Martyn Caplin

Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

Long Term Results of Treatment of Malignant Carcinoid Syndrome With Lanreotide Autogel

Aliment Pharmacol Ther 2011; 34: 235–242

6LBA 177-Lu-Dotatate significantly improves progression-free survival in patients with midgut neuroendocrine tumours: Results of the phase III NETTER-1 trial

177-Lu-Dotatate significantly improves progression-free survival in patients with midgut neuroendocrine tumours : Results of the phase III NETTER-1 trial

Accuracy and Reproducibility of Right Ventricular Quantification in Patients with Pressure and Volume Overload Using Single-Beat Three-Dimensional Echocardiography

Background The right ventricle is a complex structure that is challenging to quantify by two-dimensional (2D) echocardiography. Unlike disk summation three-dimensional (3D) echocardiography (3DE), single-beat 3DE can acquire large volumes at high volume rates in one cardiac cycle, avoiding stitching artifacts or long breath-holds. The aim of this study was to assess the accuracy and test-retest reproducibility of single-beat 3DE for quantifying right ventricular (RV) volumes in adult populations of acquired RV pressure or volume overload, namely, pulmonary hypertension (PH) and carcinoid heart disease, respectively. Three-dimensional and 2D echocardiographic indices were also compared for identifying RV dysfunction in PH. Methods A prospective cross-sectional study was performed in 100 individuals who underwent 2D echocardiography, 3DE, and cardiac magnetic resonance imaging: 49 patients with PH, 20 with carcinoid heart disease, 11 with metastatic carcinoid tumors without cardiac involvement, and 20 healthy volunteers. Two operators performed test-retest acquisition and postprocessing for inter- and intraobserver reproducibility in 20 subjects. Results: RV single-beat 3DE was attainable in 96% of cases, with mean volume rates of 32 to 45 volumes/sec. Bland-Altman analysis of all subjects (presented as mean bias ± 95% limits of agreement) revealed good agreement for end-diastolic volume (−2.3 ± 27.4 mL) and end-systolic volume (5.2 ± 19.0 mL) measured by 3DE and cardiac magnetic resonance imaging, with a tendency to underestimate stroke volume (−7.5 ± 23.6 mL) and ejection fraction (−4.6 ± 13.8%) by 3DE. Subgroup analysis demonstrated a greater bias for volumetric underestimation, particularly in healthy volunteers (end-diastolic volume, −11.9 ± 18.0 mL; stroke volume, −11.2 ± 20.2 mL). Receiver operating characteristic curve analysis showed that 3DE-derived ejection fraction was significantly superior to 2D echocardiographic parameters for identifying RV dysfunction in PH (sensitivity, 94%; specificity, 88%; area under the curve, 0.95; P = .031). There was significant interobserver test-retest bias for RV volume underestimation (end-diastolic volume, −12.5 ± 28.1 mL; stroke volume, −10.6 ± 23.2 mL). Conclusions Single-beat 3DE is feasible and clinically applicable for volumetric quantification in acquired RV pressure or volume overload. It has improved limits of agreement compared with previous disk summation 3D echocardiographic studies and has incremental value over standard 2D echocardiographic measures for identifying RV dysfunction. Despite the ability to obtain and postprocess a full-volume 3D echocardiographic RV data set, the quality of the raw data did influence the accuracy of the data obtained. The technique performs better with dilated rather than nondilated RV cavities, with a learning curve that might affect the test-retest reproducibility for serial RV studies.

Peptide Receptor Radionuclide Treatment and (131)I-MIBG in the management of patients with metastatic/progressive phaeochromocytomas and paragangliomas

Radionuclide therapy has been used to treat patients with progressive/metastatic paragangliomas (PGLs) and phaeochromocytomas (PCCs). The aim of the present study is to retrospectively compare the therapeutic outcomes of these modalities in patients with progressive/metastatic PCCs and PGLs.

Health-Related Quality of Life in Patients With Progressive Midgut Neuroendocrine Tumors Treated With 177Lu-Dotatate in the Phase III NETTER-1 Trial

Purpose Neuroendocrine tumor (NET) progression is associated with deterioration in quality of life (QoL). We assessed the impact of 177Lu-Dotatate treatment on time to deterioration in health-related QoL. Methods The NETTER-1 trial is an international phase III study in patients with midgut NETs. Patients were randomly assigned to treatment with 177Lu-Dotatate versus high-dose octreotide. European Organisation for Research and Treatment of Cancer quality-of-life questionnaires QLQ C-30 and G.I.NET-21 were assessed during the trial to determine the impact of treatment on health-related QoL. Patients completed the questionnaires at baseline and every 12 weeks until tumor progression. QoL scores were converted to a 100-point scale according to European Organisation for Research and Treatment of Cancer instructions, and individual changes from baseline scores were assessed. Time to QoL deterioration (TTD) was defined as the time from random assignment to the first QoL deterioration ≥ 10 points for each patient in the corresponding domain scale. All analyses were conducted on the intention-to-treat population. Patients with no deterioration were censored at the last QoL assessment date. Results TTD was significantly longer in the 177Lu-Dotatate arm (n = 117) versus the control arm (n = 114) for the following domains: global health status (hazard ratio [HR], 0.406), physical functioning (HR, 0.518), role functioning (HR, 0.580), fatigue (HR, 0.621), pain (HR, 0.566), diarrhea (HR, 0.473), disease-related worries (HR, 0.572), and body image (HR, 0.425). Differences in median TTD were clinically significant in several domains: 28.8 months versus 6.1 months for global health status, and 25.2 months versus 11.5 months for physical functioning. Conclusion This analysis from the NETTER-1 phase III study demonstrates that, in addition to improving progression-free survival, 177Lu-Dotatate provides a significant QoL benefit for patients with progressive midgut NETs compared with high-dose octreotide.

Selected For Oral Presentation: Overall Survival, Progression-Free Survival, and Quality of Life Updates from the NETTER-1 Study : 177Lu-Dotatate Vs. High Dose Octreotide In Progressive Midgut Neuroendocrine Tumors

Pre-Treatment Tumor Growth Rate (TGR0) in Patients Diagnosed with Well-Differentiated Neuroendocrine Tumors (NETs) Treated with Systemic Therapies : Subgroup Analysis of the GREPONET StudySelected For Oral Presentation: Overall Survival, Progression-Free Survival, and Quality of Life Updates from the NETTER-1 Study : 177Lu-Dotatate Vs. High Dose Octreotide In Progressive Midgut Neuroendocrine TumorsSelected For Oral Presentation: Peptide Receptor Radionuclide Therapy (PRRT) in Gastroenteropancreatic Grade 3 Neuroendocrine Neoplasms : A Retrospective International Multicenter StudySelected For Poster Walks : Can Insulin-Like Growth Factor 1 (IGF-1), IGF-1 Receptor, Connective Tissue Growth Factor and Ki-67 Labelling Index Have a Prognostic Role in Pulmonary Carcinoids?Ex Vivo Activity of Cytotoxic Drugs and Targeted Agents in Small Intestinal Neuroendocrine TumorsA Prospective Nordic Study on the Use of Chromogranin A for the Prediction of Progression in Patients with Pancreatic and Small Intestinal Neuroendocrine TumorsPlasma Protein Kallikrein-14 Strongly Predicts Pronounced Chromogranin A (CgA) Response in Small Intestinal Neuroendocrine Tumor (NET) Patients after Somatostatin Analog (SSA) Treatment : The Nordic EXPLAIN Biomarker StudyIntravenous versus Oral Etoposide : Efficacy and Correlation to Clinical Outcome in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)

438PDImproved time to quality of life deterioration in patients with progressive midgut neuroendocrine tumors treated with 177Lu-DOTATATE: The NETTER-1 phase III trial

Improved time to quality of life deterioration in patients with progressive midgut neuroendocrine tumors treated with 177Lu-DOTATATE : The NETTER-1 phase III trial

Treatment Satisfaction, Symptom Control, and Quality of Life (QoL) With Lanreotide Autogel/Depot (LAN) in Neuroendocrine Tumor (NET) Patients With Carcinoid Syndrome (CS): Results From the SymNET Study

Abstracts Presented at the 7th Annual Meeting of the North American NeuroEndocrine Tumor Society, October 10–11, 2014, Nashville, Tennessees Presented at the 7th Annual Meeting of the North American NeuroEndocrine Tumor Society, October 10–11, 2014, Nashville, Tennessee Drug Discovery for Atypical Pulmonary Carcinoid Using a Library of Targeted Agents Curtis R. Chong, Bruce E. Johnson, Pasi A. Jänne. Dana-Farber Cancer Institute, Boston, MA. Background: On average it costs ~

NETTER-1 phase III in patients with midgut neuroendocrine tumors treated with 177Lu-dotatate: Efficacy, safety, QoL results and subgroup analysis

1 billion and takes > 15 years to develop a new drug; this is a major challenge to drug discovery for rare forms of lung cancer like atypical pulmonary carcinoid. One way to overcome this challenge is to identify existing drugs active against multiple types of neuroendocrine lung cancers. Methods:We created a library of 292 targeted agents that inhibit 104 different cellular pathways, including drugs that are FDA-approved (31 drugs, 11%), in phase III (29 drugs, 10%), phase II (51 drugs, 18%), or phase I (30 drugs, 10%) clinical trials or in pre-clinical drug development (150 agents, 51%). We screened this collection on a panel of pulmonary neuroendocrine tumor cell lines: atypical carcinoid (NCI-H720 and H835) and small cell lung cancer (G1C, H69). Results: Navitoclax, which targets Bcl-2/BCL-XL, showed potent inhibition against NCI-H720 vs. NCI-H835 (IC50 = 66 and 460 nM, respectively). The BCL-XL-specific agents 334092 and 354961 also inhibited NCI-H720 (IC50 = 80 and 350 nM, respectively),while the Bcl-2 specific inhibitor ABT199 was much less potent (IC50 ~ 5mM). Other promising inhibitors of NCIH720 and H835 include the HSP-90 inhibitor AUY-922 (IC50 = 4 nM for both), the PI3 kinase/mTOR inhibitor GSK-2126458 (IC50 = 7 and 38 nM, respectively), and the polo-like kinase inhibitor volasertib (IC50 = 6 nM and > 1mM, respectively), which was also active against the small cell lines tested (11 nM and 24 nM for G1C and H69, respectively). Conclusion: Our screen of a collection of targeted agents identifies navitoclax, AUY-922, GSK-2126458, and volasertib as inhibitors of atypical pulmonary carcinoid cell lines. As this form of lung cancer is quite rare, a clinical trial may need to include patients with other types of neuroendocrine lung cancers. We are expanding our screening efforts to include every available targeted therapy. Pathologic Classification of Pulmonary Carcinoid Cell Lines Curtis R. Chong, Ilona Linnoila, Pasi A. Jänne, Bruce E. Johnson, Lynette M. Sholl. Dana-Farber Cancer Institute, Boston, MA; National Cancer Institute, Bethesda, MD; Department of Pathology, Brigham and Women’s Hospital, Boston, MA. Background: The scarcity of available pulmonary carcinoid cell lines and the difficulty in creating new ones from patient tumor samples hinders efforts to identify new drugs and understand the biology of this rare type of lung cancer. Methods: We searched cell line repositories throughout the world for pulmonary carcinoid cell lines. Board-certified anatomic pathologists (IL and LMS) then reviewed the original pathologic specimens to confirmwhether tumor samples met the most current diagnostic criteria for pulmonary carcinoid tumors. Results: Using the definition established by Travis et. al. in 1998 we reviewed the original pathologic specimens for five cell lines previously reported as being derived from pulmonary carcinoid tumors (NCI-H720, NCI-H727, NCI-H835, NCI-H1770, and UMC-11). Notably, two cell lines (NCI-H720 and NCI-H835) were derived from aggressive atypical pulmonary carcinoids, with 14 and 20 mitoses/HPF, respectively, as the tumor specimens lacked the morphology seen in large cell neuroendocrine carcinoma or small cell lung cancer. Two cell lines (NCI-H727 and UMC-11) were derived from specimens best characterized as large cell neuroendocrine carcinomas, with 20 and 22 mitoses/HPF, respectively. The NCI-H1770 cell line was derived from a poorly differentiated neoplasm that was positive for chromogranin, negative for TTF-1, and had weak keratin expression, which was most consistent with a poorly differentiated carcinoma with neuroendocrine features. Conclusion: Applying the most current diagnostic criteria to original tumor specimens, none of the existing “pulmonary carcinoid” cell lines can be strictly categorized as atypical carcinoid. However, despite a high mitotic index, Pancreas • Volume 44, Number 2, March 2015 Copyright