Breast Neoplasm FemalePhase 2ATRANCT04113863
Evaluation of ATRA Activity in Combination With Anastrozole in Pre-operative Phase of Operable Early Breast Cancer
A Phase 2 study testing all-trans retinoic acid and Anastrozole 1mg in people with Breast Neoplasm Female, run by Mario Negri Institute for Pharmacological Research at 2 sites in Italy.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 to 75 years, women only
- Conditions the study is for
- Breast Neoplasm Female
- What is being tested?
- all-trans retinoic acid and Anastrozole 1mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 76 participants
- Where
- 2 sitesItaly
- Study dates
- 18 Jun 2019to 30 Jan 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Signed, informed consent
- Histologically confirmed non-metastatic operable primary invasive HR-positive breast cancer subjected to diagnostic core biopsy
- Menopausal status
- HR-positive/HER2-negative eBC defined as
- ER>1% on immunohistochemistry (IHC) staining
- HER2 score equal to 0, 1+, 2+ (if FISH neg) on IHC staining
Show all 14Show fewer
- Available paraffin-embedded tumor block (FFPE) taken at diagnostic biopsy for Ki67 determination (IHC)
- Adequate bone marrow, hepatic and renal function including the following:
- Hb ≥ 9.0 g/dL, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥100 x 109/L
- Total bilirubin ≤ 1.5 x upper normal limit, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome
- AST (SGOT), ALT (SGPT) ≤ 2.5 x upper normal limit (or 5x UNL in the presence of liver metastases)
- Creatinine ≤ 1.5 x upper normal limit
- Age ≥ 18 years
- Performance status (PS) ≤ 1 (ECOG scale)
Who cannot join
- Presence of metastatic disease
- Pre-menopausal status
- Previous investigational treatment for any condition within 4 weeks of randomization date
- Treatment including radiation therapy, chemotherapy, biotherapy and/or hormonal therapy for the currently diagnosed breast cancer prior to study entry
- Co-existing active infection or serious concurrent illness
- Any medical or other condition that in the Investigator's opinion renders the patient unsuitable for this study due to unacceptable risk
- Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies
- Gastrointestinal disorders that may interfere with absorption of the study drug.
Trial locations and contacts
2 sites in 1 country.
Italy2 sites
ASST Papa Giovanni XXIII
Bergamo, 24127
Ospedale Santa Maria della Misericordia di Udine
Udine, UD, 33100
About this study
Official title: A Randomized Phase 2 Clinical Trial to Evaluate the Activity of ATRA in Combination With Anastrozole in Pre-operative Phase of Operable HR-positive/HER2-negative Early Breast Cancer (ATRA)
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.
Read the detailed description
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
- Conditions
- Breast Neoplasm Female
- Being tested
- all-trans retinoic acid, Anastrozole 1mg
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
all-trans retinoic acidDrug
Also called Vesanoid
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
Anastrozole 1mgDrug
Anastrozole will be administered orally at the dosage of 1 mg/die.
| Study group | Role | What they receive |
|---|---|---|
| ARM A - Anastrozole | Active comparator | Anastrozole at the dosage of 1 mg/die. Treatment will last 28 days Receives: Drug: Anastrozole 1mg |
| ARM B - Anastrozole + ATRA | Experimental | 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 Receives: Drug: all-trans retinoic acid; Drug: Anastrozole 1mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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.
Secondary outcomes (4)
Ki67 reduction
To assess the activity of ATRA according to the % of Ki67 reduction, measured before and after treatment
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Safety assessments will occur at day 1 (D1) and after 2 weeks (D14) and after 4 weeks (D28) during treatment.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Oct 2019
- Study start18 Jun 2019
- Primary completion30 Jan 2025
- Study completion30 Jan 2025
Why it stopped: Low enrolment rate
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Breast Neoplasm FemaleStudies of the same condition, open and under way.
- More trials run by Mario Negri Institute for Pharmacological ResearchThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 76 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04113863
- Sponsor's protocol ID
- RF-2016-02362383
- Acronym
- ATRA
- Status last verified
- Mar 2025
- First submitted
- 26 Jun 2019
- Last updated
- 18 Dec 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Phase 2 Clinical Trial to Evaluate the Activity of ATRA in Combination With Anastrozole in Pre-operative Phase of Operable HR-positive/HER2-negative Early Breast Cancer (ATRA)
- ClinicalTrials.gov ID
- NCT04113863
- Acronym / sponsor ID
- ATRA / RF-2016-02362383
- Conditions
- Breast Neoplasm Female
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Low enrolment rate
- Enrolment
- 76 participants (actual)
- Lead sponsor
- Mario Negri Institute for Pharmacological ResearchUniversity, hospital or other
- Study start
- 18 Jun 2019 (actual)
- Primary completion
- 30 Jan 2025 (actual)
- Study completion
- 30 Jan 2025 (actual)
- First posted
- 3 Oct 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| ARM A - Anastrozole | Active comparator | Drug: Anastrozole 1mgAnastrozole at the dosage of 1 mg/die. Treatment will last 28 days |
| ARM B - Anastrozole + ATRA | Experimental | Drug: all-trans retinoic acid, Drug: Anastrozole 1mgAnastrozole 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 |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- Signed, informed consent
- Histologically confirmed non-metastatic operable primary invasive HR-positive breast cancer subjected to diagnostic core biopsy
- Menopausal status
- HR-positive/HER2-negative eBC defined as
- Available paraffin-embedded tumor block (FFPE) taken at diagnostic biopsy for Ki67 determination (IHC)
Key exclusion criteria (8 listed)
- Presence of metastatic disease
- Pre-menopausal status
- Previous investigational treatment for any condition within 4 weeks of randomization date
- Treatment including radiation therapy, chemotherapy, biotherapy and/or hormonal therapy for the currently diagnosed breast cancer prior to study entry
- Co-existing active infection or serious concurrent illness
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| all-trans retinoic acidAlso: VesanoidVesanoid 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 | Drug | ARM B - Anastrozole + ATRA |
| Anastrozole 1mgAnastrozole will be administered orally at the dosage of 1 mg/die. | Drug | ARM A - Anastrozole, ARM B - Anastrozole + ATRA |
Primary outcome
Responders
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.
Evaluate the proportion of responder patients in the 2 arm (Aa vs. a) according to the Ki67 assessment, measured at baseline and after treatment
4 secondary outcomes
Ki67 reduction
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)
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
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
Time frame: Safety assessments will occur at day 1 (D1) and after 2 weeks (D14) and after 4 weeks (D28) during treatment.
Results and safety
The study was stopped early (reason given: Low enrolment rate). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Dec 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing all-trans retinoic acid and Anastrozole 1mg in people with Breast Neoplasm Female, run by Mario Negri Institute for Pharmacological Research at 2 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 18 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Low enrolment rate). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Responders (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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Dec 2025.