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Study of Tamoxifen in Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression (HORMONET)

Primary Purpose

Neuroendocrine Tumors, Progesterone Receptor Positive Tumor, Estrogen Receptor Positive Tumor

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Tamoxifen
Sponsored by
AC Camargo Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuroendocrine Tumors focused on measuring neuroendocrine tumor, tamoxifen, Progesterone Receptor, Estrogen Receptor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • H. Lee Moffitt Cancer Center & Research Institute
  • AC Camargo Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Tamoxifen

Arm Description

The participants will receive tamoxifen 20mg orally once daily with a glass of water. Each cycle will be defined for 42 days (6 weeks).

Outcomes

Primary Outcome Measures

Disease control rate
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.

Secondary Outcome Measures

Progression-free survival
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.
Rate of Biochemical response
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
Radiological response rate
Assessed by RECIST criteria 1.1
Disease control rate
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)
Incidence of Treatment-related Adverse Events
Frequency of adverse events of grades 2 or more by Common Adverse Event Toxicity Criteria (CTCAE) version 5.0

Full Information

First Posted
March 6, 2019
Last Updated
January 13, 2023
Sponsor
AC Camargo Cancer Center
Collaborators
H. Lee Moffitt Cancer Center and Research Institute
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1. Study Identification

Unique Protocol Identification Number
NCT03870399
Brief Title
Study of Tamoxifen in Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression
Acronym
HORMONET
Official Title
Phase II Study of Hormone Therapy With Tamoxifen in Patients With Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 13, 2019 (Actual)
Primary Completion Date
May 13, 2023 (Anticipated)
Study Completion Date
May 13, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
AC Camargo Cancer Center
Collaborators
H. Lee Moffitt Cancer Center and Research Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroendocrine Tumors, Progesterone Receptor Positive Tumor, Estrogen Receptor Positive Tumor
Keywords
neuroendocrine tumor, tamoxifen, Progesterone Receptor, Estrogen Receptor

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
A single-arm, unicentric, single-stage clinical study
Masking
None (Open Label)
Allocation
N/A
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tamoxifen
Arm Type
Experimental
Arm Description
The participants will receive tamoxifen 20mg orally once daily with a glass of water. Each cycle will be defined for 42 days (6 weeks).
Intervention Type
Drug
Intervention Name(s)
Tamoxifen
Intervention Description
The treatment to be used will be tamoxifen 20mg orally once daily.
Primary Outcome Measure Information:
Title
Disease control rate
Description
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.
Time Frame
at 24 weeks after initiation of tamoxifen (at the end of cycle 6 - each cycle is 28 days)
Secondary Outcome Measure Information:
Title
Progression-free survival
Description
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.
Time Frame
Through study completion, an average of 5 years
Title
Rate of Biochemical response
Description
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
Time Frame
Through study completion, an average of 5 years
Title
Radiological response rate
Description
Assessed by RECIST criteria 1.1
Time Frame
Through study completion, an average of 5 years
Title
Disease control rate
Description
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)
Time Frame
Through study completion, an average of 5 years
Title
Incidence of Treatment-related Adverse Events
Description
Frequency of adverse events of grades 2 or more by Common Adverse Event Toxicity Criteria (CTCAE) version 5.0
Time Frame
Through study completion, an average of 5 years
Other Pre-specified Outcome Measures:
Title
PET-CT gallium-68 intake variation
Description
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.
Time Frame
Through study completion, an average of 3 years
Title
PET-CT gallium-68 number variation
Description
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.
Time Frame
Through study completion, an average of 3 years
Title
CTC positivity rate
Description
Evaluate the percentage of CTC positivity in NET.
Time Frame
Through study completion, an average of 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rachel SP Riechelmann, Phd
Organizational Affiliation
Fundacao Antonio Prudente
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jonathan R Strosberg, MD
Organizational Affiliation
H. Lee Moffitt Cancer Center and Research Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
H. Lee Moffitt Cancer Center & Research Institute
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
AC Camargo Cancer Center
City
São Paulo
State/Province
SP
ZIP/Postal Code
01525000
Country
Brazil

12. IPD Sharing Statement

Plan to Share IPD
No
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Study of Tamoxifen in Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression

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