A phase II study of perifosine in androgen independent prostate cancer

Posadas, Edwin M.; Gulley, James L.; Arlen, Philip M.; Trout, A.; Parnes, Howard L.; Wright, John J.; Lee, Min-Jung; Chung, Eun Joo; Trepel, Jane B.; Sparreboom, Alex; Chen, Clara; Steinberg, Seth M.; Daniels, Andrew; Figg, William D.; Dahut, William L.

doi:10.4161/cbt.4.10.2064

Cited by 98 publications

(57 citation statements)

References 23 publications

(34 reference statements)

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“…Perifosine failed to show significant antitumor activity in prostate cancer, melanoma, and pancreatic cancer. [29][30][31] In addition, perifosine at a similar dose and schedule as in the present study showed some activity in patients with refractory sarcomas, however, this did not satisfy criteria for continuation of accrual beyond the first stage of a two-stage design. 32 Ongoing or recently completed clinical trials are evaluating perifosine in combination with radiation as well as standard chemotherapy.…”

Section: Discussionmentioning

confidence: 84%

A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer

Argiris

Cohen

Karrison

et al. 2006

Cancer Biology & Therapy

109

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Background: Novel, effective therapies are warranted in the management of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Perifosine is an oral alkylphospholipid that inhibits AKT phosphorylation and has shown preclinical antitumor activity in head and neck cancer cell lines and xenografts.Patients And Methods: We conducted a phase II trial of perifosine in patients with incurable, recurrent or metastatic SCCHN. Previous therapy for recurrent or metastatic disease was limited to no more than one prior chemotherapy and one prior targeted/ biologic agent regimen. Patients had to have measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and adequate laboratory parameters. Perifosine was given as a loading dose of 150 mg every 6 hours × 6 doses orally in the first two days, with antiemetic prophylaxis, followed by 100 mg/day orally without interruption. Administration via gastrostomy tube was allowed. Tumor response was assessed every two cycles (eight weeks). Biomarkers in pathways potentially affected by perifosine, including AKT, P-AKT, P38, p53 and p21 were measured on tumor tissue by immunohistochemistry by manual and automated methods.Results: Nineteen patients were enrolled. No objective responses were observed. One patient had stable disease as best response and 18 patients progressed at first evaluation. The median overall survival time was 5.5 months and the median progression-free survival time was 1.7 months. The most frequent toxicities were gastrointestinal (constipation, nausea, vomiting) and fatigue. One patient developed grade 4 anorexia. Although the sample size was small, a significant correlation was detected between high expression of P38 and AKT in baseline tumor tissue and better survival.Conclusions: Perifosine in the doses and schedule used lacks single-agent activity in SCCHN. Our data do not justify further investigation of perifosine as a single agent in SCCHN.

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Section: Discussionmentioning

confidence: 84%

A phase II trial of perifosine, an oral alkylphospholipid, in recurrent or metastatic head and neck cancer

Argiris

Cohen

Karrison

et al. 2006

Cancer Biology & Therapy

109

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“…53 A National Cancer Institute study of 19 men with metastatic AI CaP and average PSA of 180 ng/ml showed no objective or PSA responses, and four patients with PSA stabilization for 12 weeks. 54 Although perifosine is apparently relatively ineffective as monotherapy, the strong preclinical rationale combined with preclinical results showing synergism with other Akt inhibitory drugs suggest the need for more trials examining its role in an adjunctive setting. 55 Phase I trials are already underway for perifosine combined with docetaxel, paclitaxel, gemcitabine and radiation therapy.…”

Section: Perifosinementioning

confidence: 99%

Inhibition of Akt pathways in the treatment of prostate cancer

Nelson

Evans

Mack

et al. 2007

Prostate Cancer Prostatic Dis

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Akt is a serine/threonine kinase mediating multiple intracellular pathways involved in prostate cancer (CaP) biology. Increased understanding of the molecular mechanisms of Akt activation and signaling have led to the development of an increasing number of Akt inhibitors. These biologic agents demonstrate activity against a wide range of cancers in preclinical studies. Clinical studies of Akt inhibition in CaP are in progress, including agents such as celecoxib, perifosine and genistein. How best to integrate Akt inhibitors with standard CaP therapy or select patients most likely to benefit is the subject of ongoing research.

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“…Encouraging evidence of antitumor activity as single agent or in combination with radiation was reported in phase I clinical trials, in particular, in the treatment of non-small cell lung cancer patients. However, no significant clinical activity was observed in phase II studies in previously untreated patients with metastatic melanoma (Ernst et al, 2005), and in patients with progressive, metastatic androgenindependent prostate cancer (Posadas et al, 2005). An extensive phase II clinical program is currently under way, including trials in breast, head and neck, kidney, lung, prostate, glioma, leukemia, sarcoma and multiple myeloma.…”

Section: Phospholipids-antagonists Of Ph Domainsmentioning

confidence: 99%