A Study to Evaluate Changes in Human Breast Cancer Tissue Following Short-Term Use of Darolutamide

Overview

The purpose of this study is to evaluate the effect of short-term treatment with darolutamide on breast cancer cells (i.e., how the treatment may change the genes or proteins in breast cancer cells) and to evaluate its safety and the way it is tolerated by subjects. The intent is to study these changes in order to have a better understanding of the potential use of darolutamide for women with EBC, know which patients are likely or unlikely to respond to this treatment, and determine how darolutamide may be combined with other anti-cancer drugs.

This current study will enroll EBC subjects with differing breast cancer (BC) subtypes, with the intent of characterizing the molecular alterations in BC tissue before and after short-term exposure to the anti-androgen darolutamide. Studying the biological mechanisms in which darolutamide targets the androgen receptor (AR) in BC will be crucial in understanding its' potential role, as well as provide the foundation for further development of darolutamide in this disease. TRIO030 will evaluate the following objectives: Primary -To identify the molecular alterations that occur in human BC tissue, following short-term exposure to darolutamide in female subjects with EBC; Secondary - To evaluate the safety and tolerability of short-term exposure to darolutamide in female subjects with EBC. Design: This will be a multi-center, open-label, tissue-acquisition study involving up to 60 subjects from approximately 20 sites in North America and Europe, and will enroll EBC subjects of differing subtypes (i.e., triple negative \[TNBC\], ER+/HER2-, and HER2+), with the intent of characterizing the molecular alterations in BC tissue before and after short-term exposure to the anti-androgen darolutamide. Such information may suggest that darolutamide be combined with other modalities; for example, if treatment with the drug is discovered to affect multiple signaling pathways. Molecular profiling of tumor samples before and after darolutamide treatment may permit the identification of patients likely or unlikely to respond to the agent based on the biological and molecular characteristics of their tumors. Duration: It is recommended that the surgery date is defined prior to starting protocol treatment and then the start date of darolutamide (Day 1) will be derived as minus 14 to 21 days from the scheduled surgery date. Treatment will be taken until the day prior to surgery or when the subject is ordered to stop all oral intake (i.e., "nil per os" (npo)), which ever occurs first. If for some reason surgery takes place more than 21 days after treatment start, it is acceptable that the subject receives darolutamide for more than 21 days and up to a maximum of 35 days; subject should continue protocol treatment until the day prior to surgery, or npo is ordered. In these cases it is strongly recommended to have surgery performed as soon as possible after 21 days of treatment are completed. After surgery, an End of Study (EoS) visit will occur 30 days (+/- 3 days) after the subject's last intake of darolutamide. In case of ongoing protocol treatment-related AEs/SAEs at the time of the EoS visit, monitoring of these events will continue as clinically indicated until (a) the events have resolved or (b) the events have reached a status which, in the Investigator's opinion, is unlikely to resolve due to the nature of the condition and/or the subject's underlying disease. Total Number of Sites: A total of 14 sites were opened worldwide, with 5 sites located within the U.S, 6 in Canada, and 3 in Germany. Sample Size/Patient Population: Up to 60 subjects will be enrolled in the study. To be able to assess the molecular alterations after darolutamide, exposure in different BC subtypes, subjects being either triple-negative, or ER+/HER2 negative, or HER2 positive, will be enrolled in the study. Up to 20 subjects with each of these subtypes will be included (with an acceptable minimum of 8 evaluable patients in each cohort). Dosage Regimen: Darolutamide will be given at a dose of 600 mg (2 x 300 mg tablets) twice daily (b.i.d) to a daily dose of 1200 mg. The first day of darolutamide administration in the study is considered Day 1. The last darolutamide intake will be on the day prior to breast cancer surgery, when the pre-surgery visit should occur. darolutamide should be taken approximately at the same time each day twice a day. It is recommended that darolutamide be taken with food; recommendation is to take it with breakfast and dinner each day. Supportive measures and dose modifications: A subject who experiences a treatment-related grade 3 or higher adverse event (AE) must be withdrawn from protocol treatment and should proceed to surgery and undergo an EoS visit. In the case of a grade 1-2 treatment-related AE, the Investigator should contact the Medical Monitor if a dose reduction or treatment hold is required. Washout pre-trial: Prior treatment of ovarian hormone replacement therapy should be stopped at least 28 days prior to registration. Use of other investigational drugs should be stopped within 28 days of enrollment. No major surgery within 28 days before enrollment (Major surgery is defined as requiring a general anesthesia or respiratory assistance; involving openings into the great cavities of the body, organs removed, or normal anatomy altered; implying risks of severe hemorrhage; implying risk for life of the patient or severe disability). Concomitant Medication: Subjects will be instructed to consult with the Investigator before taking any medications (including over-the-counter medications). Supportive medications may be provided prophylactically or therapeutically per Investigator discretion. Any concomitant treatment NOT listed below is considered permitted in the study and may be prescribed as clinically appropriate during the study: * Investigational agents other than the protocol treatment. * Any additional standard or investigational anticancer agents, such as chemotherapy, immunotherapy, targeted/biologic therapy, endocrine therapy, etc., even if utilized as treatment of non-cancer indications. darolutamide must be permanently discontinued upon initiation of a non-protocol standard or investigational antineoplastic therapy prior to surgery. Rescue Medication and Risk Management: No specific pre-medication is required. Based on the current available data , there are no special warnings and precautions associated with the use of darolutamide. Premature Withdrawal / Discontinuation Criteria: The patient may withdraw from the study at any time without prejudicing future medical treatment. In any case, the withdrawal should be clearly documented in the subject's clinical records. Should a patient decide to withdraw consent, all efforts will be made to complete and report the observations as thoroughly as possible. A complete final evaluation at the time of the patient's withdrawal should be made with an explanation of why the patient is withdrawing from the study. After complete withdrawal of consent, no further study procedure is performed and no further data will be collected. Discontinuation: The Investigator will also discontinue protocol treatment if any of the following conditions is met: * Intercurrent illness or a change in subject´s condition or unacceptable toxicity that warrants protocol treatment discontinuation according to Investigator's judgment * Any event, condition, criterion which would warrant discontinuation of darolutamide (i.e., severe toxicities), including grade ≥ 3 protocol-treatment related AE * Any event, condition, reason which would warrant darolutamide to be held for more than the maximum acceptable delay of 7 consecutive days * Subject receives non-protocol anti-cancer therapy at any time during the protocol treatment * Subject's decision to withdraw protocol treatment * Lost to follow up * Death * Pregnancy * Investigator's decision * Discontinuation of the study by the sponsor * Patient is enrolled but does not receive protocol treatment for any reason