Clinical Trials /

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

NCT03870399

Description:

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.

Related Conditions:
  • Gastrointestinal Neuroendocrine Tumors
  • Lung Neuroendocrine Neoplasm
  • Pancreatic Neuroendocrine Carcinoma
  • Pancreatic Neuroendocrine Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Tamoxifen in Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression
  • Official Title: Phase II Study of Hormone Therapy With Tamoxifen in Patients With Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression

Clinical Trial IDs

  • ORG STUDY ID: 2626/18
  • NCT ID: NCT03870399

Conditions

  • Neuroendocrine Tumors
  • Progesterone Receptor Positive Tumor
  • Estrogen Receptor Positive Tumor

Interventions

DrugSynonymsArms
TamoxifenTamoxifen

Purpose

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.
    

Trial Arms

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

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.

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Disease control rate
Time Frame:at 24 weeks after initiation of tamoxifen (at the end of cycle 6)
Safety Issue:
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.

Secondary Outcome Measures

Measure:Progression-free survival
Time Frame:Through study completion, an average of 5 years
Safety Issue:
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.
Measure:Rate of Biochemical response
Time Frame:Through study completion, an average of 5 years
Safety Issue:
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
Measure:Radiological response rate
Time Frame:Through study completion, an average of 5 years
Safety Issue:
Description:Assessed by RECIST criteria 1.1
Measure:Disease control rate
Time Frame:Through study completion, an average of 5 years
Safety Issue:
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)
Measure:Incidence of Treatment-related Adverse Events
Time Frame:Through study completion, an average of 5 years
Safety Issue:
Description:Frequency of adverse events of grades 2 or more by Common Adverse Event Toxicity Criteria (CTCAE) version 5.0

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:AC Camargo Cancer Center

Trial Keywords

  • neuroendocrine tumor
  • tamoxifen
  • Progesterone Receptor
  • Estrogen Receptor

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