 occasions at least one week apart, had dex 20 mg twice per week added to peri. Toxicities were assessed by NCI-CTCAE, v3.0. RESULTS: 64 pts (35 M/ 29 F, median age 62, range 38–79) have been treated to date. Median lines of prior treatment was 4 (range 1–11); 32 (50%) pts had relapsed and refractory MM. Prior therapy included dex (95%), thalidomide (89%), bortezomib (73%), lenalidomide (30%) and ASCT (61%). Among 48 pts currently evaluable for response, best response (EBMT criteria) to single agent peri after ≥ 2 cycles was MR in 1 pt, stable disease (〈 25% reduction in M-protein) in 22 pts (46%). Dex was added in 37 pts with PD, with 31 pts evaluable for response on the combination as follows: Peri + Dex N (%) Duration (wks) PR 4 (13%) 17, 24, 44+, 46+ MR 8 (25%) 3+, 12+, 19, 21, 25, 30, 32, 55+ Stable Disease 15 (47%) 6+ − 46 (median 12)* *4 pts ongoing at 6, 9, 11 and 24 wks Most common adverse events included nausea (74%, 8% G3); vomiting (61%, 5% G3); diarrhea (65%, 2% G3); fatigue (31%, 2% G3), increased creatinine (51%, 7% G3/4 in the context of PD and light chain nephropathy but reversible) and anemia (63%, 5% G3). 10 pts had G3/4 neutropenia which resolved. Dose reduction was required to 100 mg/d (n=16) or to 50 mg/d (n=4). 9 pts discontinued treatment due to side effects. Attributable toxicities otherwise proved manageable with supportive care and no peripheral neuropathy or DVT seen. CONCLUSION: Perifosine as monotherapy has modest activity, but in combination with dex showed significant activity in pts with relapsed/refractory MM, achieving PR + MR in 38%, and/or stabilization of disease in 47% of evaluable pts to date. It was generally well tolerated, although caution in pts with renal dysfunction is warranted. PK, IHC and gene array studies are ongoing. Other novel studies with peri in combination with bortezomib and with lenalidomide +/−dex are underway.
Print ISSN:
0006-4971
Digitale ISSN:
1528-0020
Thema:
Biologie
,
Medizin
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