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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00363051
First received: August 2, 2006
Last updated: May 6, 2013
Last verified: May 2013
  Purpose

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.


Condition Intervention Phase
Islet Cell Carcinoma
Neuroendocrine Carcinoma
Neuroendocrine Tumor
Pancreatic Neoplasms
Drug: Everolimus 10 mg
Drug: Octreotide Depot
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • 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) [ Time Frame: from date of randomization/start of treatment until first documented response confirmed 4 weeks later( at least 3 months) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Duration of Overall Response (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST)- Central Radiology Review [ Time Frame: from date of first documented confirmed response to time to progression, at least 3 months ] [ Designated as safety issue: No ]

    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


  • Duration of Overall Response (Stratum 2) Based on Response Evaluation Criteria in Solid Tumors (RECIST)- Central Radiology Review [ Time Frame: from date of first documented confirmed response to time to progression, at least 3 months ] [ Designated as safety issue: No ]

    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


  • 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) [ Time Frame: from date of randomization/start of treatment until first documented response confirmed 4 weeks later (at least 3 months) ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs)[Stratum 1] [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
    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.

  • Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs) [Stratum 2] [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
    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.

  • Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 1) [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 2) [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • Time to Overall Survival (OS)(Stratum 1) [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • Time to Overall Survival (OS) (Stratum 2) [ Time Frame: 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 ] [ Designated as safety issue: No ]

    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.


  • Everolimus Trough Level Determination by Pharmacokinetics Parameter in Both Strata (Stratum 1 and 2) [ Time Frame: Cycle 1 Day 15 ] [ Designated as safety issue: No ]
    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.

  • Effect of Octreotide Depot on the Trough Concentrations of Everolimus [ Time Frame: Cycle 1 Day 1, Cycle 2 Day 1 ] [ Designated as safety issue: No ]
    The effect of Octreotide Depot on the trough concentrations of everolimus was assessed at Cycle 1 Day 15.


Enrollment: 160
Study Start Date: June 2006
Study Completion Date: April 2012
Primary Completion Date: January 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Everolimus 10 mg

Stratum 1 patients who were not receiving regular Octreotide Depot therapy. These patients were to receive everolimus monotherapy at 10 mg/day.

Stratum 2 patients who were to receive everolimus 10 mg/day in addition to continuing their entry dose of Octreotide Depot therapy.

Patients were instructed to take two 5 mg tablets of everolimus orally with a glass of water, once daily (preferably in the morning). Dosing was strongly recommended to occur at the same time every day.

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.
Other Name: RAD001
Drug: Octreotide Depot

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00363051

  Show 54 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Additional Information:
No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00363051     History of Changes
Other Study ID Numbers: CRAD001C2239
Study First Received: August 2, 2006
Results First Received: December 2, 2011
Last Updated: May 6, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Novartis:
Pancreatic
Tumor
Islet Cell
Carcinoma
Neuroendocrine
Endocrine
Atypical Carcinoid
RADIANT1
RADIANT-1

Additional relevant MeSH terms:
Neoplasms
Carcinoma
Pancreatic Neoplasms
Carcinoma, Neuroendocrine
Neuroendocrine Tumors
Carcinoma, Islet Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Adenocarcinoma
Neoplasms, Nerve Tissue
Octreotide
Sirolimus
Everolimus
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Gastrointestinal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic

ClinicalTrials.gov processed this record on July 20, 2014