RAD001 in Pheochromocytoma or Nonfunctioning Carcinoid (PheoCarcRAD001)
- According to Martin F et al, AKT is highly phosphorylated in phenochromocytoma but not in benign adrenocortical tumors.
- In nonfunctioning carcinoid, the PI3K/AKT/mTOR pathway is activated.
- Although mTOR is clearly an attractive therapeutic target in tumor, no clinical study on mTOR inhibition by RAD001 have been conducted in pheochromocytoma or extra-adrenal paraganglioma or non-functioning carcinoid.
- So we design this phase II study of RAD001 in pheochromocytoma or extra-adrenal paraganglioma or non-functioning carcinoid to evaluate the efficacy of RAD001 in this orphan disease.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase II Study of RAD001monotherapy in Patients With Unresectable Pheochromocytoma or Extra-adrenal Paraganglioma or Non-functioning Carcinoid|
- progression-free survival rate at 4 months [ Time Frame: 10 months ] [ Designated as safety issue: No ]proportion of patients who are alive and progression-free at the time of 4 months of treatment among all patients
- time to progression (TTP) [ Time Frame: 10 months ] [ Designated as safety issue: No ]
- overall survival (OS) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
- response rate (RR) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
- metabolic response rate by PET-CT [ Time Frame: 2 months ] [ Designated as safety issue: No ]
|Study Start Date:||July 2008|
|Study Completion Date:||December 2011|
|Primary Completion Date:||May 2011 (Final data collection date for primary outcome measure)|
RAD001 10 mg daily po medication
RAD001 10 mg daily po medication.
Treatments will be continued until any of the following events occur
Although several therapeutic options exist for patients with metastatic pheochromocytoma, all options are limited and there is no cure. Reduction of tumor size palliates symptoms, but a survival advantage of debulking is unproven. A reduced tumor burden can facilitate subsequent radiotherapy or chemotherapy. External-beam irradiation of bone metastases and radio frequency ablation of lesions are treatment alternatives. Chemotherapy with a combination of cyclophosphamide, vincristin, and dacarbazine can provide tumor regression and symptom relief in up to 50% of patients, but the responses are usually short-lived. To date, 131I-labeled MIBG therapy is the single most valuable adjunct to surgical treatment of malignant pheochromocytomas. As a single agent, 131I-labeled MIBG has a limited efficacy of cure, and there is no consensus on what doses to use for treating either bone or organ metastases. Multicenter studies are required to reach a consensus on the efficacy of high-dose versus fractionated medium doses of 131I-labeled MIBG and monotherapy versus combination therapy with other radio nuclides or modes of chemotherapy.
The PI3-K/Akt/mTOR pathway is dysregulated in many cancers and is activated by several upstream proteins, such as ras, TCL1, and bcr-abl, and membrane receptor tyrosine kinases, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, c-kit, and Flt3. Increased expression and constitutive activation of the catalytic subunit of PI3-K and Akt and/or decreased or absent PTEN protein expression have been reported in many types of cancer. Activating mutation in PIK3CA, the gene for the catalytic subunit of PI3-K have been reported in 25% of gastric cancer.
Upstream in the growth-promoting pathways that converge on mTOR are critical molecules that are often deregulated in cancer. These deregulated molecules precede inappropriate signals that activate the mTOR switch, driving the growth and proliferation of the cancer cell. Because the number of potential defects that can cause inappropriate activation of mTOR is large and one or another is common to most cancer cells, blocking their effect at the point of convergence is a rational approach.
According to Martin F et al, AKT is highly phosphorylated in phenochromocytoma but not in benign adrenocortical tumors.
Although mTOR is clearly an attractive therapeutic target in tumor, no clinical study on mTOR inhibition by RAD001 have been conducted in pheochromocytoma or extra-adrenal paraganglioma.
So we conduct this phase II study of RAD001 in this disease And we also include the nonfunctioning carcinoid in this study.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01152827
|Korea, Republic of|
|Seoul National University Hospital|
|Seoul, Korea, Republic of, 110-744|
|Principal Investigator:||Yung-Jue Bang, MD, PhD||Seoul National University Hospital|
|Study Director:||Do-Youn Oh, MD, PhD||Seoul National University Hospital|