- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03870399
Study of Tamoxifen in Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression (HORMONET)
January 13, 2023 updated by: Rachel Riechelmann, AC Camargo Cancer Center
Phase II Study of Hormone Therapy With Tamoxifen in Patients With Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression
This is a single-arm, unicentric, single-stage clinical study of tamoxifen for patients with well differentiated neuroendocrine tumors and radiological progression with positive (> 1 percent) HR (estrogen and / or progesterone) expression by IHC.
It will evaluate if Tamoxifen exerts antitumor action in patients with well differentiated NET and positive for the expression of HR, estrogen and / or progesterone.
Study Overview
Status
Active, not recruiting
Conditions
Intervention / Treatment
Detailed Description
Neuroendocrine tumors (NET) are rare neoplasms, but with increasing incidence and prevalence in the last decades.
Although they may manifest in the most diverse tissues, the vast majority of cases will affect organs of the digestive tract and lung.
At diagnosis, more than half of the cases present metastatic disease, and among patients with localized disease, up to one-third will have recurrence of the disease.
Unfortunately, the minority of patients with metastatic disease are eligible for curative intent.
Although there are many types of NET, they are often studied together as a group because their cells share common histological findings, have special secretory granules, and the ability to secrete bioactive amines and polypeptide hormones.
Approximately 25 percent of the tumors present functional hormonal syndromes (situation of great morbidity for these patients), being the carcinoid syndrome, the most common one.
From the molecular point of view, these neoplasias are largely dependent on the activation of the mTOR pathway and neoangiogenesis.
Another striking feature of neuroendocrine cells is the expression of cell surface hormone receptors whose activation or blockade may exert an important regulatory function.
The discovery of somatostatin, and consequently its receptors, is one of the major advances in the treatment of this neoplasm.
Due to the increased ability of somatostatin to inhibit the secretion of several hormones, its antitumor property has long been studied.
However, only after the development of synthetic long-life formulations can their use be used in clinical practice.
Well-differentiated neuroendocrine tumors (G1 and G2 according to World Health Organization (WHO) classification) present in more than 80 percent of somatostatin receptor cases.
In this population, the use of somatostatin analogues promotes symptomatic improvement of functioning syndromes in the order of 70 to 77 percent and biochemical improvement around 50 percent .
Regarding antiproliferative activity, two phase III studies evaluated the role of octreotide LAR and of lanreotide autogel, both somatostatin analogs, in the population of well differentiated tumors and, almost entirely, somatostatin receptor hyperexpressors when evaluated by octreoscan.
In these studies, the use of somatostatin analogue was associated with reduced risk of progression or death from 53 percent to 66 percent when compared to placebo.
Currently, this class of drugs is often considered as the first treatment option for patients with progressing metastatic disease, when the strategy of watchful waiting is not opted for (because they are tumors of sometimes indolent behavior, some cases are selected for observation only).
In general, there are few options for systemic therapies that are approved for these tumors in addition to somatostatin analogs (mTOR and antiangiogenic inhibitors), none of which clearly demonstrate overall survival gain, are costly and none are available for use in the public health system (SUS).
Therefore, it is very important to develop studies with new therapies for patients with NET, especially, molecularly defined therapies with greater access to patients.
In this context, other anti-hormonal therapies could be explored in patients with NET, such as the role of the sex hormones estrogen and progesterone, as well as their receptors.
A few studies have evaluated the expression of estrogen and progesterone receptors in NET and suggest interesting results.
One of the largest series was conducted at the AC Camargo Cancer Center where the immunohistochemical expression of these receptors was evaluated in 96 patients with NET from various sites.
About 35 percent of the cases presented positivity for some hormonal receptor (HR) in the tumor tissue.
Among the HR positive cases, there was no difference between sex, more frequent in thin, pancreatic and lung tumors and in well differentiated tumors (G1 and G2 by the WHO).
Viale et al.
Evaluated the expression of progesterone receptors (PR) in 96 patients with pancreatic neuroendocrine tumors.
Nuclear immunoreactivity for PR was observed in 58 percent of cases, with no difference in PR expression according to gender, age, or functioning syndromes.
About 163 primary tumors of the gastroenteropancreatic site and 115 metastases were evaluated by Zimmermann and colleagues for expression of female hormone receptors.
Progesterone receptor was more frequently found in pancreatic tumors and rarely in non-pancreatic (p <0.001), estrogen receptor was more frequently expressed in non-pancreatic tumors (<0.001) and in women (p: 0.019).
There was no difference between primary site and presence of metastases.
Apparently, HR positive tumors may present a more favorable evolution.
A study evaluated 160 patients with pancreatic neuroendocrine tumors operated for expression by PTEN immunohistochemistry (negative regulator of the mTOR pathway) and PR.
Approximately 69 percent of the cases were positive for PR and PTEN, 28 percent were positive for one of the two markers and only 3 percent were negative for both.
Combined positivity for PTEN and PR was associated with metastasis-free survival in stages I and II (p <0.001) and overall survival in all patients (p <0.001), even after adjustment for other prognostic variables.
Patients with negative PR and PTEN tumors had the shorter survival times when compared to those who had only one or both markers (p <0.001).
9 Similarly, other author demonstrated a retrospective analysis of 277 patients with neuroendocrine tumors (95 percent vs. 76 percent, p <0.05), and a higher survival rate (p <0.05) than in the control group (p <0.05) 0.015).
Even rarer in the literature is the role of antiestrogen therapies as a form of control of this neoplasia.
Case reports point to antiproliferative activity of tamoxifen in patients with NET and, in some cases, patients presenting more than 12 months of disease control.11
Reports of control of carcinoid syndrome and even regression of associated retroperitoneal fibrosis have also been described.
However, the only study to assess the activity of tamoxifen in neuroendocrine tumors dates back to 1984.
Sixteen patients were evaluated clinical benefit in only 19 percent of cases and no radiological response.
However, in this study, no patient was previously selected for HR tumor expression or degree of differentiation, which the investigators believe limited benefit in disease control.
Therefore, based on the premise that there is a need for research and treatment strategies for this rare neoplasm; there is clear therapeutic embezzlement in the public heath system due to the high cost of the treatments approved in the country for this neoplasia; NET are tumors that may present positivity to estrogen and / or progesterone receptors; evidence points to the possibility of antiproliferative effect using hormonal therapy, the investigators propose a phase II study of tamoxifen for patients with well differentiated NET and positive for HR, estrogen and / or progesterone expression.
Study Type
Interventional
Enrollment (Actual)
23
Phase
- Phase 2
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
SP
-
São Paulo, SP, Brazil, 01525000
- AC Camargo Câncer Center
-
-
-
-
Florida
-
Tampa, Florida, United States, 33612
- H. Lee Moffitt Cancer Center & Research Institute
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
Inclusion Criteria:
- Age greater than or equal to 18 years
- Histological diagnosis of well differentiated NET (typical and atypical lung carcinoids, NET G1, NET G2 of all gastroenteropancreatic sites and pancreatic NET G3 according to WHO 2017 classification) 20 advanced / metastatic, inoperable, with no possibility of curative treatment
- Immunohistochemical expression ≥ 1 percent for estrogen and / or progesterone receptor
- Disease with radiological progression (at least 10 percent tumor volume growth) in the last 12 months before day 1 cycle 1.
- No possibility of established treatments due to lack of access, risk of toxicities or without clinical indication. Patients who meet criteria for watchful waiting (low-dose disease and non-functioning NET) may be included.
- Measurable disease
- ECOG performance scale 0 to 2.
Adequate organic function as defined by the following criteria:
- serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT) ≤ 2.5 times the upper limit of local laboratory normality (LSN-LL);
- Total serum bilirubin ≤ 2.0 x ULN-LL;
- Absolute neutrophil count ≥ 1,500 / mm^3;
- Platelet count ≥ 80,000 / mm^3;
- Hemoglobin ≥ 9.0 g / dL;
- Estimated creatinine clearance by the MDRD equation ≥ 30ml / min
- Albumin ≥ 3.5 g / dL;
- INR ≤ 1.5
- Term of free and informed consent signed by the patient or legal representative.
Exclusion Criteria:
- Patients already on tamoxifen, but other prior treatment are allowed
- Patients with aggressive disease requiring cytotoxic therapy or locoregional therapies (eg hepatic embolization)
- A history of serious clinical or psychiatric illness that, by clinical judgment, may involve participation risk in this study
- Patients participating in other protocols with experimental drugs.
- Patients with oral food difficulties.
- Patients who underwent major recent surgery less than 4 weeks previously.
- Patients receiving chemotherapy or other oncologic therapy for less than 3 weeks.
- Patients who use oral anticoagulation
- Previous history of deep vein thrombosis or pulmonary embolism in the last 12 months.
- Pregnant or lactating patients.
- Patients with postmenopausal vaginal bleeding with no defined etiology.
- Patients with breast cancer who need to use tamoxifen for this neoplasm
- Another synchronous neoplasm that requires systemic treatment
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Tamoxifen
The participants will receive tamoxifen 20mg orally once daily with a glass of water.
Each cycle will be defined for 42 days (6 weeks).
|
The treatment to be used will be tamoxifen 20mg orally once daily.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Disease control rate
Time Frame: at 24 weeks after initiation of tamoxifen (at the end of cycle 6 - each cycle is 28 days)
|
Defined by absence of radiological progression in conventional imaging examinations by RECIST 1.1.
Isolated increase of biomarker (chromogranin A) or specific hormone will not be considered progression.
|
at 24 weeks after initiation of tamoxifen (at the end of cycle 6 - each cycle is 28 days)
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Progression-free survival
Time Frame: Through study completion, an average of 5 years
|
Defined by time from tamoxifen day 1 cycle 1 to death from any cause or radiological progression by RECIST 1.1, whichever occurs first.
Patients alive and without progression at the time of study analysis will be censored for time-to-event analysis.
|
Through study completion, an average of 5 years
|
Rate of Biochemical response
Time Frame: Through study completion, an average of 5 years
|
Defined by at least 30 percent drop in the marker (chromogranin and / or specific hormone) at any time of treatment in relation to pre-treatment value
|
Through study completion, an average of 5 years
|
Radiological response rate
Time Frame: Through study completion, an average of 5 years
|
Assessed by RECIST criteria 1.1
|
Through study completion, an average of 5 years
|
Disease control rate
Time Frame: Through study completion, an average of 5 years
|
defined by absence of radiological progression by RECIST 1.1 criteria, according to the intensity of expression by immunohistochemistry (IHC) of HR and also according to primary site (pancreas, gastrointestinal or lung)
|
Through study completion, an average of 5 years
|
Incidence of Treatment-related Adverse Events
Time Frame: Through study completion, an average of 5 years
|
Frequency of adverse events of grades 2 or more by Common Adverse Event Toxicity Criteria (CTCAE) version 5.0
|
Through study completion, an average of 5 years
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
PET-CT gallium-68 intake variation
Time Frame: Through study completion, an average of 3 years
|
Evaluate possible variations in intensity of intake between PET-CT gallium-68 pre-treatment and 12 weeks after initiation of tamoxifen as a continuous variable for each capture lesion.
|
Through study completion, an average of 3 years
|
PET-CT gallium-68 number variation
Time Frame: Through study completion, an average of 3 years
|
Evaluate possible variations in number of sites with intake between PET-CT gallium-68 pre-treatment and 12 weeks after initiation of tamoxifen as a continuous variable for each capture lesion.
|
Through study completion, an average of 3 years
|
CTC positivity rate
Time Frame: Through study completion, an average of 3 years
|
Evaluate the percentage of CTC positivity in NET.
|
Through study completion, an average of 3 years
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010 Jan 15;31(2):169-88. doi: 10.1111/j.1365-2036.2009.04174.x. Epub 2009 Oct 21.
- Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999 May;17(5):1474-81. doi: 10.1200/JCO.1999.17.5.1474.
- Caplin ME, Buscombe JR, Hilson AJ, Jones AL, Watkinson AF, Burroughs AK. Carcinoid tumour. Lancet. 1998 Sep 5;352(9130):799-805. doi: 10.1016/S0140-6736(98)02286-7.
- Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008 Jun 20;26(18):3063-72. doi: 10.1200/JCO.2007.15.4377.
- Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, Mayer C, Aminossadati B, Pape UF, Blaker M, Harder J, Arnold C, Gress T, Arnold R; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656-63. doi: 10.1200/JCO.2009.22.8510. Epub 2009 Aug 24.
- Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J, de Vries EG, Tomassetti P, Pavel ME, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011 Feb 10;364(6):514-23. doi: 10.1056/NEJMoa1009290.
- Caplin ME, Pavel M, Ruszniewski P. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014 Oct 16;371(16):1556-7. doi: 10.1056/NEJMc1409757. No abstract available.
- Viale G, Doglioni C, Gambacorta M, Zamboni G, Coggi G, Bordi C. Progesterone receptor immunoreactivity in pancreatic endocrine tumors. An immunocytochemical study of 156 neuroendocrine tumors of the pancreas, gastrointestinal and respiratory tracts, and skin. Cancer. 1992 Nov 1;70(9):2268-77. doi: 10.1002/1097-0142(19921101)70:93.0.co;2-x.
- Zimmermann N, Lazar-Karsten P, Keck T, Billmann F, Schmid S, Brabant G, Thorns C. Expression Pattern of CDX2, Estrogen and Progesterone Receptors in Primary Gastroenteropancreatic Neuroendocrine Tumors and Metastases. Anticancer Res. 2016 Mar;36(3):921-4.
- Estrella JS, Broaddus RR, Mathews A, Milton DR, Yao JC, Wang H, Rashid A. Progesterone receptor and PTEN expression predict survival in patients with low- and intermediate-grade pancreatic neuroendocrine tumors. Arch Pathol Lab Med. 2014 Aug;138(8):1027-36. doi: 10.5858/arpa.2013-0195-OA.
- Kim SJ, An S, Lee JH, Kim JY, Song KB, Hwang DW, Kim SC, Yu E, Hong SM. Loss of Progesterone Receptor Expression Is an Early Tumorigenesis Event Associated with Tumor Progression and Shorter Survival in Pancreatic Neuroendocrine Tumor Patients. J Pathol Transl Med. 2017 Jul;51(4):388-395. doi: 10.4132/jptm.2017.03.19. Epub 2017 Jun 8.
- Arganini M, Spinelli C, Cecchini GM, Miccoli P. Long term treatment with tamoxifen for metastatic carcinoid tumor. Acta Chir Belg. 1989 Jul-Aug;89(4):209-11.
- Myers CF, Ershler WB, Tannenbaum MA, Barth R. Tamoxifen and carcinoid tumor. Ann Intern Med. 1982 Mar;96(3):383. doi: 10.7326/0003-4819-96-3-383_1. No abstract available.
- Biasco E, Antonuzzo A, Galli L, Baldi GG, Derosa L, Marconcini R, Farnesi A, Ricci S, Falcone A. Small-bowel neuroendocrine tumor and retroperitoneal fibrosis: efficacy of octreotide and tamoxifen. Tumori. 2015 Mar 20;101(1):e24-8. doi: 10.5301/tj.5000259.
- Stathopoulos GP, Karvountzis GG, Yiotis J. Tamoxifen in carcinoid syndrome. N Engl J Med. 1981 Jul 2;305(1):52. doi: 10.1056/NEJM198107023050115. No abstract available.
- Moertel CG, Engstrom PF, Schutt AJ. Tamoxifen therapy for metastatic carcinoid tumor: a negative study. Ann Intern Med. 1984 Apr;100(4):531-2. doi: 10.7326/0003-4819-100-4-531. No abstract available.
- Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ; Panel members. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol. 2005 Oct;16(10):1569-83. doi: 10.1093/annonc/mdi326. Epub 2005 Sep 7.
- Krebs MG, Hou JM, Sloane R, Lancashire L, Priest L, Nonaka D, Ward TH, Backen A, Clack G, Hughes A, Ranson M, Blackhall FH, Dive C. Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches. J Thorac Oncol. 2012 Feb;7(2):306-15. doi: 10.1097/JTO.0b013e31823c5c16.
- Crippa S, Partelli S, Belfiori G, Palucci M, Muffatti F, Adamenko O, Cardinali L, Doglioni C, Zamboni G, Falconi M. Management of neuroendocrine carcinomas of the pancreas (WHO G3): A tailored approach between proliferation and morphology. World J Gastroenterol. 2016 Dec 7;22(45):9944-9953. doi: 10.3748/wjg.v22.i45.9944.
- Furr BJ, Jordan VC. The pharmacology and clinical uses of tamoxifen. Pharmacol Ther. 1984;25(2):127-205. doi: 10.1016/0163-7258(84)90043-3. No abstract available.
- Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell. 1998 Dec 23;95(7):927-37. doi: 10.1016/s0092-8674(00)81717-1.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
March 13, 2019
Primary Completion (Anticipated)
May 13, 2023
Study Completion (Anticipated)
May 13, 2023
Study Registration Dates
First Submitted
March 6, 2019
First Submitted That Met QC Criteria
March 8, 2019
First Posted (Actual)
March 12, 2019
Study Record Updates
Last Update Posted (Actual)
January 17, 2023
Last Update Submitted That Met QC Criteria
January 13, 2023
Last Verified
January 1, 2023
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Neoplasms
- Neuroendocrine Tumors
- Physiological Effects of Drugs
- Antineoplastic Agents
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Hormone Antagonists
- Bone Density Conservation Agents
- Estrogen Antagonists
- Selective Estrogen Receptor Modulators
- Estrogen Receptor Modulators
- Tamoxifen
Other Study ID Numbers
- 2626/18
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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