Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors (GI or Lung Origin)

Phase 3

Completed

Conditions: Advanced NET of Lung Origin
Advanced NET of GI Origin
Neuroendocrine Tumors

Interventions: Drug: Placebo
Drug: Everolimus
Other: Best suportive care (BSC)

Registration Number: NCT01524783

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: The purpose of this study is to compare the antitumor activity of everolimus plus best supportive care versus placebo plus best supportive care in patients with progressive nonfunctional neuroendocrine tumor (NET) of gastrointestinal (GI) or lung origin without a history of, or current symptoms of carcinoid syndrome.

Detailed Description: This was a prospective, multi-center, randomized, double-blind, parallel-group, placebo-controlled, two-arm Phase III study comparing the efficacy and safety of everolimus 10 mg daily to placebo in patients with advanced NET of GI or lung origin without a history of, or current symptoms of carcinoid syndrome.

After assessment of eligibility, participants qualifying for the study were randomized in a 2:1 ratio to receive either everolimus or matching placebo. Participants received daily oral doses of 10 mg everolimus or matching placebo as study drug. In both arms, the study drug was combined with best supportive care and treatment cycles were defined as 28 days. Participants were treated until disease progression as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.0, intolerable toxicity, death, lost to follow-up or consent withdrawal. Regardless of the reason for study drug discontinuation, participants had a safety follow-up visit scheduled 30 days after the last dose of the study drug.

Per data monitoring committee recommendation, all participants on treatment with placebo were allowed to crossover to open-label treatment with everolimus. This change was implemented through protocol amendment 3 (issued on 06-May-2016) after which remaining participants entered into open-label phase of the study.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 302

Inclusion Criteria

Pathologically confirmed, well differentiated (G1 or G2), advanced (unresectable or metastatic), neuroendocrine tumor of GI or lung origin
No history of and no active symptoms related to carcinoid syndrome
In addition to treatment-naive patients, patients previously treated with SSA, Interferon (IFN), one prior line of chemotherapy, and/or PRRT were allowed into the study. Pretreated patients had to have progressed on or after the last treatment
Radiological documented disease progression within 6 months prior to randomization
Measurable disease
WHO performance status ≤1
Adequate bone marrow, liver and renal function

Exclusion Criteria

Patients with poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, pancreatic islet cell carcinoma, insulinoma, glucagonoma, gastrinoma, goblet cell carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma
Patients with pancreatic NET or NET of origins other than GI or Lung
Patients with history of or active symptoms of carcinoid syndrome (e.g. flushing, diarrhea)
Patients with more than one line of prior chemotherapy
Prior targeted therapy
Hepatic intra-arterial embolization within the last 6 months. Cryoablation or radiofrequency ablation of hepatic metastases within 2 months of randomization
Prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus, deforolimus)
Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy
Patients who had any severe and/or uncontrolled medical conditions such as:
- unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to randomization, serious uncontrolled cardiac arrhythmia
- active or uncontrolled severe infection
- liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HbsAg, quantifiable HCV-RNA)
Chronic treatment with corticosteroids or other immunosuppressive agents
Known history of HIV seropositivity
Pregnant or nursing (lactating) women

Other protocol-defined inclusion/exclusion criteria might apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo + BSC	Best suportive care (BSC)	Participants received matching placebo once daily plus best supportive care (BSC) during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period.
Everolimus + BSC	Best suportive care (BSC)	Participants received everolimus 10 mg once daily plus best supportive care (BSC) throughout the study
Placebo + BSC	Placebo	Participants received matching placebo once daily plus best supportive care (BSC) during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period.
Everolimus + BSC	Everolimus	Participants received everolimus 10 mg once daily plus best supportive care (BSC) throughout the study

Primary Outcome Measures

Name	Time	Method
Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment	From date of randomization to progression or death, whichever comes first, assessed up to 27 months	PFS is defined as the time from randomization to the date of the first documented tumor progression or death from any cause, whichever comes first. Progression was defined using modified RECIST 1.0 and as per central radiology assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Progression was assessed by cat scan (CT) and/or magnetic resonance imaging (MRI). For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. The percentage event-free probability estimate is the estimated probability that a patient will remain event-free in PFS up to the specified time point.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS)	From date of randomization to date of death, assessed up to approximately 8 years	OS is defined as the time from the date of randomization to date of death due to any cause. If a death had not been observed by the date of analysis cut-off, then OS was censored at the date of last contact. All participants randomized to placebo arm who crossed over to everolimus were censored.
Change From Baseline in Neuron Specific Enolase (NSE) Levels	From baseline (every 4 weeks) up to Week 116	NSE is a potential biomarker for tumor response. Blood samples were collected for assessment of NSE levels. Change from Baseline at a particular visit was calculated as the NSE level at that visit minus Baseline.
Overall Response Rate (ORR) as Per Modified RECIST 1.0 According to Central Evaluation	From randomization until end of treatment, assessed up to approximately 2.5 years	ORR is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), according to central evaluation and as per modified RECIST 1.0. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
Disease Control Rate (DCR) Based on Modified RECIST 1.0 and as Per Central Radiology Assessment	From randomization until end of treatment, assessed up to approximately 2.5 years	DCR is defined as the proportion of subjects with best overall response of CR or PR or stable disease based on modified RECIST 1.0 and as per central radiology assessment. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression.
Time to Definitive Deterioration in Functional Assessment of Cancer Therapy - General (FACT-G) Questionnaire Total Score	From randomization to definitive deterioration of FACT-G total score, assessed up to approximately 3 years	FACT-G is a self-assessed health-related quality of life questionnaire. The questionnaire is comprised of 27 questions examining physical, social/family, emotional, and functional well-being. Participants responded to the items on a five-point scale, ranging from 0: "Not at all" to 4: "Very much." The total score ranges from 0 to 108, with higher scores indicating a better patient-reported outcome/quality of life. Definitive deterioration is defined as a decrease in the total score by at least 7 points compared to baseline with no further improvement. Death was considered as worsening of the FACT-G total score if it occurred close to the last available assessment, where "close" was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment.
Time to Definitive Deterioration in World Health Organization (WHO) Performance Status (PS) Change	From randomization to definitive deterioration of WHO performance status, assessed up to approximately 3 years	WHO PS is a scale rated from 0 (fully active) to 5 (death) by a healthcare professional to assess the overall status of a patient: a lower score represents a higher ability to perform daily tasks. Deterioration is defined as an increase of at least one point compared to baseline. Deterioration is considered definitive if no improvements in the WHO PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. Death was considered as worsening of the WHO PS if it occurred close to the last available assessment, where "close" was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment.
Change From Baseline in Chromogranin A (CgA) Levels	From baseline (every 4 weeks) up to 116 weeks	CgA is a potential biomarker for tumor response. Blood samples were collected for assessment of CgA levels. Change from Baseline at a particular visit was calculated as the CgA level at that visit minus Baseline.
Pharmacokinetics (PK): Predose Concentration (Cmin) of Everolimus at Day 29	Pre-dose at Day 29.	A pre-dose blood sample at day 29 was collected to determine the exposure of everolimus at the steady-state pre-dose concentration (Cmin). Cmin is provided for participants randomized to everolimus+BSC who received 10mg of everolimus daily and also for participants randomized to everolimus+BSC who received 5mg of everolimus daily which was required for a number of participants in the study experiencing adverse events requiring dose modifications

Trial Locations

Locations (18): Cedars Sinai Medical Center SC
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Los Angeles, California, United States
Dana Farber Cancer Institute SC
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Boston, Massachusetts, United States
Texas Oncology P A Texas Oncology Amarillo
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Dallas, Texas, United States
Texas Oncology P A TX Oncology Baylor
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Dallas, Texas, United States
University of Texas Southwestern Medical Center
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Dallas, Texas, United States
Goshen Center for Cancer Care IU Health SC
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Indianapolis, Indiana, United States
Oregon Health and Science University OH&SU
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Portland, Oregon, United States
Vanderbilt University Medical Center Vanderbilt Med Ctr
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Nashville, Tennessee, United States
H Lee Moffitt Cancer Center and Research Institute HLM
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Tampa, Florida, United States
University of Colorado Cancer Centre SC
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Aurora, Colorado, United States
University of California San Diego - Moores Cancer Center Regulatory
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La Jolla, California, United States
Scripps Clinic Regulatory
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La Jolla, California, United States
University of Chicago UC SC
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Chicago, Illinois, United States
Memorial Sloan Kettering MSkCC SC
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New York, New York, United States
University of Texas MD Anderson Cancer Center UT MD Anderson Cancer Ctr
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Houston, Texas, United States
Novartis Investigative Site
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Southampton, United Kingdom
Montefiore Medical Center MMC
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Bronx, New York, United States
University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc
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Madison, Wisconsin, United States