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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT00363051
Other study ID # CRAD001C2239
Secondary ID
Status Completed
Phase Phase 2
First received August 2, 2006
Last updated May 6, 2013
Start date June 2006
Est. completion date April 2012

Study information

Verified date May 2013
Source Novartis
Contact n/a
Is FDA regulated No
Health authority United States: Food and Drug Administration
Study type Interventional

Clinical Trial Summary

The purpose of this study was to assess the efficacy and safety of everolimus in the treatment of advanced pancreatic neuroendocrine tumor (NET) not responsive to cytotoxic chemotherapy. All patients were treated with everolimus until either tumor progression was documented using a standard criteria that measures tumor size called Response Evaluation Criteria in Solid tumors (RECIST), or until unacceptable toxicity occurred, or until the patient or investigator requested discontinuation of treatment.


Description:

This was a stratified two-stage, single-arm, phase 2 study of treatment with everolimus in patients with advanced (unresectable or metastatic) pancreatic neuroendocrine tumor (NET) after failure of cytotoxic chemotherapy.

Stratum 1, consisted of patients not receiving chronic Octreotide Depot therapy, will receive everolimus monotherapy at 10 mg/day.

Stratum 2, consisting of patients with tumors that have progressed during Octreotide Depot treatment will continue their entry dose of Octreotide Depot plus everolimus 10 mg/day.


Recruitment information / eligibility

Status Completed
Enrollment 160
Est. completion date April 2012
Est. primary completion date January 2008
Accepts healthy volunteers No
Gender Both
Age group 18 Years and older
Eligibility Inclusion criteria for both strata:

- Advanced (unresectable or metastatic) biopsy-proven pancreatic Neuroendocrine tumor (NET)

- Confirmed low-grade or intermediate-grade neuroendocrine carcinoma

- Objective disease progression by Response Evaluation Criteria in Solid tumors (RECIST) criteria while receiving cytotoxic chemotherapy or at any time after receiving an adequate course of cytotoxic chemotherapy (i.e., at least 3 consecutive cycles or months of treatment with the same cytotoxic drug or regimen)

- Presence of at least one measurable disease using RECIST criteria at screening (computer tomography [CT] or Magnetic resonance imaging [MRI])

- Adequate bone marrow, liver and kidney function

- WHO Performance Status 0-2.

Inclusion criteria for Stratum 2 only:

- Meet all inclusion criteria defined above for both strata.

- Receiving treatment (at least 3 consecutive months) with Octreotide Depot.

- In addition to documentation of progressive disease on or after chemotherapy, patients in stratum 2 must have documented objective progression of disease while receiving Octreotide Depot.

Exclusion criteria for both strata:

- Anticancer therapy within 3 weeks of enrollment.

- Patients with poorly differentiated neuroendocrine carcinoma

- Hepatic artery embolization within the last 6 months

- Prior therapy with everolimus or other rapamycins (sirolimus, temsirolimus)

- Other concurrent malignancy

- Other serious intercurrent infections or nonmalignant uncontrolled medical illnesses

Exclusion Criterion for Stratum 1 only:

• Received treatment with Octreotide Depot or any other long-acting somatostatin analogue in the 60 days prior to enrollment or any short-acting somatostatin analogue in the two weeks prior to enrollment.

Other protocol-defined inclusion/exclusion criteria applied.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment


Intervention

Drug:
Everolimus 10 mg
Participants took two 5 mg tablets of Everolimus orally with a glass of water, once daily (preferably in the morning) in a fasting state or after no more than a light, fat-free meal. Dosing was to occur at the same time each day. If vomiting occurred, the vomited dose was not to be replaced.
Octreotide Depot


Locations

Country Name City State
Argentina Novartis Investigative Site Buenos Aires
Argentina Novartis Investigative Site Santa Fe
Australia Novartis Investigative Site Heidelberg
Australia Novartis Investigative Site Herston
Australia Novartis Investigative Site Kogarah
Belgium Novartis Investigative Site Leuven
Canada Novartis Investigative Site Halifax Nova Scotia
Canada Novartis Investigative Site London Ontario
Canada Novartis Investigative Site Montreal Quebec
Canada Novartis Investigative Site Toronto Ontario
Canada Novartis Investigative Site Vancouver British Columbia
France Novartis Investigative Site Billancourt
France Novartis Investigative Site Clichy Cedex
France Novartis Investigative Site Lyon Cedex
France Novartis Investigative Site Reims
France Novartis Investigative Site Toulouse
France Novartis Investigative Site Villejuif Cedex
Germany Novartis Investigative Site Berlin
Germany Novartis Investigative Site Erlangen
Germany Novartis Investigative Site Essen
Germany Novartis Investigative Site Frankfurt
Germany Novartis Investigative Site Heidelberg
Germany Novartis Investigative Site Marburg
Germany Novartis Investigative Site Ulm
Italy Novartis Investigative Site Milano
Italy Novartis Investigative Site Modena
Italy Novartis Investigative Site Pisa
Italy Novartis Investigative Site Rome
Italy Novartis Investigative Site Torrette di Ancona
Netherlands Novartis Investigative Site Gronigen
Spain Novartis Investigative Site Barcelona
Spain Novartis Investigative Site L'Hospitalet de Llobregat
Spain Novartis Investigative Site Madrid
Sweden Novartis Investigative Site Uppsala
United States Emory University Hospital Atlanta Georgia
United States The University of Alabama at Birmingham Birmingham Alabama
United States Dana Farber Cancer Institute Boston Massachusetts
United States Arthur G. James Cancer Hospital/Ohio State University Columbus Ohio
United States Duke University Medical Center Durham North Carolina
United States M. D Anderson Cancer Center Houston Texas
United States University of Iowa Hospitals and Clinics Iowa City Iowa
United States Dartmouth Hitchcock Medical Center Lebanon New Hampshire
United States Cedars-Sinai Outpatient Cancer Center/Samuel Oschin Comprehensive Cancer Inst. Los Angeles California
United States UCLA Medical Center Los Angeles California
United States USC Medical Center Los Angeles California
United States University of Wisconsin Hospital & Clinics Madison Wisconsin
United States University of Miami Miami Florida
United States LSUHC Multispecialty Clinic New Orleans Louisiana
United States Lynn Ratner, M.D. New York New York
United States Oregon Health and Science University Portland Oregon
United States Mayo Clinic Rochester Minnesota
United States UCSF Comprehensive Cancer Center San Francisco California
United States H. Lee Moffit Cancer Center & Research Institute Tampa Florida
United States Scott & White Memorial Hospital Temple Texas

Sponsors (1)

Lead Sponsor Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Canada,  France,  Germany,  Italy,  Netherlands,  Spain,  Sweden, 

Outcome

Type Measure Description Time frame Safety issue
Primary Objective Response Rate: Percentage of Participants With Best Over All Response of Complete Response or Partial Response by Central Radiology Review (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Objective response rate was defined by RECIST criteria: Partial response (PR) must have = 30% decrease in the sum of longest diameter of all target lesions, from the baseline sum. Complete response (CR) must have disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks. Progression = 20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions. from date of randomization/start of treatment until first documented response confirmed 4 weeks later( at least 3 months) No
Secondary Duration of Overall Response (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST)- Central Radiology Review Duration of overall response applies only to patients whose best overall response was complete response (CR) or partial response (PR):
Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression.
Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression.
Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions
from date of first documented confirmed response to time to progression, at least 3 months No
Secondary Duration of Overall Response (Stratum 2) Based on Response Evaluation Criteria in Solid Tumors (RECIST)- Central Radiology Review Duration of overall response applies only to patients whose best overall response was complete response (CR) or partial response (PR):
Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression.
Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression.
Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions
from date of first documented confirmed response to time to progression, at least 3 months No
Secondary Objective Response Rate: Percentage of Participants With Best Over All Response of Complete Response or Partial Response by Central Radiology Review (Stratum 2) Based on Response Evaluation Criteria in Solid Tumors (RECIST) Objective response rate was defined by RECIST criteria: Partial response (PR) must have = 30% decrease in the sum of longest diameter of all target lesions, from the baseline sum. Complete response (CR) must have disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks. Progression = 20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions. from date of randomization/start of treatment until first documented response confirmed 4 weeks later (at least 3 months) No
Secondary Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs)[Stratum 1] Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. on or after the day of the first intake of study treatment to starting no later than 28 days after study treatment discontinuation, at least every month Yes
Secondary Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs) [Stratum 2] Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. on or after the day of the first intake of study treatment to starting no later than 28 days after study treatment discontinuation, at least every month Yes
Secondary Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 1) Progression free survival (PFS) is defined as the time from randomization to the date of first documented disease progression or death from any cause. The Kaplan-Meier estimate of the PFS survival function was constructed.
Median PFS was obtained and displayed along with 95% confidence intervals.
from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 26 June 2006, until cut-off date 13 September 2010 No
Secondary Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 2) Progression free survival (PFS) is defined as the time from randomization to the date of first documented disease progression or death from any cause. The Kaplan-Meier estimate of the PFS survival function was constructed.
Median PFS was obtained and displayed along with 95% confidence intervals.
from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 26 June 2006, until cut-off date 13 September 2010 No
Secondary Time to Overall Survival (OS)(Stratum 1) Overall survival measures the time of survival , with any response or disease progression, until death. The OS is defined as the time from date of start of treatment to date of death due to any cause.
If a patient is not known to have died, survival was censored at the date of last contact. In each treatment stratum, the Kaplan-Meier estimate of the overall survival function was constructed.
from randomisation to dates of disease progression, death from any cause, reported between day of first patient randomised, 26 June 2006, until cut-off date 13 April 2012 No
Secondary Time to Overall Survival (OS) (Stratum 2) Overall survival measures the time of survival , with any response or disease progression, until death. The OS is defined as the time from date of start of treatment to date of death due to any cause.
If a patient is not known to have died, survival was censored at the date of last contact. In each treatment stratum, the Kaplan-Meier estimate of the overall survival function was constructed.
from randomisation to dates of disease progression, death from any cause, reported between day of first patient randomised, 26 June 2006, until cut-off date 13 April 2012 No
Secondary Everolimus Trough Level Determination by Pharmacokinetics Parameter in Both Strata (Stratum 1 and 2) For all patients in both strata, a blood sample for everolimus trough level determination will be collected immediately prior to the everolimus administration on Cycle 1 Day 15, Cycle 2 Day 1, and every month thereafter. A treatment cycle was defined as 28 days of consecutive daily treatment with everolimus and treatment continued until tumor progression. It is critical that patients not take their daily everolimus dose before the sample is drawn. Cycle 1 Day 15 No
Secondary Effect of Octreotide Depot on the Trough Concentrations of Everolimus The effect of Octreotide Depot on the trough concentrations of everolimus was assessed at Cycle 1 Day 15. Cycle 1 Day 1, Cycle 2 Day 1 No
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