Dejka M. Araujo. Assistant Professor, Sarcoma Medical Oncology, MD Anderson Cancer Center in Houston, Texas is the Principal Investigator for this clinical trial which is open to accrual at sites across the United States.
Trial Background
Akt activation has been shown to be important in a number of different cancer types, and for this reason it has become one of the most intensely studied signal transduction pathways in the past several years. Signaling through the PI3-K/Akt pathway, with the Akt proteins (also called protein kinase B (PKB)), acts to promote cell proliferation and survival though promotion of the cell cycle, meaning the cell will divide at an irregular, heightened pace.
Thus far, Akt proteins have been found to be overexpressed in ovarian, breast, prostate, and pancreatic cancers. Elevated levels have also been found to correlate with poor prognosis in patients with gastric, hepatocellular, endometrial, prostate, renal cell and head and neck cancers, as well as glioblastoma. The majority of tumors expressing pAkt were high-grade, advanced stage or had other features associated with poor prognosis. Akt proteins have also been implicated in the diagnosis of many sarcomas.
There are several ways in which Akt can be abnormally or persistently activated in cancer cells. Constituents of the pathway may be found in abnormally high concentrations in certain types of cancers. In other types, mutations of a related tumor suppressor gene are the cause of increased Akt activation and may rival p53 mutations in frequency in relevance to a substantial fraction of common adult cancer types.
Perifosine is an active oral anticancer agent with a novel mechanism of action that is known to inhibit or otherwise modify activity in the Akt pathway. It is designed to reduce the activity of the protein to stop tumor cell proliferation, differentiation, invasion, and metastasis.
In prior studies, KRX-0401 (perifosine) has been shown to be quite active in the treatment of soft tissue sarcoma. Responding patients experienced very little toxicity and the duration of responses observed varied from 6 months to more than 18 months. Several types of sarcomas that responded to perifosine in prior trials are particularly interesting because they are generally thought to be unresponsive to chemotherapy and no treatment has been approved for them by the FDA.
Its safety profile has been found to be distinctly different from that of most cytotoxic agents, and consists of generally mild side effects. It causes dose-related nausea, vomiting, diarrhea and fatigue. Responding patients, however, have been treated for months to more than a year with almost no symptoms at all.
Results from the Phase I and II trials previously conducted with Perifosine have prompted Keryx to collaborate with SARC and conduct another study to further investigate the efficacy of this drug in treating sarcomas.
Trial
This is a phase II study of perifosine in patients with chondrosarcomas, alveolar soft part sarcomas and extra-skeletal myxoid chondrosarcomas. Patients will take 100 mg (two 50 mg tablets) of perifosine each day at bedtime with food.
Patients may continue to take perifosine for as long as they are benefitting. They will be taken off study if the disease gets worse or intolerable side effects occur.
Response to therapy will be based on regression of measurable disease according to Choi criteria. Time to progression and duration of stable disease will be measured as secondary endpoints of the study.
Up to 111 patients will take part in this multicenter study.
Participation in the trial
To be eligible to participate in this trial a patient must:
· Patients must have a confirmed diagnosis of chondrosarcoma, extra-skeletal myxoid chondrosarcoma or alveolar soft part sarcoma.
· At least 13 years of age.
· Patients may have had prior chemotherapy, but if the patient has had three or more forms of prior chemotherapy for metastases, the patient's clinical course should be discussed with the study chairman before the patient is enrolled on study
· Patients must have evidence of disease progression (as defined by Choi criteria).
· The patient may still be able to participate if he/she is restricted in physically strenuous activity but is mostly able to carry out work of a light or sedentary nature, e.g., light house work, office work.
· Patients must have normal organ and marrow function.
· Patients must have recovered from side effects related to prior treatments
· Female patients who are pregnant or lactating are ineligible.
Patients would NOT be able to participate in the study if they have:
· History of allergic reactions attributed to compounds of similar chemical or biologic composition to perifosine (miltefosine or edelfosine).
· Uncontrolled intercurrent illness—including, but not limited to, ongoing or active infection—and psychiatric illness/social situations that would limit compliance with study requirements.
· Patients with a history of unstable or newly diagnosed angina pectoris, recent myocardial infarction (within 6 months of enrollment) or other conditions affecting the heart.
*this represents only a partial list of requirements to be included or excluded from the study. A complete list is available from SARC or Dr. Araujo.
For more information contact SARC at 734.930.7600 or Dr. Araujo at 713.792.3626.
This trial is registered at clinicaltrials.gov and can be found at: http://www.clinicaltrials.gov/ct/show/NCT00401388?order=1
The full title is: A Phase II Trial of Perifosine in Patient with Chemo-Insensitive Sarcomas
Glossary:
*tumor suppressor gene: One of a pair of genes (units of heredity passed from parent to offspring) that causes the cell to make a protein that controls cell growth. Cancer may develop when the tumor suppressor protein does not work because of mutations (changes in the DNA ) in the genes. The mutations in the tumor suppressor genes can be inherited or acquired. Also called antioncogene
*p53 gene: A tumor suppressor gene that normally inhibits the growth of tumors. This gene is altered in many types of cancer.
*PI3-K/Akt pathway:
