| General information |
| Database: | DB00492 |
| Objective: | The clinical activity of allosteric inhibitors of mammalian target of rapamycin (mTOR) inhibitors in renal cell carcinoma (RCC) may be limited by upstream activation of phosphatidylinositol 3 (PI3)kinase/Akt resulting from mTOR1 inhibition. On the basis of this rationale, 2 independentphase 2 trials (Perifosine 228 and 231) were conducted to assess the efficacy and safety of the novel Akt inhibitor perifosine in patients with advanced RCC who had failed on previous vascular endothelial growth factor (VEGF)targeted therapy. |
| Authors: | Cho DC, et al |
| Title: | Twophase 2 trials of the novel Akt inhibitor perifosine in patients with advanced renal cell carcinoma after progression on vascular endothelial growth factortargeted therapy. |
| Journal: | Cancer. |
| Year: | 2012 |
| PMID: | 22674198 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | perifosine
|
| Target: | AKT1 protein kinase
|
| Cancer Type: | renal cell carcinoma |
| Cancer Subtype: | advanced renal cell carcinoma |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | singlearm open labelphase II trial |
| Key Patients Feature: | adult patients (>18 years old) with ECOG performancestatus 0 or 1 with confirmed metastatic RCC were required to have documented RECIST(Response Evaluation Criteria in Solid Tumors) defined disease progression followingtreatment with sunitinib or sorafenib. Prior therapy with bevacizumab and/or cytokines (i.e., IL2, interferon) was permitted, as was prior vaccine therapy in the adjuvant setting. Patientsenrolled in Perifosine 228 and Group A of Perifosine 231 were not allowed to have had priortreatment with an mTOR inhibitor while patients enrolled in Group B of Perifosine 231 wereallowed to have failed therapy with one prior mTOR inhibitor. No prior brain metastasiswere allowed on Perifosine 228 while patients with CNS metastases were allowed onPerifosine 231 provided that: 1) CNS disease was documented by stable or regressinglesions on MRI after radiation therapy, surgery, or both; 2) patients were off corticosteroidsfor at least 1 month; and 3) patients had completed radiation therapy >28 days prior to studyentry |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | 2 independentphase 2 trials (Perifosine 228 and 231):: Perifosine 228 trial, 24 patients with advanced RCC received oral perifosine (100 mg daily). ;Perifosine 231:Group A comprised 32 patients who had received no prior mTOR inhibitor, and Group B comprised 18 patients who had received 1 prior mTOR inhibitor. |
| Treatment Info: | In the Perifosine 228 trial, 24 patients with advanced RCC received oral perifosine (100 mg daily). Perifosine 231 enrolled 2 groups that received daily oral perifosine (100 mg daily): Group A comprised 32 patients who had received no prior mTOR inhibitor, and Group B comprised 18 patients who had received 1 prior mTOR inhibitor |
| Primary End Point: | the proportion of patients progression free at 12 weeks. |
| Secondary End Point: | NA |
| Patients Number: | 74 |
| Trial Results |
| DLT_MTD: | NA |
| Objective Response Rate: | In the Perifosine 228 trial, 1 patient achieved a partial response (objective response rate, 4%; 95% confidence interval, 0.7%20%), and 11 patients (46%) had stable disease as their best response. In the Perifosine 231 trial, 5 patients achieved a partial response (objective response rate, 10%; 95% confidence interval, 4.5%22.2%) and 16 patients (32%) had stable disease as their best response. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 14 weeks [95% CI (12.9, 20.7)] |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Overall, perifosine was well tolerated with very few grade 3 and 4 events. Most common toxicities included nausea, diarrhea, musculoskeletal pain, and fatigue. |
| Conclusions: | Although perifosine demonstrated activity in patients with advanced RCC after failure on VEGFtargeted therapy, its activity was not superior to currently available secondline agents. Nonetheless, perifosine may be worthy of further study in RCC in combination with other currently available therapies. |