3-arm Trial to Evaluate Pasireotide LAR/Everolimus Alone/in Combination in Patients With Lung/Thymus NET - LUNA Trial

Phase 2

Completed

Conditions: Neuroendocrine Carcinoma of the Lung and Thymus

Interventions: Drug: Pasireotide LAR
Drug: Pasireotide LAR and Everolimus Combination
Drug: Everolimus

Registration Number: NCT01563354

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This was a multicenter, randomized, phase II study evaluating Everolimus or Pasireotide LAR alone or in combination in adult patients with advanced (unresectable or metastatic) neuroendocrine carcinoma of the lung and thymus

Detailed Description: This was a prospective, multicenter, randomized, open-label, 3-arm, phase II study with a single-stage design in each arm. The purpose of this study was to test the effectiveness and safety of Everolimus or Pasireotide LAR alone or in combination in adult patients with advanced (unresectable or metastatic) neuroendocrine carcinoma (typical and atypical) of the lung and thymus. It was expected that a total of 120 patients with 40 patients in each arm were to be enrolled into this study. Patients were seen weekly for one month and monthly thereafter. Radiological and biochemical response assessments were performed every 3 months.

Patients with disease control (stable disease or better) in the combination arm or monotherapy with pasireotide LAR and everolimus who had not experienced unacceptable toxicity were permitted to continue treatment in the extension phase of the study and were seen every 3 months. Patients could remain in the extension phase as long as they continued to have clinical benefit and had not fulfilled any of the study discontinuation criteria. All patients had a safety follow-up visit 56 days after last treatment dose.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 124

Inclusion Criteria

Histological confirmed advanced well differentiated typical and atypical carcinoid tumors of the lung or thymus
Patients of all treatment lines including naive patients could have been enrolled
At least one measurable lesion of disease on CT scan or MRI
Radiological documentation of disease progression within 12 months prior to randomization
Adequate liver, renal and bone marrow function
WHO Performance Status 0-2

Exclusion Criteria

Poorly differentiated neuroendocrine carcinoma
Non-neuroendocrine thymoma
Patients with severe functional disease who required symptomatic treatment with somatostatin analogs
Prior therapy with mTOR inhibitors
History of liver disease
Baseline QTcF> 470 msec
Uncontrolled diabetes mellitus despite adequate therapy

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Pasireotide LAR	Pasireotide LAR	Pasireotide long acting release (LAR) 60 mg will be administered as an intra muscular (i.m.) depot injection once every 28 days starting on Day 1
Pasireotide LAR and Everolimus Combination	Pasireotide LAR and Everolimus Combination	Pasireotide LAR 60 mg i.m. injected once every 28 days + Everolimus 10 mg p.o. daily starting on Day 1
Everolimus	Everolimus	Everolimus 10 mg taken orally (p.o) once daily starting on Day 1

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1)	Baseline up to 9 months	Patients with Complete Response (CR), Partial Response (PR), or Stable Disease (SD) at Month 9 were to be considered as "progression-free" based on RECIST v1.1. Patients with missing tumor assessment, or with overall lesion response "unknown" at Month 9 were considered as "non progression-free", unless any of the following assessments at Week 48 or Week 52 indicate CR, PR, or SD, in which case the patient was to be considered as progression-free at Month 9. Patients discontinuing the study for any reason prior to the 9 month assessment were to be considered as "non progression-free".

Secondary Outcome Measures

Name	Time	Method
Summary of Progression-free Survival (PFS) Based on RECIST v1.1	Baseline, every 3 months up to 69 months	Time from first study drug administration to objective tumor progression or death from any cause according to RECIST v1.1
Summary of Time to Response (Months)	Every 3 months up to Year 1	Time from start of treatment to the first observed objective tumor response (partial response or complete response) observed according to RECIST v1.1.
Kaplan-Meier Estimates of Progression-free Survival (PFS)	Baseline, every 3 months up to 69 months	Percent (%) event-free probability estimate is the estimated probability that a patient will remain event-free up to the specified time point. Percent event-free probability estimates are obtained from the Kaplan-Meier survival estimates. Events are time from first study drug administration to objective tumor progression or death from any cause according to RECIST v1.1.
12-month Disease Control Rate (DCR) and Objective Response Rate (ORR)	Baseline up to Month 12	Objective response rate (ORR) was defined as the percentage of patients showing a best overall response (BOR) of CR or PR during the core study according to RECIST v1.1 criteria. The best overall response is interpreted as the best response recorded from the start of the treatment until disease progression/recurrence, death from any cause or until the patient withdraws consent, whichever is earliest. DCR was was defined as the percentage of participants with a best overall response of complete response, partial response or stable disease during 12 months of treatment according to RECIST v1.1.
Kaplan-Meier Event-free Probability Estimate Based on CgA Levels	Baseline, every 3 months up to Month 18	Kaplan Meier estimates are for Duration of biochemical response (DBR) outcome measure. Events are biochemical progressions i.e. an increase of CgA levels \>= 25% compared to baseline or deaths due to any cause. Percent (%) Event-free probability estimate is the estimated probability that a patient will remain event-free up to the specified time point.
Summary of Biochemical Progression-free Survival Based on CgA Levels by Treatment	Baseline up Month 24	Time from the first documentation of biochemical response to the first documentation of biochemical progression or to death due to any cause, whichever occurred first. Biochemical progression is defined as an increase of serum CgA levels ≥ 25% compared to baseline.
Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels	Baseline up to Week 52	Percentage of patients showing normalization or a decrease of ≥ 30% of serum CgA concentrations compared to baseline.
Biochemical Response Rate (BRR) for 5HIAA Levels	Baseline up Week 52	The percentages are the biochemical response rates i.e. percentage of patients showing normalization i.e. return to within normal ranges, or a decrease of \>= 50% from baseline of 5HIAA concentrations.
Summary of Duration of Response (Months)	Every 3 months up to Year 1	Date of first objective tumor response to date of tumor progression or death due to any cause.
Duration of Biochemical Response (DBR), by Treatment (Full Analysis Set)	Baseline up to Month 18	Time from the first documentation of biochemical response to the first documentation of biochemical progression or to death due to any cause, whichever occurred first. Biochemical progression is defined as an increase of serum CgA levels ≥ 25% compared to baseline.
Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels	Baseline, every 3 months up to Month 24	Percent (%) Event-free probability estimate is the estimated probability that a patient will remain event-free up to the specified time point. Percent event-free probability estimates are obtained from the Kaplan-Meier survival estimates. Events are biochemical progressions, i.e., an increase of CgA levels \>= 25% compared to baseline or deaths due to any cause.