Symptomatic Refractory Resistant Carcinoid Disease
Conditions
Keywords
Carcinoid, neuroendocrine, gastroenteropancreatic, somatostatin analogue, Symptomatic Refractory Resistant Carcinoid Disease
Brief summary
The purpose of this randomized, multicenter, Phase III study was to compare the efficacy of paseriotide LAR and octreotide LAR in patients whose disease-related symptoms are inadequately controlled by currently available somatostatin analogues.
Interventions
DRUGPasireotide
Pasireotide LAR 60mg i.m. injection - patients may also receive pasireotide 600 µg s.c 3 times a day for symptom control as needed
DRUGOctreotide
Octreotide LAR 40mg i.m. depot injection - Patients may also receive octreotide 100 µg s.c. 3 times a day for symptom control as needed
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients aged 18 or greater * Patients with carcinoid tumors and symptoms (diarrhea and flushing) that are not adequately controlled by somatostatin analogues. * Female patients of child bearing potential must have a negative pregnancy test at baseline. * Patients for whom written informed consent to participate in the study has been obtained.
Exclusion criteria
* Patients receiving radiolabeled somatostatin analogue therapy within the 3 months or any cytotoxic chemotherapy or interferon therapy within the 4 weeks prior to randomization * Diabetic patients on anti-diabetic medications whose fasting blood glucose is poorly controlled as indicated by HBA1C \> 8% * Patients with symptomatic cholelithiasis * Patient with malabsorption syndrome, short bowel or cholegenic diarrhea not controlled by specific therapeutic means. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Who Achieved Clinical Symptom Improvement by Randomization Stratum and Treatment. | Month 6 | Percentage of patients who received clinical benefit in symptom (diarrhea and/or flushing) improvement as: Diarrhea (D)+Flushing (F): Patients with a daily mean number (#) of at least four bowel movements and a total of five or more flushing episodes. Clinical Benefit Response Criteria (CBRC): \<4 daily mean bowel movements AND at least 20% reduction from Baseline in the daily mean # of bowel movements AND any reduction in the total # of flushing episodes compared with Baseline. (D) Patients with a daily mean # of at least four bowel movements and a total # of \<5 flushing episodes. (CBRC) \<4 daily mean bowel movements AND at least a 20% reduction from Baseline in the daily mean # of bowel movements. (F) Patients with a total # of at least 14 flushing episodes and a daily mean # of \<4 bowel movements (CBRC) At least a 30% reduction from Baseline in the total # of flushing episodes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Daily Mean Number of Flushing Episodes by Randomization Stratum and Treatment. | 6 months | Percent change from Baseline in total number of flushing episodes comprising Month 6 were compared between the two treatment groups using ANCOVA model with treatment as the main effect and symptom levels at Baseline (e.g. total number of flushing episodes at Baseline) and randomization stratum (D+F or F) as covariates. |
| Pasireotide LAR vs. Octreotide LAR on Time to Symptom Response. | Month 6 | — |
| Objective Tumor Response Rate Assessed by Investigator | Month 6 | Baseline evaluations were to include Triphasic CT scan or MRI of the abdomen. Triphasic CT or MRIs were to be read by same radiologist at each assessment, measuring the same target and non-target lesions and accounting for all lesions that were present at Baseline. All known disease was accounted for when assessing objective tumor status. Current objective tumor status was to be captured on Tumor Assessment CRF. 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. |
| Pasireotide LAR vs. Octreotide LAR on Disease Control Rate Based on RECIST Criteria | Month 6 | Disease control rate (DCR) is the proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD). Complete Response (CR): Disappearance of all target lesions Partial Response (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. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference 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. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. Unknown (UNK) Progression has not been documented and one or more target lesions have not been assessed or have been assessed using a different method than baseline. |
| Improvement in Daily Mean Number of Diarrhea Bowel Movement Episodes by Randomization Stratum and Treatment. | 6 months | Percent change from Baseline in mean daily bowel movements at Month 6 were compared between the two treatment groups using ANCOVA model with treatment as the main effect and symptom levels at Baseline (e.g. mean daily bowel movement at Baseline) and randomization stratum (D+F or D) as covariates. Percentage change = (Month 6 - baseline)/baseline. |
| Pasireotide LAR vs. Octreotide LAR on Time to Symptom Progression | Month 6 | — |
| Pasireotide LAR vs. Octreotide LAR on Duration of Symptom Response | Month 6 | — |
| Assess the Proportion of Patients Who Achieved at Least a 30% Reduction in Frequency of Bowel Movements | Month 6 | — |
| Pasireotide LAR vs. Octreotide LAR on Quality of Life Assessed by FACIT-D Questionnaire | Month 6 | — |
Countries
Argentina, Austria, Belgium, Brazil, Canada, France, Germany, Israel, Italy, Norway, Poland, Singapore, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
186 patients were screened and 110 were randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| Pasireotide LAR Patients assigned to pasireotide LAR will receive a 60 mg dose of pasireotide LAR i.m. depot injection once every 28 days (+/- 3 days) for 6 months at visits 2, 4, 5, 6, 7 and 8. A dose reduction to 40 mg is permitted if tolerability issues arise. In addition, after 24 hours of the first LAR injections the patients were permitted to use pasireotide s.c. formulation for breakthrough symptoms as needed. | 53 |
| Octreotide LAR Patients assigned to octreotide LAR will receive a 40mg dose of octreotide LAR i.m. depot injection once every 28 days (+/- 3 days) for 6 months at visits 2, 4, 5, 6, 7 and 8. A dose reduction to 30 mg is permitted if tolerability issues arise. Patients requiring a dose reduction are to return to the higher dose once the tolerability issue is resolved, if required for efficacy. In addition, after 24 hours of the first LAR injections the patients were permitted to use octreotide s.c. formulation for breakthrough symptoms as needed. | 57 |
| Total | 110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Core Phase | Abnormal Laboratory value | 0 | 1 | 0 |
| Core Phase | Administrative Problems | 0 | 1 | 0 |
| Core Phase | Adverse Event | 5 | 1 | 0 |
| Core Phase | Death | 0 | 2 | 0 |
| Core Phase | Early Termination | 0 | 5 | 0 |
| Core Phase | Lack of Efficacy | 8 | 10 | 0 |
| Core Phase | Protocol Violation | 1 | 0 | 0 |
| Core Phase | Subject no longer requires study drug | 1 | 0 | 0 |
| Core Phase | Withdrawal by Subject | 3 | 3 | 0 |
| Extension Phase | Abnormal Lab Values | 1 | 0 | 0 |
| Extension Phase | Abnormal test procedure results | 1 | 0 | 0 |
| Extension Phase | Administrative Problems | 0 | 1 | 1 |
| Extension Phase | Adverse Event | 2 | 1 | 2 |
| Extension Phase | Death | 1 | 1 | 1 |
| Extension Phase | Early Termination | 10 | 1 | 3 |
| Extension Phase | Lack of Efficacy | 3 | 1 | 4 |
| Extension Phase | Withdrawal by Subject | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Pasireotide LAR | Octreotide LAR | Total |
|---|---|---|---|
| Age Continuous | 61.2 Years STANDARD_DEVIATION 9.21 | 62.8 Years STANDARD_DEVIATION 11.91 | 62 Years STANDARD_DEVIATION 10.67 |
| Sex: Female, Male Female | 24 Participants | 23 Participants | 47 Participants |
| Sex: Female, Male Male | 29 Participants | 34 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 50 / 53 | 48 / 57 | 19 / 20 | 5 / 6 | 12 / 15 |
| serious Total, serious adverse events | 15 / 53 | 19 / 57 | 9 / 20 | 2 / 6 | 7 / 15 |
Outcome results
Primary
Percentage of Patients Who Achieved Clinical Symptom Improvement by Randomization Stratum and Treatment.
Percentage of patients who received clinical benefit in symptom (diarrhea and/or flushing) improvement as: Diarrhea (D)+Flushing (F): Patients with a daily mean number (#) of at least four bowel movements and a total of five or more flushing episodes. Clinical Benefit Response Criteria (CBRC): \<4 daily mean bowel movements AND at least 20% reduction from Baseline in the daily mean # of bowel movements AND any reduction in the total # of flushing episodes compared with Baseline. (D) Patients with a daily mean # of at least four bowel movements and a total # of \<5 flushing episodes. (CBRC) \<4 daily mean bowel movements AND at least a 20% reduction from Baseline in the daily mean # of bowel movements. (F) Patients with a total # of at least 14 flushing episodes and a daily mean # of \<4 bowel movements (CBRC) At least a 30% reduction from Baseline in the total # of flushing episodes.
Time frame: Month 6
Population: The Efficacy analyzable set consists of subset of FAS patients who were randomized at least six months prior to futility interim analysis data cut-off. It is for the primary efficacy analysis and secondary efficacy analysis except for tumor response assessment. Data reported was based on randomized patients at the time of the interim analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pasireotide LAR | Percentage of Patients Who Achieved Clinical Symptom Improvement by Randomization Stratum and Treatment. | Diarrhea and Flushing (N=37, 39) | 13.5 Percentage of Participants |
| Pasireotide LAR | Percentage of Patients Who Achieved Clinical Symptom Improvement by Randomization Stratum and Treatment. | Diarrhea (N=2, 5) | 100 Percentage of Participants |
| Pasireotide LAR | Percentage of Patients Who Achieved Clinical Symptom Improvement by Randomization Stratum and Treatment. | Flushing (N=4, 1) | 50 Percentage of Participants |
| Pasireotide LAR | Percentage of Patients Who Achieved Clinical Symptom Improvement by Randomization Stratum and Treatment. | Overall (N=43, 45) | 20.9 Percentage of Participants |
| Octreotide LAR | Percentage of Patients Who Achieved Clinical Symptom Improvement by Randomization Stratum and Treatment. | Overall (N=43, 45) | 26.7 Percentage of Participants |
| Octreotide LAR | Percentage of Patients Who Achieved Clinical Symptom Improvement by Randomization Stratum and Treatment. | Diarrhea and Flushing (N=37, 39) | 28.2 Percentage of Participants |
| Octreotide LAR | Percentage of Patients Who Achieved Clinical Symptom Improvement by Randomization Stratum and Treatment. | Flushing (N=4, 1) | 0.0 Percentage of Participants |
| Octreotide LAR | Percentage of Patients Who Achieved Clinical Symptom Improvement by Randomization Stratum and Treatment. | Diarrhea (N=2, 5) | 20.0 Percentage of Participants |
Secondary
Assess the Proportion of Patients Who Achieved at Least a 30% Reduction in Frequency of Bowel Movements
Time frame: Month 6
Population: This Outcome Measure was planned in the protocol but not included in the analysis due to early termination of study due to lack of efficacy in symptom control.
Secondary
Improvement in Daily Mean Number of Diarrhea Bowel Movement Episodes by Randomization Stratum and Treatment.
Percent change from Baseline in mean daily bowel movements at Month 6 were compared between the two treatment groups using ANCOVA model with treatment as the main effect and symptom levels at Baseline (e.g. mean daily bowel movement at Baseline) and randomization stratum (D+F or D) as covariates. Percentage change = (Month 6 - baseline)/baseline.
Time frame: 6 months
Population: The Efficacy analyzable set consists of the subset of FAS patients who were randomized at least six months prior to the futility DMC data cut-off. Patients who had symptoms at baseline and at 6 months were included in this analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pasireotide LAR | Improvement in Daily Mean Number of Diarrhea Bowel Movement Episodes by Randomization Stratum and Treatment. | Diarrhea and Flushing (N=24, 28) | -23.5 Percentage of Episodes | Standard Deviation 24.28 |
| Pasireotide LAR | Improvement in Daily Mean Number of Diarrhea Bowel Movement Episodes by Randomization Stratum and Treatment. | Predominantly Diarrhea (D) (N=2, 4) | -44.2 Percentage of Episodes | Standard Deviation 10.26 |
| Pasireotide LAR | Improvement in Daily Mean Number of Diarrhea Bowel Movement Episodes by Randomization Stratum and Treatment. | Overall (N=26, 32) | -25.1 Percentage of Episodes | Standard Deviation 24.04 |
| Octreotide LAR | Improvement in Daily Mean Number of Diarrhea Bowel Movement Episodes by Randomization Stratum and Treatment. | Diarrhea and Flushing (N=24, 28) | -38.4 Percentage of Episodes | Standard Deviation 28.74 |
| Octreotide LAR | Improvement in Daily Mean Number of Diarrhea Bowel Movement Episodes by Randomization Stratum and Treatment. | Predominantly Diarrhea (D) (N=2, 4) | -22.9 Percentage of Episodes | Standard Deviation 31.68 |
| Octreotide LAR | Improvement in Daily Mean Number of Diarrhea Bowel Movement Episodes by Randomization Stratum and Treatment. | Overall (N=26, 32) | -36.5 Percentage of Episodes | Standard Deviation 29.05 |
Secondary
Improvement in Daily Mean Number of Flushing Episodes by Randomization Stratum and Treatment.
Percent change from Baseline in total number of flushing episodes comprising Month 6 were compared between the two treatment groups using ANCOVA model with treatment as the main effect and symptom levels at Baseline (e.g. total number of flushing episodes at Baseline) and randomization stratum (D+F or F) as covariates.
Time frame: 6 months
Population: The Efficacy analyzable set consists of the subset of FAS patients who were randomized at least six months prior to the futility DMC data cut-off. Patients were analyzed according the treatment they were assigned to at randomization. (ITT) principle.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pasireotide LAR | Improvement in Daily Mean Number of Flushing Episodes by Randomization Stratum and Treatment. | Diarrhea and Flushing (N=24, 28) | -41.0 Percentage of Episodes | Standard Deviation 41.06 |
| Pasireotide LAR | Improvement in Daily Mean Number of Flushing Episodes by Randomization Stratum and Treatment. | Predominately Flushing (N=4, 1) | -48.4 Percentage of Episodes | Standard Deviation 23.13 |
| Pasireotide LAR | Improvement in Daily Mean Number of Flushing Episodes by Randomization Stratum and Treatment. | Overall (N=28, 29) | -42.1 Percentage of Episodes | Standard Deviation 38.76 |
| Octreotide LAR | Improvement in Daily Mean Number of Flushing Episodes by Randomization Stratum and Treatment. | Diarrhea and Flushing (N=24, 28) | -52.8 Percentage of Episodes | Standard Deviation 32.18 |
| Octreotide LAR | Improvement in Daily Mean Number of Flushing Episodes by Randomization Stratum and Treatment. | Predominately Flushing (N=4, 1) | 47.2 Percentage of Episodes | — |
| Octreotide LAR | Improvement in Daily Mean Number of Flushing Episodes by Randomization Stratum and Treatment. | Overall (N=28, 29) | -49.4 Percentage of Episodes | Standard Deviation 36.65 |
Secondary
Objective Tumor Response Rate Assessed by Investigator
Baseline evaluations were to include Triphasic CT scan or MRI of the abdomen. Triphasic CT or MRIs were to be read by same radiologist at each assessment, measuring the same target and non-target lesions and accounting for all lesions that were present at Baseline. All known disease was accounted for when assessing objective tumor status. Current objective tumor status was to be captured on Tumor Assessment CRF. 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.
Time frame: Month 6
Population: Full Analysis Set (FAS) consists of all patients randomized into the study. Patients were analyzed according to the treatment they were assigned to at randomization. Patients randomized 6 months before the final clinical cutoff date were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pasireotide LAR | Objective Tumor Response Rate Assessed by Investigator | 2.0 Percentage of Participants |
| Octreotide LAR | Objective Tumor Response Rate Assessed by Investigator | 3.8 Percentage of Participants |
Secondary
Pasireotide LAR vs. Octreotide LAR on Disease Control Rate Based on RECIST Criteria
Disease control rate (DCR) is the proportion of patients with a best overall response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD). Complete Response (CR): Disappearance of all target lesions Partial Response (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. Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference 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. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. Unknown (UNK) Progression has not been documented and one or more target lesions have not been assessed or have been assessed using a different method than baseline.
Time frame: Month 6
Population: Full Analysis Set (FAS) consists of all patients randomized into the study. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization. Patients with analyzable data at month 6 were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pasireotide LAR | Pasireotide LAR vs. Octreotide LAR on Disease Control Rate Based on RECIST Criteria | 62.7 Percentage of participants |
| Octreotide LAR | Pasireotide LAR vs. Octreotide LAR on Disease Control Rate Based on RECIST Criteria | 46.2 Percentage of participants |
Secondary
Pasireotide LAR vs. Octreotide LAR on Duration of Symptom Response
Time frame: Month 6
Population: This Outcome Measure was planned in the protocol but not included in the analysis due to early termination of study due to lack of efficacy in symptom control.
Secondary
Pasireotide LAR vs. Octreotide LAR on Quality of Life Assessed by FACIT-D Questionnaire
Time frame: Month 6
Population: This Outcome Measure was planned in the protocol but not included in the analysis due to early termination of study due to lack of efficacy in symptom control.
Secondary
Pasireotide LAR vs. Octreotide LAR on Time to Symptom Progression
Time frame: Month 6
Population: This Outcome Measure was planned in the protocol but not included in the analysis due to early termination of study due to lack of efficacy in symptom control.
Secondary
Pasireotide LAR vs. Octreotide LAR on Time to Symptom Response.
Time frame: Month 6
Population: This Outcome Measure was planned in the protocol but not included in the analysis due to early termination of study due to lack of efficacy in symptom control.