Male or pre/post-menopausal women age = 18 years with advanced HR+/HER2-negative locally advanced/metastatic breast cancer resistant to endocrine therapy.
Conditions
Interventions
Trade Name: Xtandi
Product Name: Enzalutamida
Pharmaceutical Form: Capsule, soft
INN or Proposed INN: ENZALUTAMIDE
CAS Number: 915087-33-1
Concentration unit: mg milligram(s)
Concentration type: equal
Sponsors
SOLTI
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: * Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures. * Subjects with progression on or following at least 1 prior standard of care systemic anti-cancer therapy. * Female and male patients. * Performance status of 0-2. * Age =18 years. * Pre/peri-menopausal and post-menopausal women. Post-menopausal status is defined either by: -Prior bilateral oophorectomy or -Age =60 or -Age 1% of cells expressing HR via IHC analysis as per ASCO-CAP guideline (74) * Patients must have a site of disease amenable to safely perform a biopsy, as per Investigator’s assessment, and be a candidate for tumor biopsy according to the treating institution’s guidelines. * Possibility of performing a biopsy prior to the start of treatment and its repetition after 2 weeks (14-21 days) on the same location. It will be provided formalin-fixed paraffin-embedded (FFPE) tumor block. The tumor tissue should be of good quality based on total and viable tumor content and must be evaluated centrally for PAM50 analysis prior to enrollment. Patients whose tumor tissue is not evaluable for central testing are not eligible. It is recommended to send the biopsy directly to the central lab after confirming the existence of a tumor, so as not to delay the inclusion, without the need to carry out IHC studies in the same. -Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions or biopsies from bone metastases. -Fine needle aspiration, brushing, cell pellet from pleural effusion and lavage samples are not acceptable. * Patient must be willing to provide biopsy prior to the start of treatment and its repetition after 2 weeks (14-21 days) on the same location. * The following subtypes identified in the pre-treatment tumor biopsy, as assessed by PAM50 assay at the Central Laboratory: -HER2-E (Cohort A) -Luminal A and Luminal B (Cohort B). * No more than 4 prior lines of chemotherapy regimens for recurrent, locally advanced or metastatic breast cancer. * Endocrine resistant disease, defined as the presence of disease recurrence while receiving adjuvant endocrine therapy for early stage breast cancer or disease progression of locally advanced/metastatic BC under ongoing endocrine therapy. There is no limit of previous received hormonal agents. * Measurable and non-measurable (but evaluable) dise
Exclusion criteria
Exclusion criteria: * History of current or previously treated CNS metastases or leptomeningeal disease. Testing for CNS metastasis is not mandatory. * History of seizure or any condition that may predispose to seizure. * Clinically significant cardiovascular disease within 6 months prior to enrolment defined as: -Myocardial infarction. -Inadequately controlled angina or serious cardiac arrhythmia not controlled by adequate medication. -Congestive heart failure (CHF) New York Health Association (NYHA) Class = II. -History of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, torsade de pointes). - History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place. -Hypotension as indicated by systolic blood pressure 170 mmHg or diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the screening visit. * Inability to swallow tablets, extensive reduction surgery of the stomach or small bowel or any active gastrointestinal disorder which may impair the absorption of the trial treatment (e.g. active peptic ulcer disease; uncontrolled celiac disease). *Major surgical procedure within 4 weeks prior to allocation or anticipation of the need for major surgery during the course of study treatment. *Use of medications that could reduce seizure threshold or concomitant treatment with potent CYP3A4 inducers. *Treatment with warfarin and coumarin-like anticoagulants. Prophylactic use of low molecular weight heparin (LMWH) is allowed. *Fructose intolerance. * Treatment with any anticancer commercially available or investigational drug within 14 days prior to commencing trial treatment. *Hypersensitivity reaction to the active pharmaceutical ingredient or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene. *Current severe disease, infection, or systemic condition that renders the patient inappropriate for enrollment in the opinion of the investigator. *Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. *Has a known history of Human Immunodeficiency Virus (HIV). *Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. *Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. *Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of enzalutamide.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the anti-proliferative effect of enzalutamide after 2 weeks (14-21 days) of treatment in endocrine-resistant, locally advanced or metastatic HR+/HER2-negative breast cancer with a PAM50 HER2-E subtype (Cohort A).;Secondary Objective: -To evaluate the anti-proliferative effect of enzalutamide after 2 weeks of treatment in Cohort B. -To compare the anti-proliferative effect between Cohort A and B. -To assess the safety of enzalutamide. -To identify global gene expression and PAM50 subtypes changes before and after treatment -To derive a new gene expression-based signature of response to enzalutamide. -To identify differences in the distribution of somatic mutations between cohorts. -To measure AR and Ki-67 expression by immunohistochemistry in tumor cells in baseline and treated samples. -To identify changes of Intratumoral and Stromal lymphocytes in biopsy samples before and after treatment and changes in ctDNA levels during treatment in each cohort. -To assess the tumor overall objective response rate using modified RECIST v.1.1. -To evaluate the disease control rate. -To determine the duration of response, time to tumor progression and PFS.;Primary end point(s): Relative changes of the PAM50 11-gene proliferation signature after 2 weeks (14-21 days) of treatment with enzalutamide. These changes will be analyzed according to the formula: Mean suppression = 100 - [geometric mean (post-treatment / pretreatment · 100)].;Timepoint(s) of evaluation of this end point: 2 weeks (14-21 days) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Relative changes of the PAM50 11-gene proliferation signature after 2 weeks (14-21 days) of treatment with enzalutamide. These changes will be analyzed according to the formula: Mean suppression = 100 - [geometric mean (post-treatment / pretreatment · 100)]. Mean suppression in both cohorts will be compared. - Mean suppression in both cohorts will be compared. -Incidence, duration and severity of Adverse Events (AEs) assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 5, including dose reductions, delays and treatment discontinuations. -Relative changes of 33 gene signatures and 770 genes after 2 weeks (14-21 days) of treatment with enzalutamide and from week 3 to progression (in those patients who consent for optional biopsy). This study will be performed using the nCounter Breast 360TM panel. -Change in PAM50 tumor subtype “call” between before and after 2 weeks (14-21 days) of the treatment. And from week 3 to progression (in those patients who consent for optional biopsy). -Identification of genes or signatures at baseline whose expression is associated with an anti-proliferative effect (PAM50 11-gene proliferation signature) following enzalutamide. -Proportion of somatic mutations in samples from both cohorts using a targeted gene sequencing panel. -Analysis of AR expression by IHC (% nuclear expression in tumoral cell) before and after 21 days of treatment in Cohorts A and B. -Relative changes in percentage of cells expressing Ki67 by IHC after 21 days of enzalutamide in HER2-E and Luminal A/B tumors. -Analysis of lymphocyte infiltrate on hematoxylin and eosin-stained FFPE-sections. Percentage (%) change in It-TILs and Str-TILs infiltration between pre- and after 2 weeks (14-21 days) of treatment with enzalutamide and progression (in those patients who consent for optional biopsy). -Quantification of baseline ctDNA levels and 2 weeks (14-21 days) post-treatment. Determination of | — |
Countries
Spain
Contacts
Public ContactAREA INVESTIGACON CLINICA
SOLTI
Outcome results
None listed