A Phase 2 interventional study of all-trans retinoic acid and Anastrozole 1mg in Breast Neoplasm Female, sponsored by Mario Negri Institute for Pharmacological Research. Terminated at 2 sites in Italy. Open to female participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2025-12-18.
Sponsored by Mario Negri Institute for Pharmacological Research · Phase 2, Interventional, and Treatment
This is an Italian, single center, randomized, phase II study. ATRA (all-trans retinoic acid) and derivatives (retinoids) are promising anticancer agents and exert their anti-proliferative, differentiating and apoptotic effects through the nuclear retinoic acid receptors, including RARα (retinoic acid receptor alpha). Although the clinical use of ATRA in haematological malignancies (Acute Promyelocytic Leukemia, APL) is well established, its use in solid tumors is limited. However, some recent pre-clinical evidence suggests a possible role of ATRA in the treatment of specific subtypes of HR-positive (Hormonal Receptor)/HER2-negative early breast cancer (eBC).
Moving from pre-clinical evidence and given the well-known retinoid mechanism of action, The hypotheses is that ATRA contributes to tumor regression in a specific sub-population of eBCs. Using a preoperative "window-of-opportunity" model, aimed at testing the activity of ATRA in combination with anastrozole in postmenopausal women with newly diagnosed, resectable, HR+/HER2- eBCs.
This is an Italian, single center, randomized, phase II study. ATRA (all-trans retinoic acid) and derivatives (retinoids) are promising anticancer agents and exert their anti-proliferative, differentiating and apoptotic effects through the nuclear retinoic acid receptors, including RARα (retinoic acid receptor alpha). Although the clinical use of ATRA in haematological malignancies (Acute Promyelocytic Leukemia, APL) is well established, its use in solid tumors is limited. However, some recent pre-clinical evidence suggests a possible role of ATRA in the treatment of specific subtypes of HR-positive (Hormonal Receptor)/HER2-negative early breast cancer (eBC).
This is a prospective, randomized Phase 2 window-of opportunity pre-operative clinical trial to study the activity of ATRA in combination with anastrozole in HR+/HER2- eBCs. All patients will receive primary treatment with anastrozole p.o. (intended as standard of care) and will be randomized to add or not ATRA p.o. Patients will receive study treatments by continuous once-daily administration for a period of 4 weeks before definitive surgery. Treatment will start 28 days before the scheduled surgical resection and will be completed at the time of surgery, scheduled no more than 1 week after completion of the study treatment. The interval between diagnostic core biopsy, baseline clinical evaluation and study entry must be no more than 4 weeks.
The study will compare the anti-tumor activity of the treatments in the two arms (ATRA+anastrozole or Aa vs. anastrozole alone or a). In this comparison, the primary outcome measure is the proportion of complete BC cells cycle arrest (defined as Ki67 \< 2.7%), as previously reported. Indeed, the responder patients will be defined according the achievement of an absolute value of Ki67 \< 2.7% because of its predictive value on relapse-free survival. The study aims at demonstrating that the ATRA+anastrozole (Aa) arm is characterized by significant therapeutic superiority over the anastrozole (a) arm.
Clinical and ultrasound examinations, trascriptome analysis on formalin-fixed paraffin-embedded (FFPE) samples will be performed, at baseline and at the time of definitive surgery
Mario Negri Institute for Pharmacological Research is the lead sponsor of 159 studies on the registry; 36 are open to participants now.
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HR-positive/HER2-negative eBC defined as
Adequate bone marrow, hepatic and renal function including the following:
Exclusion Criteria:
Anastrozole at the dosage of 1 mg/die. Treatment will last 28 days
Drug: Anastrozole 1mg
Anastrozole at the dosage of 1mg/die in combination with ATRA at the total dosage of 45mg/m2/die (two daily administrations of 22.5 mg/m2 each). Treatment will last 28 days
Drug: all-trans retinoic acid · Drug: Anastrozole 1mg
Vesanoid will be supplied orally at the total dosage of 45mg/m2/d (two daily administrations of 22.5 mg/m2 each). Treatment will last 28 days
Also known as: Vesanoid
Anastrozole will be administered orally at the dosage of 1 mg/die.
Responders
Evaluate the proportion of responder patients in the 2 arm (Aa vs. a) according to the Ki67 assessment, measured at baseline and after treatment
Time frame: At time of surgery. Analyses will be performed approximately 24 months after the enrolment of the first patient, i.e. when all the 112 patients required by simple size specifications complete their treatment schedule and reach the surgical phase.
Ki67 reduction
To assess the activity of ATRA according to the % of Ki67 reduction, measured before and after treatment
Time frame: At time of surgery. Analyses will be performed approximately 24 months after the enrolment of the first patient, i.e. when all the 112 patients required by simple size specifications complete their treatment schedule and reach the surgical phase.
ORR (Overall Response Rate)
To assess the activity of ATRA in terms of tumor size reduction and response rate, according to the RECIST criteria, after 4 weeks of therapy.
Time frame: At time of surgery. Analyses will be performed approximately 24 months after the enrolment of the first patient, i.e. when all the 112 patients required by simple size specifications complete their treatment schedule and reach the surgical phase.
ATRA-21
To validate the predictive power of ATRA-21, a gene-expression model associated with ATRA activity.
Time frame: At time of surgery. Analyses will be performed approximately 24 months after the enrolment of the first patient, i.e. when all the 112 patients required by simple size specifications complete their treatment schedule and reach the surgical phase.
Safety evaluation
Patients will be monitored for adverse events (AEs) weekly using the definitions and criteria for grading provided in the Common Terminology Criteria for adverse Events (CTCAE) 4.03.
Time frame: Safety assessments will occur at day 1 (D1) and after 2 weeks (D14) and after 4 weeks (D28) during treatment.
Plan to share: No
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This study is terminated, as verified in Mar 2025. You cannot join it, but the record below documents what was studied.
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Mario Negri Institute for Pharmacological Research