Title
A Clinical Trial to Assess the Safety of 0.005 % Estriol Vaginal Gel in Hormone Receptor-Positive Postmenopausal Women With Early Stage Breast Cancer in Treatment With Aromatase Inhibitor in the Adjuvant Setting
A Phase II Prospective, Randomized, Double-Blind, Placebo-Controlled and Multi-Centre Clinical Trial to Assess the Safety of 0.005 % Estriol Vaginal Gel in Hormone Receptor-Positive Postmenopausal Women With Early Stage Breast Cancer in Treatment With Aromatase Inhibitor in the Adjuvant Setting
Phase
Phase 2Lead Sponsor
ITF Research Pharma, S.L.U.Study Type
InterventionalStatus
Completed Results PostedIndication/Condition
Vaginal AtrophyIntervention/Treatment
estriol ...Study Participants
61This is a phase II, prospective, randomized, double-blind, placebo-controlled, international (Spain and Sweden) and multicentre study to explore the safety of 0.005% estriol vaginal gel in women with early stage breast cancer in treatment with Non-Steroidal Aromatase Inhibitors (NSAIs) in the adjuvant setting and symptoms of vaginal atrophy.
This is a phase II, prospective, randomized, double-blind, placebo-controlled, international (Spain and Sweden) and multicentre study.
In the setting of postmenopausal hormone receptor positive breast cancer, treatment with aromatase inhibitors (AIs) is the most effective and well-studied therapy. Vaginal dryness is one of the most frequently reported symptom caused by this adjuvant therapy which may lead to a reduced adherence in breast cancer women.
This study will explore the safety of 0.005% estriol vaginal gel in this oncological context, to demonstrate that this medicinal product is a safe option to treat the vaginal atrophy caused by AIs, without a clinically relevant influence in gonadotropins or systemic estrogen levels.
The main objective is to evaluate the levels of Follicle Stimulating Hormone (FSH) after treatment with 0.005% estriol vaginal gel in hormone receptor-positive postmenopausal women with early stage breast cancer in treatment with Non-Steroidal Aromatase Inhibitors (NSAIs) in the adjuvant setting and symptoms of vaginal atrophy.
placebo vaginal gel
0.005% estriol vaginal gel
Route: Vaginal. Administration by an applicator inserted deep inside the vagina Dose: 1 g of gel, containing 50 Mcg of estriol Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: twice weekly administration
Route: Vaginal. Administration by an applicator inserted deep inside the vagina Dose: 1 g of gel. Dosage schedule: Weeks 1-3: single daily application Weeks 4-12: twice weekly administration
Inclusion Criteria: Written informed consent prior to beginning specific protocol procedures. Patients must have histological confirmation of breast adenocarcinoma with stage I-IIIA, documented at a local pathology department. The breast tumors must be estrogen-receptor positive and/or progesterone receptor positive (≥1% of stained tumor cells by Immunohistochemistry (IHC) as determined by the local laboratory) with any Human Epidermal Growth Factor Receptor 2(HER2) status. Postmenopausal status defined as: 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40 Milli-international units per milliliter (mIU/ml) or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. Patient must be receiving the non-steroidal aromatase inhibitors anastrozole or letrozole as breast cancer treatment in the adjuvant setting for a minimum of 6 months. Women suffering from moderate to severe vaginal dryness according to the FDA guidelines for drug development in postmenopausal women (Center for Drug Evaluation and Research, (CDER) Jan 2003). A moderate symptom will be considered if the symptom is present, bothersome and annoying, and a severe symptom will be considered if the symptom is present, bothersome and annoying, and interferes with the normal patient activity. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1. Adequate bone marrow as defined by the following laboratory values: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L. Platelets (plt) ≥ 100 x 109/L. Hemoglobin (Hgb) ≥ 10 g/dl. Patient has adequate organ function as defined by the following laboratory values: Serum creatinine ≤ 1.5 x Upper Limit of Normal (ULN). Bilirubin ≤ 1.5 × ULN. Alkaline phosphatase ≤ 2 × ULN. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2 × ULN. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. Exclusion Criteria: Stage IIIB-IV breast cancer or bilateral breast cancer. Treatment with any other current anti-tumoral therapy (chemotherapy, anti-Her2…etc) besides the NSAI. Pamidronate or Alendronate are permitted. Prior history of other malignancy within 5 years of study entry, aside from non-melanoma skin cancer or carcinoma-in-situ of the uterine cervix adequately treated. Postmenopausal uterine bleeding. Vaginal bleeding of unknown etiology. Patients with endometrial thickness equal to or greater than 4 mm measured by transvaginal ultrasound. Patients who have received any type of vulvovaginal treatment in the 15 days prior to the start of the study. Use of any hormone, natural (phytoestrogens) or herbal products for the treatment of menopausal symptoms within the last 3 months. Current or previous history of thromboembolic disease or coagulopathies. Severe cardiovascular or respiratory diseases in the previous 6 months. Renal Impairment. Hepatitis B and/or hepatitis C carriers (unless with normal hepatic function). Known human immunodeficiency virus infection. Known hypersensitivity to NSAI. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into this study. Previous investigational treatment for any condition or participation in any clinical trial within 4 weeks of inclusion date.
Event Type | Organ System | Event Term | 0.005% Estriol Vaginal Gel | Placebo Vaginal Gel |
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Change from Baseline (mean screening-baseline) to Week 12 in Serum Levels of Follicle Stimulating Hormone (FSH) compare to natural physiological variability (screening-baseline variation)
Change in plasma levels of estradiol at weeks 1, 3, 8 and 12 compared to baseline.
Change in plasma levels of estrona at weeks 1, 3, 8 and 12 compared to baseline.
Change from Baseline (mean screening-baseline) to Week 1, Week 3 and Week 8 in Serum Levels of Follicle Stimulating Hormone (FSH) compare to natural physiological variability ( screening-baseline variation)
Change from (mean screening-baseline) in plasma levels of LH to Week 1, Week 3, Week 8 and Week 12 in Serum Levels of LH compare to natural physiological variability ( screening-baseline variation)
Measurement of vaginal pH on the vaginal secretion using a reactive strip and compare pH value between baseline and the diferent timepoints
Changes in dyspareunia from baseline to week 3 and week 12 Each symptom will be scored in a numeric scale from 0 to 3, as shown 0 Absence. The symptom is not present The symptom is of mild intensity, without interfering in the patient's activity The symptom is of moderate intensity, causing obvious discomfort to the patient The symptom is stated as very irritating and severe in intensity
Change in pruritus or itching from baseline to week 3 and week 12 Each symptom will be scored in a numeric scale from 0 to 3, as shown below: 0 Absence. The symptom is not present The symptom is of mild intensity, without interfering in the patient's activity The symptom is of moderate intensity, causing obvious discomfort to the patient The symptom is stated as very irritating and severe in intensity
Change in vaginal dryness puntuation score from baseline to w3 and w12 Each symptom will be scored in a numeric scale from 0 to 3, as shown below: 0 Absence. The symptom is not present The symptom is of mild intensity, without interfering in the patient's activity The symptom is of moderate intensity, causing obvious discomfort to the patient The symptom is stated as very irritating and severe in intensity
Changes in Symptoms of vaginal atrophy (vaginal dryness, dyspareunia and pruritus) at week 3 and week 12 vs baseline. Each symptom will be scored in a numeric scale from 0 to 3, as shown below: 0 Absence. The symptom is not present The symptom is of mild intensity, without interfering in the patient's activity The symptom is of moderate intensity, causing obvious discomfort to the patient The symptom is stated as very irritating and severe in intensity A Global Symptoms Score will be calculated by summing the intensities of all the three symptoms of vaginal atrophy in a certain time point, thus ranging between 0 and 9.
It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. The sign is present and is considered a mild alteration The sign is present and is considered a moderate alteration The sign is present and is considered a severe alteration
It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. The sign is present and is considered a mild alteration The sign is present and is considered a moderate alteration The sign is present and is considered a severe alteration
It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. The sign is present and is considered a mild alteration The sign is present and is considered a moderate alteration The sign is present and is considered a severe alteration
The signs evaluated Will be the following: vaginal mucosa with flattening of folds or thinning, dryness of the mucosa and Fragility of the mucosa. It will be scored by the investigator on a numerical scale in accordance with their presence and degree of severity as follows: 0 Absence. The sign is not present. The sign is present and is considered a mild alteration The sign is present and is considered a moderate alteration The sign is present and is considered a severe alteration A Total Signs Score will be calculated by summing the intensities of all the three signs of vaginal atrophy in a certain time point, thus ranging between 0 and 9.
Change in plasma levels of estriol at weeks 1, 3, 8 and 12 compared to baseline
Vaginal cytology sample to evaluate the vaginal Maturation Value. For the cytologic evaluation, the number of parabasal, intermediate and superficial cells will be calculated in duplicate on 100 consecutive cells of vaginal cytology. The average of the two percentages obtained for each cell type will be calculated, which will serve to determine the maturation value (MV) based on the following formula: 0.2 x (% parabasal) + 0.6 x (% intermediate) + 1.0 x (% superficial).