Safety/Efficacy of Everolimus in Adults With Advanced Pancreatic Neuroendocrine Cancer Not Responsive to Chemotherapy

Pancreatic Neoplasms Clinical Trial

Official title:

An Open Label, Stratified, Single-arm Phase II Study of Everolimus in Patients With Advanced Pancreatic Neuroendocrine Tumor (NET) After Failure of Cytotoxic Chemotherapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00363051
• Other study ID #: CRAD001C2239
• 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

Related Conditions & MeSH terms

• Carcinoid Tumor
• Carcinoma
• Carcinoma, Islet Cell
• Carcinoma, Neuroendocrine
• Islet Cell Carcinoma
• Neuroendocrine Carcinoma
• Neuroendocrine Tumor
• Neuroendocrine Tumors
• Pancreatic Neoplasms

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