Phase II study of perifosine in metastatic renal cell carcinoma (RCC) progressing after prior therapy (Rx) with a VEGF receptor inhibitor

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5034 Background: Perifosine, a synthetic alkylphospholipid, inhibits or modulates a number of different signal transduction pathways (AKT, MAPK and JNK). In a prior trial, 15 RCC patients (pts) were enrolled in a randomized dose finding study, 9 were evaluable for response and 3 (33%) had a partial response (PR). Thus phase II trials were begun for pts who had been treated with one prior VEGFr inhibitor (Group A) or with a prior VEGFr inhibitor and prior mTOR inhibitor (Group B). We report the results of Group A (closed), and Group B (enrollment open). Methods: To measure the objective response rate (RECIST) and PFS to single agent perifosine (100 mg qhs with food) after 3 mos of Rx; Prior Rx with vaccine therapy, bevacizumab and/or cytokines was permitted. Normal organ/marrow function was required. Results: From 12/07–12/08, 46 pts (31 Group A/ 15 Group B) were treated at 13 sites. Median age 64 (range 46–80) and 36 were male; Median prior Rx was 2 (range 1 - 5); Clear cell = 37, non clear cell = 6, data n/a = 3. Prior sunitinib = 35, prior sorafenib = 10, 1 unknown due to blinded study. Prior mTOR; Tem = 9 and Rad001 = 6. As of 12/08, 44 pts were evaluable for response and PFS (two pts not eval; 1 withdrew consent, 1 toxicity < 5 days on Rx). Results listed in the table below. As of 12/08, 12/44 pts (5 Group A/ 7 Group B) remain on treatment. Median survival; not reached. Most common toxicity was grade 1 & 2 nausea (56%), arthralgia (47%), vomiting (36%), fatigue (33%) and cognitive changes (28%). Grade 3 & 4 toxicity was uncommon; arthralgia (14%) and hyperuricemia/gout (8%). Conclusions: Perifosine, similar to mTOR inhibitors, appears to have clinical benefit in mRCC as reflected by the PR rate and a 15 wk median overall PFS. This is most notably in patients who failed both a prior VEGFr and mTOR inhibitor where 7/14 remain on study as of 12/08. Randomized studies are under consideration to further evaluate perifosine's clinical benefit as 2nd or 3rd line therapy of mRCC. [Table: see text] [Table: see text]