Phase II Study of RAD001monotherapy in Patients With Unresectable Pheochromocytoma or Extra-adrenal Paraganglioma or Non-functioning Carcinoid
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
So we conduct this phase II study of RAD001 in this disease And we also include the
nonfunctioning carcinoid in this study.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
progression-free survival rate at 4 months
proportion of patients who are alive and progression-free at the time of 4 months of treatment among all patients
Yung-Jue Bang, MD, PhD
Seoul National University Hospital
Korea, Republic of :Food and Drug Administration