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Phase II Study of RAD001monotherapy in Patients With Unresectable Pheochromocytoma or Extra-adrenal Paraganglioma or Non-functioning Carcinoid

Phase 2
18 Years
Open (Enrolling)
Pheochromocytoma, Extra-Adrenal Paraganglioma, Non-functioning Carcinoid

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Trial Information

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.

Inclusion Criteria:

- 1. Histologically or cytologically confirmed pheochromocytoma or extra-adrenal
paraganglioma or carcinoid

- 2. Local, locally-advanced or metastatic disease documented as having shown
progression on a scan (CT, MRI, MIBI scan) taken 2 to 12 months prior to baseline
compared to a previous scan taken at any time in the past. Progression must be
documented according to RECIST criteria.

- 3. Disease that is not amenable to surgery, radiation or combined modality therapy
with curative intent.

- 4. Presence of at least one measurable target lesion for further evaluation according
to RECIST criteria

- 5. 18 years or older

- 6. ECOG performance status 0, 1

- 7. Previous treatment with chemotherapy, loco-regional therapy (e.g
chemoembolization) are permitted providing that toxicity has resolved to ≤grade 1 at
study entry and that last treatment was at least 4 weeks prior to baseline

- 8. Adequate organ function

- 9. A patient with the willingness to comply with the study protocol during the study
period and capable of complying with it

- 10. A patient who signed the informed consent prior to the participation of the study
and who understands that he/she has a right to withdrawal from participation in the
study at any time without any disadvantages.

Exclusion Criteria:

- 1. A patient with no measurable disease

- 2. Prior chemotherapy, radiation therapy or surgery within 4 weeks prior to study
entry except palliative radiotherapy to non-target lesions (within 2 weeks prior to
study entry)

- 3. A patient with functioning carcinoid

- 4. A patient with previous active or passive immunotherapy

- 5. A patient with intestinal obstruction or impending obstruction, recent active
upper GI bleeding

- 6. A pregnant or lactating patient

- 7. A patient of childbearing potential without being tested for pregnancy at baseline
or with being tested for positive. (A postmenopausal woman with the amenorrhea period
of at least 12 months or longer is considered to have non-childbearing potential)

- 8. A man or woman of childbearing potential who has no willingness to use a
contraceptive measure during the study

- 9. A patient with history of another malignant disease within past 5 years, except
curatively treated basal cell carcinoma of skin and cervical carcinoma in situ.

- 10. A patient with history of uncontrolled seizures, central nervous system disorder
or psychiatric disorders that are considered clinically significant by the
investigator that would prohibit the understanding of informed consent or that may be
considered to interfere with the compliance of the administration of the study

- 11. A patient with clinically significant heart disease (e.g. congestive heart
failure, symptomatic coronary artery diseases, cardiac arrhythmia, etc) or myocardial
infarction within past 12 months.

- 12. Ongoing cardiac arrhythmia of grade ≥2, atrial fibrillation of any grade, or QTc
interval>450msec for males or >470msec for female.

- 13. A patient with interstitial pneumonia or diffuse symptomatic fibrosis of the

- 14. A patient with peripheral neuropathy of grade 1 by NCI CTC, caused by other
factors (e.g. alcohol, diabetes, etc). If the absence of deep tendon reflexes is the
only neurologic disorder, this condition does not apply to the exclusion criteria.

- 15. A patient with organ transplantation requiring immunosuppressive therapy

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

progression-free survival rate at 4 months

Outcome Description:

proportion of patients who are alive and progression-free at the time of 4 months of treatment among all patients

Outcome Time Frame:

10 months

Safety Issue:


Principal Investigator

Yung-Jue Bang, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Seoul National University Hospital


Korea, Republic of :Food and Drug Administration

Study ID:




Start Date:

July 2008

Completion Date:

December 2011

Related Keywords:

  • Pheochromocytoma
  • Extra-adrenal Paraganglioma
  • Non-functioning Carcinoid
  • Pheochromocytoma
  • extra-adrenal paraganglioma
  • non-functioning carcinoid
  • RAD001
  • Carcinoid Tumor
  • Paraganglioma
  • Paraganglioma, Extra-Adrenal
  • Pheochromocytoma