Neoplasms

All Conditions

Rare Diseases

Carcinoma

Neuroendocrine Tumors

Carcinoma, Neuroendocrine

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Gastrointestinal Agents

Capecitabine

Bevacizumab

Somatostatin

Octreotide

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Antimetabolites

Antineoplastic Agents, Hormonal

bevacizumab + octreotide + metronomic capecitabine

long acting octreotide acetate at a dose of 20 or 30 mg administered intramuscularly every 4 weeks; Bevacizumab at a dose of 5 mg/kg every 2 weeks; orally capecitabine administered at a dose of 2000 mg/daily

bevacizumab + octreotide LAR + capecitabine

Maria P Brizzi, MD, PhD

Anna Ferrero, MD

Elisabetta Nobili, MD

Guido Biasco, MD, PhD

Alfredo Berruti, MD, PhD

Well differentiated neuroendocrine (NE) carcinomas have low proliferative activity and conventional chemotherapy is not recommended. Metronomic chemotherapy, i.e. the frequent administration of cytotoxic drugs at low doses, has demonstrated antiangiogenetic properties. Since well differentiated NE carcinomas are highly vascular, there is a rationale for testing metronomic chemotherapy and antiangiogenetic drugs. This is a national, multicenter, phase II study.

Metastatic or locally advanced well differentiated neuroendocrine carcinoma will be treated with a combination of bevacizumab (5 mg/kg) plus octreotide LAR (long- acting release) 20/30 mg plus capecitabine administered on a metronomic schedule (2000 mg/day).

Patients with stable disease, complete or partial response will continue treatment until progressive disease or unacceptable toxicity.

Primary endpoint: the response to treatment, evaluated according to the RECIST criteria.

Secondary endpoint: - toxicity, graded according to the NCI-CTG criteria;

* symptomatic response: evaluated according to the changes in both the frequency and intensity of symptoms;
* biochemical response: evaluated considering the changes in the tumor marker levels (circulating Chromogranin A);
* relationship between vascular endothelial growth factor (VEGF) polymorphisms and response to treatment;
* time to progression and survival: measured from the date of treatment start to the date of progression and the date of last follow-up or death, respectively.

Bevacizumab Plus Somatostatin Analogue and Metronomic Capecitabine in Patients With Advanced Neuroendocrine Tumors

Phase II Study of the Combination of Bevacizumab Plus Somatostatin Analogue and Metronomic Capecitabine in Patients With Advanced Inoperable Well-Differentiated Neuroendocrine Tumors

All adverse events encountered during the clinical study will be reported. The intensity of clinical adverse events will be graded according to the NCI Common Toxicity Criteria (CTC) version 3.0 grading system.

TTF is the time from first day of treatment to the first occurrence of any adverse events with withdrew prematurely the treatment.

Overall survival (OS) will be computed as the time between the first day of treatment and the date of death or the last date the patient was known to be alive.

University of Turin, Italy

Alfredo Berruti

Gastro-enteropancreatic Neuroendocrine Tumor

Lanreotide

Lanreotide autogel 90-120 mcg, every 4 weeks

Lanreotide autogel

Changhoon Yoo

Changhoon Yoo, MD

Lanreotide Autogel® has been established as a standard of care for patients with locally advanced or metastatic GEP-NETs based on the success of CLARINET trial. However, only few patients with Asian ethnicity were included in the trial.

According to the nationwide comprehensive study of patients with GEP-NET in Korea, hindgut primary NETs(Rectal) occured more frequently than western countries. However, small intestine or lung primary NET is relatively rare compared with western countries.1) Considering the clinical characteristics of GEP-NETs are distinct between the patients in Asian and Western countries, further evaluation on the efficacy and safety of Lanreotide Autogel® in Asian patients with GEP-NETs is needed.

Asian Investigation of Lanreotide Autogel® in the Management of GEP-NETs

Prospective Observational Study to Assess the Effectiveness and Safety of Lanreotide Autogel® in Patients With Locally Advanced or Metastatic Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) in Asia Region

Proportion of patients without tumor progression defined by RECIST version 1.1 at 2 years

Time between lanreotide treatment initiation and disease progression or death

Proportion of patients with tumor response by RECIST version 1.1

Proportion of patients with tumor response and stable disease by RECIST version 1.1

Time between lanreotide treatment initiation and death due to any cause

Change of serum chromogranin A levels during lanreotide treatment

Samsung Medical Center

Seoul St. Mary's Hospital

Severance Hospital

Seoul National University Bundang Hospital

Asan Medical Center

Assistant Professor

Carcinoid Tumor

Pasireotide

Hormones

Hormone Antagonists

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.

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.

Pasireotide LAR 60mg i.m. injection - patients may also receive pasireotide 600 µg s.c 3 times a day for symptom control as needed

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

Novartis Pharmaceuticals

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.

Efficacy and Safety of Pasireotide Long Acting Release vs. Octreotide Long Acting Release in Patients With Metastatic Carcinoid Disease

A Multicenter, Randomized, Blinded Efficacy and Safety Study of Pasireotide LAR vs Octreotide LAR in Patients With Metastatic Carcinoid Tumors Whose Disease-related Symptoms Are Inadequately Controlled by Somatostatin Analogues.

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.

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.

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.

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.

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.

Pasireotide 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.

Octreotide LAR

Extension Phase Pasireotide LAR

Extension Phase Octreotide LAR

After 6 month double blind core period, non-responders on Octreotide were given option to cross over to Pasireotide LAR in the Extension Phase of study.

Crossover to Pasireotide LAR

Total

Age Continuous

Sex: Female, Male

Study Director

Diarrhea and Flushing (N=37, 39)

Diarrhea (N=2, 5)

Flushing (N=4, 1)

Overall (N=43, 45)

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.

Percentage of Patients Who Achieved Clinical Symptom Improvement by Randomization Stratum and Treatment.

Diarrhea and Flushing (N=24, 28)

Predominantly Diarrhea (D) (N=2, 4)

Overall (N=26, 32)

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.

Improvement in Daily Mean Number of Diarrhea Bowel Movement Episodes by Randomization Stratum and Treatment.

Predominately Flushing (N=4, 1)

Overall (N=28, 29)

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.

Improvement in Daily Mean Number of Flushing Episodes by Randomization Stratum and Treatment.

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.

Pasireotide LAR vs. Octreotide LAR on Time to Symptom Response.

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.

Objective Tumor Response Rate Assessed by Investigator

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Bevacizumab Plus Somatostatin Analogue and Metronomic Capecitabine in Patients With Advanced Neuroendocrine Tumors	NCT01203306	Neuroendocrine ...	bevacizumab + o...	18 Years - 80 Years	University of Turin, Italy
Asian Investigation of Lanreotide Autogel® in the Management of GEP-NETs	NCT04696042	Neuroendocrine ...	Lanreotide auto...	19 Years -	Asan Medical Center
Efficacy and Safety of Pasireotide Long Acting Release vs. Octreotide Long Acting Release in Patients With Metastatic Carcinoid Disease	NCT00690430	Symptomatic Ref...	Pasireotide Octreotide	18 Years -	Novartis
Bevacizumab Plus Somatostatin Analogue and Metronomic Capecitabine in Patients With Advanced Neuroendocrine Tumors	NCT01203306	Neuroendocrine ...	bevacizumab + o...	18 Years - 80 Years	University of Turin, Italy
Asian Investigation of Lanreotide Autogel® in the Management of GEP-NETs	NCT04696042	Neuroendocrine ...	Lanreotide auto...	19 Years -	Asan Medical Center
Efficacy and Safety of Pasireotide Long Acting Release vs. Octreotide Long Acting Release in Patients With Metastatic Carcinoid Disease	NCT00690430	Symptomatic Ref...	Pasireotide Octreotide	18 Years -	Novartis

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