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RAD001 in Pheochromocytoma or Nonfunctioning Carcinoid (PheoCarcRAD001)

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ClinicalTrials.gov Identifier: NCT01152827
Recruitment Status : Completed
First Posted : June 29, 2010
Last Update Posted : May 20, 2015
Sponsor:
Information provided by (Responsible Party):
Seoul National University Hospital

Tracking Information
First Submitted Date  ICMJE May 31, 2010
First Posted Date  ICMJE June 29, 2010
Last Update Posted Date May 20, 2015
Study Start Date  ICMJE July 2008
Actual Primary Completion Date May 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 28, 2010)
progression-free survival rate at 4 months [ Time Frame: 10 months ]
proportion of patients who are alive and progression-free at the time of 4 months of treatment among all patients
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01152827 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 28, 2010)
  • time to progression (TTP) [ Time Frame: 10 months ]
  • overall survival (OS) [ Time Frame: 2 years ]
  • response rate (RR) [ Time Frame: 6 months ]
  • metabolic response rate by PET-CT [ Time Frame: 2 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE RAD001 in Pheochromocytoma or Nonfunctioning Carcinoid
Official Title  ICMJE Phase II Study of RAD001monotherapy in Patients With Unresectable Pheochromocytoma or Extra-adrenal Paraganglioma or Non-functioning Carcinoid
Brief Summary
  • 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Pheochromocytoma
  • Extra-adrenal Paraganglioma
  • Non-functioning Carcinoid
Intervention  ICMJE Drug: RAD001

RAD001 10 mg daily po medication.

Treatments will be continued until any of the following events occur

  • progression of disease
  • the subject develops unacceptable toxicity
  • consent to participate in the study is withdrawn
Study Arms  ICMJE Experimental: RAD001
RAD001 10 mg daily po medication
Intervention: Drug: RAD001
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 28, 2010)
33
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 2011
Actual Primary Completion Date May 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 assessment.
  • 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 medications.
  • 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 lungs
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01152827
Other Study ID Numbers  ICMJE H-0710-049-223
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Seoul National University Hospital
Study Sponsor  ICMJE Seoul National University Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Yung-Jue Bang, MD, PhD Seoul National University Hospital
Study Director: Do-Youn Oh, MD, PhD Seoul National University Hospital
PRS Account Seoul National University Hospital
Verification Date June 2010

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP