Neuroendocrine Carcinoma of the Lung and Thymus
Conditions
Keywords
neuroendocrine carcinoma; lung; thymus; pasireotide LAR; everolimus,adult,SOM230,carcinoma,lung cancer,
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.
Interventions
DRUGPasireotide LAR
60 mg was administered as an intra muscular depot injection once every 28 days starting at Day 1
DRUGEverolimus
10 mg tables administered orally once a day
DRUGPasireotide LAR and Everolimus Combination
Pasireotide LAR 60 mg i.m. injected once every 28 days + Everolimus 10 mg p.o. daily
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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 |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Denmark, France, Germany, Greece, Italy, Netherlands, Spain, Sweden, United Kingdom
Participant flow
Pre-assignment details
Two patients completed the core phase of the study but they did not enter the extension phase one due to worsening in clinical conditions and one for Physician decision.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 41 |
| Everolimus Everolimus 10 mg taken orally (p.o) once daily starting on Day 1 | 42 |
| 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 | 41 |
| Total | 124 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Core Phase | Adverse Event | 5 | 15 | 13 |
| Core Phase | Death | 1 | 5 | 2 |
| Core Phase | Diseasse progression | 18 | 7 | 8 |
| Core Phase | Lost to Follow-up | 1 | 0 | 0 |
| Core Phase | PI decision - did not enter extension | 0 | 1 | 0 |
| Core Phase | Protocol deviation | 2 | 0 | 0 |
| Core Phase | Withdrawal by Subject | 1 | 0 | 3 |
| Core Phase | Worsening of clinical condition - did not enter extension | 1 | 0 | 0 |
| Extension Phase | Administration problems | 3 | 2 | 3 |
| Extension Phase | Adverse Event | 0 | 3 | 2 |
| Extension Phase | Disease progression | 9 | 8 | 10 |
| Extension Phase | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Pasireotide LAR | Everolimus | Pasireotide LAR and Everolimus Combination | Total |
|---|---|---|---|---|
| Age, Customized 18 to <65 | 21 participants | 18 participants | 24 participants | 63 participants |
| Age, Customized ≥65 to 84 | 20 participants | 24 participants | 17 participants | 61 participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 40 Participants | 42 Participants | 40 Participants | 122 Participants |
| Sex: Female, Male Female | 15 Participants | 19 Participants | 13 Participants | 47 Participants |
| Sex: Female, Male Male | 26 Participants | 23 Participants | 28 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 41 | 7 / 42 | 3 / 41 |
| other Total, other adverse events | 40 / 41 | 42 / 42 | 40 / 41 |
| serious Total, serious adverse events | 17 / 41 | 20 / 42 | 16 / 41 |
Outcome results
Primary
Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1)
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.
Time frame: Baseline up to 9 months
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pasireotide LAR | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Complete response | 0 percentage of participants |
| Pasireotide LAR | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Stable disease | 34.1 percentage of participants |
| Pasireotide LAR | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Progression-free (PF) at Month 9 | 39.0 percentage of participants |
| Pasireotide LAR | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Partial response | 2.4 percentage of participants |
| Everolimus | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Complete response | 0 percentage of participants |
| Everolimus | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Partial response | 2.4 percentage of participants |
| Everolimus | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Stable disease | 31.0 percentage of participants |
| Everolimus | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Progression-free (PF) at Month 9 | 33.3 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Stable disease | 48.8 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Complete response | 0 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Partial response | 2.4 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Percentage of Participants Progression-free at 9 Months Based on Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | Progression-free (PF) at Month 9 | 58.5 percentage of participants |
Secondary
12-month Disease Control Rate (DCR) and Objective Response Rate (ORR)
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.
Time frame: Baseline up to Month 12
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pasireotide LAR | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Complete response (CR) | 0 percentage of participants |
| Pasireotide LAR | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Objective response (CR+PR) | 2.4 percentage of participants |
| Pasireotide LAR | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Disease control rate (CR+PR+SD) | 80.5 percentage of participants |
| Pasireotide LAR | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Partial response (PR) | 2.4 percentage of participants |
| Pasireotide LAR | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Stable disease | 78.0 percentage of participants |
| Pasireotide LAR | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Progressive disease | 14.6 percentage of participants |
| Pasireotide LAR | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Unknown | 2.4 percentage of participants |
| Pasireotide LAR | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Not assessed | 2.4 percentage of participants |
| Pasireotide LAR | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Discontinued before month 12 | 68.3 percentage of participants |
| Everolimus | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Disease control rate (CR+PR+SD) | 73.8 percentage of participants |
| Everolimus | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Complete response (CR) | 0 percentage of participants |
| Everolimus | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Unknown | 4.8 percentage of participants |
| Everolimus | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Partial response (PR) | 2.4 percentage of participants |
| Everolimus | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Discontinued before month 12 | 64.3 percentage of participants |
| Everolimus | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Progressive disease | 4.8 percentage of participants |
| Everolimus | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Stable disease | 71.4 percentage of participants |
| Everolimus | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Not assessed | 16.7 percentage of participants |
| Everolimus | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Objective response (CR+PR) | 2.4 percentage of participants |
| Pasireotide LAR and Everolimus Combination | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Progressive disease | 7.3 percentage of participants |
| Pasireotide LAR and Everolimus Combination | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Disease control rate (CR+PR+SD) | 78.0 percentage of participants |
| Pasireotide LAR and Everolimus Combination | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Partial response (PR) | 4.9 percentage of participants |
| Pasireotide LAR and Everolimus Combination | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Complete response (CR) | 0 percentage of participants |
| Pasireotide LAR and Everolimus Combination | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Not assessed | 14.6 percentage of participants |
| Pasireotide LAR and Everolimus Combination | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Objective response (CR+PR) | 4.9 percentage of participants |
| Pasireotide LAR and Everolimus Combination | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Unknown | 0 percentage of participants |
| Pasireotide LAR and Everolimus Combination | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Stable disease | 73.2 percentage of participants |
| Pasireotide LAR and Everolimus Combination | 12-month Disease Control Rate (DCR) and Objective Response Rate (ORR) | Discontinued before month 12 | 63.4 percentage of participants |
Secondary
Biochemical Response Rate (BRR) for 5HIAA Levels
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.
Time frame: Baseline up Week 52
Population: Full analysis set - participants with 5HIAA levels within normal range at baseline are excluded from the table, therefore 'n' stands for the number of patients with 5-HIAA levels outside normal range at baseline.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pasireotide LAR | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 36 | 5.0 percentage of participants |
| Pasireotide LAR | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 24 | 5.0 percentage of participants |
| Pasireotide LAR | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 48 | 5.0 percentage of participants |
| Pasireotide LAR | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 12 | 20.0 percentage of participants |
| Pasireotide LAR | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 52 | 5.0 percentage of participants |
| Everolimus | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 24 | 11.1 percentage of participants |
| Everolimus | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 48 | 0 percentage of participants |
| Everolimus | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 12 | 11.1 percentage of participants |
| Everolimus | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 36 | 11.1 percentage of participants |
| Everolimus | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 52 | 0 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 52 | 10.0 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 36 | 5.0 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 48 | 5.0 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 24 | 20.0 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Biochemical Response Rate (BRR) for 5HIAA Levels | Week 12 | 10.0 percentage of participants |
Secondary
Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels
Percentage of patients showing normalization or a decrease of ≥ 30% of serum CgA concentrations compared to baseline.
Time frame: Baseline up to Week 52
Population: Full analysis set participants with CgA levels outside normal range at baseline.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pasireotide LAR | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 12 | 20.6 percentage of participants |
| Pasireotide LAR | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 48 | 8.8 percentage of participants |
| Pasireotide LAR | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 36 | 8.8 percentage of participants |
| Pasireotide LAR | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 52 | 5.9 percentage of participants |
| Pasireotide LAR | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 24 | 8.8 percentage of participants |
| Everolimus | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 48 | 0 percentage of participants |
| Everolimus | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 12 | 7.4 percentage of participants |
| Everolimus | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 24 | 7.4 percentage of participants |
| Everolimus | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 36 | 3.7 percentage of participants |
| Everolimus | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 52 | 0 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 24 | 20.0 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 48 | 11.4 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 12 | 17.1 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 52 | 5.7 percentage of participants |
| Pasireotide LAR and Everolimus Combination | Biochemical Response Rate (BRR) for Chromogranin A (CgA) Levels | Week 36 | 11.4 percentage of participants |
Secondary
Duration of Biochemical Response (DBR), by Treatment (Full Analysis Set)
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.
Time frame: Baseline up to Month 18
Population: Full analysis set - participants who have experienced biochemical response during the study and had CgA levels outside normal range at baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pasireotide LAR | Duration of Biochemical Response (DBR), by Treatment (Full Analysis Set) | 14.75 months |
| Everolimus | Duration of Biochemical Response (DBR), by Treatment (Full Analysis Set) | 2.00 months |
| Pasireotide LAR and Everolimus Combination | Duration of Biochemical Response (DBR), by Treatment (Full Analysis Set) | 8.38 months |
Secondary
Kaplan-Meier Estimates of Progression-free Survival (PFS)
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.
Time frame: Baseline, every 3 months up to 69 months
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 51 months | 10.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 27 months | 14.5 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 12 months | 39.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 48 months | 10.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 30 months | 10.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 69 months | NA event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 45 months | 10.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 33 months | 10.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 60 months | 10.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 42 months | 10.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 36 months | 10.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 15 months | 32.6 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 39 months | 10.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 6 months | 68.2 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 57 months | 10.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 18 months | 21.8 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 3 months | 83.6 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 9 months | 49.6 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 21 months | 14.5 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 66 months | NA event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 54 months | 10.9 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 24 months | 14.5 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 63 months | 10.9 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 54 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 9 months | 56.9 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 3 months | 91.2 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 6 months | 63.5 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 12 months | 50.2 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 15 months | 46.8 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 18 months | 38.6 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 21 months | 29.4 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 24 months | 19.6 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 27 months | 19.6 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 30 months | 9.8 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 33 months | 9.8 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 36 months | 9.8 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 39 months | 9.8 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 42 months | 9.8 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 45 months | 9.8 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 48 months | 9.8 event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 51 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 57 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 60 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 63 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 66 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 69 months | NA event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 63 months | 7.1 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 48 months | 14.2 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 24 months | 28.5 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 6 months | 85.5 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 51 months | 14.2 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 21 months | 38.0 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 18 months | 42.7 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 54 months | 14.2 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 15 months | 51.2 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 69 months | 7.1 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 57 months | 7.1 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 12 months | 55.5 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 66 months | 7.1 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 36 months | 14.2 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 60 months | 7.1 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 39 months | 14.2 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 33 months | 19.0 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 9 months | 79.2 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 42 months | 14.2 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 30 months | 19.0 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 3 months | 88.6 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 45 months | 14.2 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Estimates of Progression-free Survival (PFS) | 27 months | 28.5 event free probability estimates |
Secondary
Kaplan-Meier Event-free Probability Estimate Based on CgA Levels
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.
Time frame: Baseline, every 3 months up to Month 18
Population: Full analysis set - participants who have experienced biochemical response during the study and had CgA levels outside normal range at baseline
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 3 months | 75.0 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 12 months | 56.3 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 9 months | 56.3 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 18 months | 37.5 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 15 months | 37.5 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 6 months | 56.3 event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 9 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 3 months | 37.5 event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 6 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 18 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 12 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 15 months | NA event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 15 months | 44.4 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 12 months | 44.4 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 3 months | 77.8 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 18 months | 44.4 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 9 months | 44.4 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate Based on CgA Levels | 6 months | 77.8 event free probability estimates |
Secondary
Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels
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.
Time frame: Baseline, every 3 months up to Month 24
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 21 months | 13.8 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 15 months | 18.5 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 9 months | 18.5 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 24 months | NA event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 3 months | 43.1 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 12 months | 18.5 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 18 months | 13.8 event free probability estimates |
| Pasireotide LAR | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 6 months | 29.5 event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 15 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 21 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 18 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 24 months | NA event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 6 months | 17.7 event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 9 months | 11.0 event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 12 months | 7.4 event free probability estimates |
| Everolimus | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 3 months | 35.4 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 24 months | 18.1 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 18 months | 18.1 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 3 months | 77.1 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 6 months | 44.5 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 9 months | 29.7 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 15 months | 18.1 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 21 months | 18.1 event free probability estimates |
| Pasireotide LAR and Everolimus Combination | Kaplan-Meier Event-free Probability Estimate for Biochemical Progression-free Survival Based on CgA Levels | 12 months | 26.4 event free probability estimates |
Secondary
Summary of Biochemical Progression-free Survival Based on CgA Levels by Treatment
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.
Time frame: Baseline up Month 24
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pasireotide LAR | Summary of Biochemical Progression-free Survival Based on CgA Levels by Treatment | 2.89 months |
| Everolimus | Summary of Biochemical Progression-free Survival Based on CgA Levels by Treatment | 2.86 months |
| Pasireotide LAR and Everolimus Combination | Summary of Biochemical Progression-free Survival Based on CgA Levels by Treatment | 5.62 months |
Secondary
Summary of Duration of Response (Months)
Date of first objective tumor response to date of tumor progression or death due to any cause.
Time frame: Every 3 months up to Year 1
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pasireotide LAR | Summary of Duration of Response (Months) | Median | NA months |
| Pasireotide LAR | Summary of Duration of Response (Months) | 25th percentile | NA months |
| Pasireotide LAR | Summary of Duration of Response (Months) | 75th percentile | NA months |
| Everolimus | Summary of Duration of Response (Months) | Median | NA months |
| Everolimus | Summary of Duration of Response (Months) | 25th percentile | NA months |
| Everolimus | Summary of Duration of Response (Months) | 75th percentile | NA months |
| Pasireotide LAR and Everolimus Combination | Summary of Duration of Response (Months) | 25th percentile | NA months |
| Pasireotide LAR and Everolimus Combination | Summary of Duration of Response (Months) | 75th percentile | NA months |
| Pasireotide LAR and Everolimus Combination | Summary of Duration of Response (Months) | Median | NA months |
Secondary
Summary of Progression-free Survival (PFS) Based on RECIST v1.1
Time from first study drug administration to objective tumor progression or death from any cause according to RECIST v1.1
Time frame: Baseline, every 3 months up to 69 months
Population: Full analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pasireotide LAR | Summary of Progression-free Survival (PFS) Based on RECIST v1.1 | 8.51 months |
| Everolimus | Summary of Progression-free Survival (PFS) Based on RECIST v1.1 | 12.48 months |
| Pasireotide LAR and Everolimus Combination | Summary of Progression-free Survival (PFS) Based on RECIST v1.1 | 16.53 months |
Secondary
Summary of Time to Response (Months)
Time from start of treatment to the first observed objective tumor response (partial response or complete response) observed according to RECIST v1.1.
Time frame: Every 3 months up to Year 1
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pasireotide LAR | Summary of Time to Response (Months) | 75th percentile | NA months |
| Pasireotide LAR | Summary of Time to Response (Months) | Median | NA months |
| Pasireotide LAR | Summary of Time to Response (Months) | 25th percentile | NA months |
| Everolimus | Summary of Time to Response (Months) | 75th percentile | NA months |
| Everolimus | Summary of Time to Response (Months) | 25th percentile | NA months |
| Everolimus | Summary of Time to Response (Months) | Median | NA months |
| Pasireotide LAR and Everolimus Combination | Summary of Time to Response (Months) | Median | NA months |
| Pasireotide LAR and Everolimus Combination | Summary of Time to Response (Months) | 25th percentile | NA months |
| Pasireotide LAR and Everolimus Combination | Summary of Time to Response (Months) | 75th percentile | NA months |