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Publications (10 of 231) Show all publications
Pavel, M., Gross, D., Benavent, M., Caplin, M., Perros, P., Srirajaskanthan, R., . . . Garcia-Carbonero, R. (2017). Efficacy and Safety Results of Telotristat Ethyl in Patients With Carcinoid Syndrome During the Double-blind Treatment Period of the TELECAST Phase 3 Clinical Trial. Paper presented at 9th Annual Meeting of the North American NeuroEndocrine Tumor Society, September 29–October 1, 2016, Jackson Hole, Wyoming. Pancreas, 46(3), 434-435.
Open this publication in new window or tab >>Efficacy and Safety Results of Telotristat Ethyl in Patients With Carcinoid Syndrome During the Double-blind Treatment Period of the TELECAST Phase 3 Clinical Trial
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2017 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 46, no 3, 434-435 p.Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-321064 (URN)10.1097/MPA.0000000000000812 (DOI)000394448600055 ()
Conference
9th Annual Meeting of the North American NeuroEndocrine Tumor Society, September 29–October 1, 2016, Jackson Hole, Wyoming
Available from: 2017-05-04 Created: 2017-05-04 Last updated: 2017-05-04Bibliographically approved
Pavel, M. E., Baudin, E., Öberg, K., Hainsworth, J. D., Voi, M., Rouyrre, N., . . . Yao, J. C. (2017). Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Annals of Oncology, 28(7), 1569-1575.
Open this publication in new window or tab >>Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study
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2017 (English)In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 28, no 7, 1569-1575 p.Article in journal (Refereed) Published
Abstract [en]

Background: In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the pre-specified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2.

Patients and methods: The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated.

Results: A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm.

Conclusion: No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates. Clinical Trial Number: NCT00412061, www.clinicaltrials.gov

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2017
Keyword
everolimus, neuroendocrine tumors, carcinoid syndrome, overall survival
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-328975 (URN)10.1093/annonc/mdx193 (DOI)000404134100024 ()
Available from: 2017-09-12 Created: 2017-09-12 Last updated: 2017-09-12Bibliographically approved
Öberg, K., Couvelard, A., Delle Fave, G., Gross, D., Grossman, A., Jensen, R. T., . . . Ferone, D. (2017). ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers. Neuroendocrinology, 105(3), 201-211.
Open this publication in new window or tab >>ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Biochemical Markers
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2017 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 105, no 3, 201-211 p.Article in journal (Refereed) Published
Abstract [en]

Biomarkers have been the mainstay in the diagnosis and follow-up of patients with neuroendocrine tumors (NETs) over the last few decades. In the beginning, secretory products from a variety of subtypes of NETs were regarded as biomarkers to follow during diagnosis and treatment: serotonin for small intestinal (SI) NETs, and gastrin and insulin for pancreatic NETs. However, it became evident that a large number of NETs were so-called nonfunctioning tumors without secreting substances that caused hormone-related symptoms. Therefore, it was necessary to develop so-called "general tumor markers." The most important ones so far have been chromogranin A and neuron-specific enolase (NSE). Chromogranin A is the most important general biomarker for most NETs with a sensitivity and specificity somewhere between 60 and 90%. NSE has been a relevant biomarker for patients with high-grade tumors, particularly lung and gastrointestinal tract tumors. Serotonin and the breakdown product urinary 5-hydroxyindoleacetic acid (U-5-HIAA) is still an important marker for diagnosing and follow-up of SI NETs. Recently, 5-HIAA in plasma has been analyzed by highperformance liquid chromatography and fluorometric detection and has shown good agreement with U-5-HIAA anal ysis. In the future, we will see new tests including circulating tumor cells, circulating DNA and mRNA. Recently, a NET test has been developed analyzing gene transcripts in circulating blood. Preliminary data indicate high sensitivity and specificity for NETs. However, its precise role has to be validated in prospective randomized controlled trials which are ongoing right now.

Keyword
Biomarkers, Chromogranin A, Urinary 5-hydroxyindoleacetic acid, Neuroendocrine tumor test
National Category
Endocrinology and Diabetes Neurology
Identifiers
urn:nbn:se:uu:diva-336660 (URN)10.1159/000472254 (DOI)000411501200003 ()28391265 (PubMedID)
Available from: 2018-01-04 Created: 2018-01-04 Last updated: 2018-01-04Bibliographically approved
Strosberg, J., El-Haddad, G., Wolin, E., Hendifar, A., Yao, J., Chasen, B., . . . Krenning, E. (2017). Phase 3 Trial of Lu-177-Dotatate for Midgut Neuroendocrine Tumors. New England Journal of Medicine, 376(2), 125-135.
Open this publication in new window or tab >>Phase 3 Trial of Lu-177-Dotatate for Midgut Neuroendocrine Tumors
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2017 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 376, no 2, 125-135 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (Lu-177)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. METHODS We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either Lu-177-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (Lu-177-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. RESULTS At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the Lu-177-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the Lu-177-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the Lu-177-Dotatate group and 26 in the control group (P = 0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the Lu-177-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. CONCLUSIONS Treatment with Lu-177-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the Lu-177-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials. gov number, NCT01578239; EudraCT number 2011-005049-11.)

National Category
General Practice
Identifiers
urn:nbn:se:uu:diva-315816 (URN)10.1056/NEJMoa1607427 (DOI)000392198400007 ()28076709 (PubMedID)
Available from: 2017-02-22 Created: 2017-02-22 Last updated: 2018-01-13Bibliographically approved
Kulke, M. H., Hoersch, D., Caplin, M. E., Anthony, L. B., Bergsland, E., Öberg, K., . . . Pavel, M. (2017). Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome. Journal of Clinical Oncology, 35(1), 14-23.
Open this publication in new window or tab >>Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome
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2017 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 35, no 1, 14-23 p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-315064 (URN)10.1200/JCO.2016.69.2780 (DOI)000391381300005 ()27918724 (PubMedID)
Available from: 2017-03-01 Created: 2017-03-01 Last updated: 2017-04-24Bibliographically approved
Strosberg, J., Wolin, E., Chasen, B., Kulke, M., Bushnell, D., Caplin, M., . . . Krenning, E. (2016). 177-Lu-Dotatate Significantly Improves Progression-Free Survival in Patients with Midgut Neuroendocrine Tumors: Results of the Phase III NETTER-1 Trial. Pancreas, 45(3), 483-483.
Open this publication in new window or tab >>177-Lu-Dotatate Significantly Improves Progression-Free Survival in Patients with Midgut Neuroendocrine Tumors: Results of the Phase III NETTER-1 Trial
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2016 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 45, no 3, 483-483 p.Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-301732 (URN)10.1097/MPA.0000000000000615 (DOI)000370956600073 ()
Available from: 2016-08-24 Created: 2016-08-24 Last updated: 2017-04-24Bibliographically approved
Öberg, K., Krenning, E., Sundin, A., Bodei, L., Kidd, M., Tesselaar, M., . . . Modlin, I. M. (2016). A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management. Endocrine Connections, 5(5), 174-187.
Open this publication in new window or tab >>A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management
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2016 (English)In: Endocrine Connections, ISSN 2049-3614, E-ISSN 2049-3614, Vol. 5, no 5, 174-187 p.Article in journal (Refereed) Published
Abstract [en]

The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.

Keyword
biomarker, carcinoid, CTC, CT scan, Delphic consensus, imaging, mRNA, MRI, multianalyte, NETest, neuroendocrine tumor, PET, RECIST, somatostatin
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-305767 (URN)10.1530/EC-16-0043 (DOI)000387476900009 ()27582247 (PubMedID)
Available from: 2016-10-21 Created: 2016-10-21 Last updated: 2017-11-29Bibliographically approved
Anthony, L., Hoersch, D., Ervin, C., Kulke, M. H., Pavel, M., Bergsland, E., . . . Lapuerta, P. (2016). Assessing Treatment Benefit of Telotristat Etiprate in Patients with Carcinoid Syndrome: Patient Exit Interviews. Pancreas, 45(3), 470-470.
Open this publication in new window or tab >>Assessing Treatment Benefit of Telotristat Etiprate in Patients with Carcinoid Syndrome: Patient Exit Interviews
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2016 (English)In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 45, no 3, 470-470 p.Article in journal, Meeting abstract (Other academic) Published
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:uu:diva-294813 (URN)000370956600035 ()
Available from: 2016-08-19 Created: 2016-05-27 Last updated: 2017-04-24Bibliographically approved
Ferolla, P., Brizzi, M. P., Meyer, T., Mansoor, W., Mazieres, J., Cao, C. D., . . . Baudin, E. (2016). Efficacy and safety of pasireotide LAR or everolimus alone, or in combination in patients with advanced carcinoids (NET) of the lung/thymus: Results from the randomized, phase 2 LUNA study. Paper presented at 41st Congress of the European-Society-for-Medical-Oncology (ESMO).Copenhagen, October 07-11, 2016. Annals of Oncology, 27(6), Article ID 4160.
Open this publication in new window or tab >>Efficacy and safety of pasireotide LAR or everolimus alone, or in combination in patients with advanced carcinoids (NET) of the lung/thymus: Results from the randomized, phase 2 LUNA study
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2016 (English)In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 27, no 6, 4160Article in journal, Meeting abstract (Refereed) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-317509 (URN)10.1093/annonc/mdw369.1 (DOI)000393912500414 ()
Conference
41st Congress of the European-Society-for-Medical-Oncology (ESMO).Copenhagen, October 07-11, 2016
Available from: 2017-04-13 Created: 2017-04-13 Last updated: 2017-04-23
Hrsch, D., Kulke, M., Caplin, M., Anthony, L., Bergsland, E., Öberg, K., . . . Pavel, M. (2016). Efficacy and Safety of Telotristat Etiprate in Patients with Carcinoid Syndrome Not Adequately Controlled by Somatostatin Analog Therapy: Analysis of the Ongoing TELESTAR Extension Period. Paper presented at 13th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 09-11, 2016, Barcelona, SPAIN. Neuroendocrinology, 103, 88-88.
Open this publication in new window or tab >>Efficacy and Safety of Telotristat Etiprate in Patients with Carcinoid Syndrome Not Adequately Controlled by Somatostatin Analog Therapy: Analysis of the Ongoing TELESTAR Extension Period
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2016 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, 88-88 p.Article in journal, Meeting abstract (Refereed) Published
Keyword
Telotristat, Carcinoid syndrome, Tryptophan
National Category
Cancer and Oncology Endocrinology and Diabetes Neurology
Identifiers
urn:nbn:se:uu:diva-313703 (URN)000386481600228 ()
Conference
13th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 09-11, 2016, Barcelona, SPAIN
Available from: 2017-01-23 Created: 2017-01-23 Last updated: 2017-04-24Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3432-118

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