Metastatic Breast CancerTIRESIASNCT04660435
To Identify Primary Resistance to CDK4/6 Inhibitors in Breast Cancer
An observational study of Metastatic Breast Cancer and ER Positive Breast Cancer, run by Fondazione Sandro Pitigliani at 1 site in Italy.
Trial summary
This is a multi-center biomarkers study aiming to prospectively collect biological samples from patients with ER+ and HER2-negative metastatic breast cancer, who are candidate to first-line treatment with an aromatase inhibitor and a CDK4/6 inhibitor as per standard clinical practice. Read more about this study
- Who is it for?
- Any age, women only
- Conditions the study is for
- Metastatic Breast Cancer, ER Positive Breast Cancer, HER2-negative Breast Cancer
- What is being tested?
- Thymidine kinase activity
- How many people
- 150 participants
- Where
- 1 siteItaly
- Study dates
- 1 Dec 2020to 1 Dec 2030
- How long will I take part?
- 5 Years
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
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 Any age
- Women only
- No healthy volunteers
- Child, Adult, Older adult
Study population: Pre- and post-menopausal patients with luminal (ER-positive and HER2-negative) MBC who have not received prior systemic therapy for MBC, who are candidate to first-line treatment with an aromatase inhibitor and a CDK4/6i as per standard clinical practice. Patients must have evaluable disease according to RECIST 1.1 (either measurable or non-measurable). Patients with bone-only disease will be allowed in a specific sub-cohort, which will comprise 10% of the total sample size.
Who may be able to join
- Women aged 18 years or older, with a diagnosis of metastatic breast cancer
- ER-positive and HER2-negative disease as assessed locally either on primary tumor tissue or on a biopsy of a metastasis
- The patient has not received any prior systemic therapy for metastatic breast cancer (may have received prior hormonal therapy or chemotherapy in the neo/adjuvant setting)
- The patient is candidate to receive first-line therapy with an aromatase inhibitor (AI) and a CDK4/6 inhibitor per local clinical practice
- The patient must have evaluable disease according to RECIST 1.1 (either measurable or non-measurable).
- Note: Patients with bone-only disease will be allowed in a specific sub-cohort, which will comprise 10% of the total sample size.
- Hystologic material from one formalin-fixed, paraffin-embedded (FFPE) tumor block from a diagnostic core or excisional biopsy of a metastatic lesion, taken before study entry must be provided (patients with bone-only disease will be accepted into the trial without a biopsy of the metastatic site). Hystologic material from an additional biopsy (core or excisional) taken at time of disease progression on the study treatment must also be provided, if clinically feasible. When available, hystologic material from an FFPE tumor block from the primary breast cancer must also be submitted.
- The patient agrees to provide blood samples. at the trial specified time points
Who cannot join
- Patients with metastatic disease isolated to the central nervous system (CNS) without metastatic involvement of any other site, unless surgical excision of CNS metastasis has been performed and the tumor tissue is available for the study.
- Previous or current non-breast malignancies within the last 5 years, with the exception of in situ carcinoma of the cervix and/or adequately treated basal cell or squamous cell carcinoma of the skin
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Italy1 site, 1 recruiting
- Recruiting
Hospital Santo Stefano
Prato, Tuscany, 59100
Luca Malorni, +390574802523, luca.malorni@uslcentro.toscana.it
About this study
Official title: Identification and Monitoring of Resistance to First-line Treatment With CDK 4/6 Inhibitors in Combination With Aromatase Inhibitors in Patients With Metastatic Luminal Breast Cancer Through Non-invasive Biomarkers
This is a multi-center biomarkers study aiming to prospectively collect biological samples from patients with ER+ and HER2-negative metastatic breast cancer, who are candidate to first-line treatment with an aromatase inhibitor and a CDK4/6 inhibitor as per standard clinical practice.
Blood and tissue samples will be collected for biomarker analysis, including thymidine kinase1 activity, gene expression signatures and circulating tumor DNA.
Read the detailed description
Enrolled patients will receive first-line treatment with a CDK4/6 inhibitor + AI (anastrozole, letrozole or exemestane) in accordance with local practice. No drugs will be provided by the study Sponsor. Following disease progression on first-line therapy, subsequent, second-line therapy will be administered at physician discretion and as per physician choice.
For all participating patients, serum and plasma samples will be collected at the following time-points:
- Baseline (< 2 weeks before treatment)
- During treatment with CDK4/6 inhibitors + AI: at day 15 (+/- 2) of the first cycle, day 1 (+/-2) of cycle 2, day 1 (+/- 2) of the cycle closest to the first trial-mandated tumor evaluation (after 12-18 weeks from study inclusion), day 1 (+/- 2) of cycle 6, and every 6 cycles thereafter
- At disease progression or permanent discontinuation of CDK4/6 inhibitors + AI (within 35 days from last CDK4/6 inhibitor dosing)
- During the immediate subsequent treatment (second line) (any type, as per physician choice): at day 1 (+/- 2) of cycle 1 (if > 7 days from last CDK4/6 inhibitors dosing), at day 1 of cycles 3, 6 and every 6 cycles thereafter
- At disease progression or permanent discontinuation of second line treatment (within 35 days from last dosing)
One sample of whole blood will be collected at baseline.
All blood samples will be taken concomitantly with blood draws for routine clinical practice.
To be eligible for the study, availability of material from one formalin fixed and paraffin embedded (FFPE) tumor block from a baseline biopsy of a metastatic site taken before starting treatment is mandatory. Although not mandatory for inclusion, material from an archival FFPE tumor block from the primary breast tumor must also be provided, whenever available. Additionally, material from one FFPE tumor block of a tissue biopsy from a metastatic site collected upon disease progression to first-line treatment with CDK4/6 in and AI will be collected whenever possible
- Being tested
- Thymidine kinase activity
- Keywords
- CDK 4/6 inhibitors, Thymidine Kinase, Palbociclib, Abemaciclib, Ribociclib, circulating tumour DNA, gene expression signatures, aromatase inhibitors
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Thymidine kinase activityDiagnostic test
Also called Divitum
DiviTum® assay determines the enzymatic activity of TK in serum samples
| Study group | Role | What they receive |
|---|---|---|
| Women with ER+/Her2 negative metastatic breast cancer | Patients with ER+/HER2-negative metastatic breast cancer candidate to first-line treatment with a CDK4/6 inhibitor and an aromatase inhibitor as per standard clinical practice Receives: Diagnostic Test: Thymidine kinase activity |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression free survival
time from inclusion date to date of first documentation of progression or death due to any cause, whichever occurs first
Measured: 5 years
Secondary outcomes (1)
Clinical benefit rate
Complete Response, Partial Response, or Stable Disease ≥24 weeks
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Dec 2020
- Study start1 Dec 2020
- Primary completion1 Dec 2029 (estimated)
- Study completion1 Dec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Metastatic Breast CancerStudies of the same condition, open and under way.
- 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 150 participants (estimated)
- Target duration
- 5 Years
Sponsor and investigators
- Lead sponsor
- Fondazione Sandro Pitigliani
- Sponsor type
- University, hospital or other
- Collaborators
- Clinical Research Technology S.r.l.
- Responsible party
- Sponsor
- Investigators
- Luca Malorni, Principal investigator, Azienda USL Toscana Centro - Prato
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04660435
- Sponsor's protocol ID
- Tiresias
- Acronym
- TIRESIAS
- Status last verified
- Sep 2026
- First submitted
- 3 Dec 2020
- Last updated
- 14 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Malorni L, Tyekucheva S, Hilbers FS, Ignatiadis M, Neven P, Colleoni M, Henry S, Ballestrero A, Bonetti A, Jerusalem G, Papadimitriou K, Bernardo A, Seles E, Duhoux FP, MacPherson IR, Thomson A, Davies DM, Bergqvist M, Migliaccio I, Gebhart G, Zoppoli G, Bliss JM, Benelli M, McCartney A, Kammler R, De Swert H, Ruepp B, Fumagalli D, Maibach R, Cameron D, Loi S, Piccart M, Regan MM; International Breast Cancer Study Group; Breast International Group and PYTHIA Collaborators. Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant. Eur J Cancer. 2022 Mar;164:39-51. doi: 10.1016/j.ejca.2021.12.030. Epub 2022 Feb 13.
PubMed 35172272
Study at a glance
From the registry record, last updated by the sponsor on 14 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Identification and Monitoring of Resistance to First-line Treatment With CDK 4/6 Inhibitors in Combination With Aromatase Inhibitors in Patients With Metastatic Luminal Breast Cancer Through Non-invasive Biomarkers
- ClinicalTrials.gov ID
- NCT04660435
- Acronym / sponsor ID
- TIRESIAS / Tiresias
- Keywords
- CDK 4/6 inhibitors, Thymidine Kinase, Palbociclib, Abemaciclib, Ribociclib, circulating tumour DNA, gene expression signatures, aromatase inhibitors
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 150 participants (estimated)
- Lead sponsor
- Fondazione Sandro PitiglianiUniversity, hospital or other
- Collaborators
- Clinical Research Technology S.r.l.
- Study start
- 1 Dec 2020 (actual)
- Primary completion
- 1 Dec 2029 (estimated)
- Study completion
- 1 Dec 2030 (estimated)
- First posted
- 9 Dec 2020 (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 a multi-center biomarkers study aiming to prospectively collect biological samples from patients with ER+ and HER2-negative metastatic breast cancer, who are candidate to first-line treatment with an aromatase inhibitor and a CDK4/6 inhibitor as per standard clinical practice.
Blood and tissue samples will be collected for biomarker analysis, including thymidine kinase1 activity, gene expression signatures and circulating tumor DNA.
Detailed description
Enrolled patients will receive first-line treatment with a CDK4/6 inhibitor + AI (anastrozole, letrozole or exemestane) in accordance with local practice. No drugs will be provided by the study Sponsor. Following disease progression on first-line therapy, subsequent, second-line therapy will be administered at physician discretion and as per physician choice.
For all participating patients, serum and plasma samples will be collected at the following time-points:
- Baseline (< 2 weeks before treatment)
- During treatment with CDK4/6 inhibitors + AI: at day 15 (+/- 2) of the first cycle, day 1 (+/-2) of cycle 2, day 1 (+/- 2) of the cycle closest to the first trial-mandated tumor evaluation (after 12-18 weeks from study inclusion), day 1 (+/- 2) of cycle 6, and every 6 cycles thereafter
- At disease progression or permanent discontinuation of CDK4/6 inhibitors + AI (within 35 days from last CDK4/6 inhibitor dosing)
- During the immediate subsequent treatment (second line) (any type, as per physician choice): at day 1 (+/- 2) of cycle 1 (if > 7 days from last CDK4/6 inhibitors dosing), at day 1 of cycles 3, 6 and every 6 cycles thereafter
- At disease progression or permanent discontinuation of second line treatment (within 35 days from last dosing)
One sample of whole blood will be collected at baseline.
All blood samples will be taken concomitantly with blood draws for routine clinical practice.
To be eligible for the study, availability of material from one formalin fixed and paraffin embedded (FFPE) tumor block from a baseline biopsy of a metastatic site taken before starting treatment is mandatory. Although not mandatory for inclusion, material from an archival FFPE tumor block from the primary breast tumor must also be provided, whenever available. Additionally, material from one FFPE tumor block of a tissue biopsy from a metastatic site collected upon disease progression to first-line treatment with CDK4/6 in and AI will be collected whenever possible
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 5 Years
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Women with ER+/Her2 negative metastatic breast cancer | – | Diagnostic Test: Thymidine kinase activityPatients with ER+/HER2-negative metastatic breast cancer candidate to first-line treatment with a CDK4/6 inhibitor and an aromatase inhibitor as per standard clinical practice |
Who may qualify
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Pre- and post-menopausal patients with luminal (ER-positive and HER2-negative) MBC who have not received prior systemic therapy for MBC, who are candidate to first-line treatment with an aromatase inhibitor and a CDK4/6i as per standard clinical practice. Patients must have evaluable disease according to RECIST 1.1 (either measurable or non-measurable). Patients with bone-only disease will be allowed in a specific sub-cohort, which will comprise 10% of the total sample size.
Key inclusion criteria (8 listed)
- Women aged 18 years or older, with a diagnosis of metastatic breast cancer
- ER-positive and HER2-negative disease as assessed locally either on primary tumor tissue or on a biopsy of a metastasis
- The patient has not received any prior systemic therapy for metastatic breast cancer (may have received prior hormonal therapy or chemotherapy in the neo/adjuvant setting)
- The patient is candidate to receive first-line therapy with an aromatase inhibitor (AI) and a CDK4/6 inhibitor per local clinical practice
- The patient must have evaluable disease according to RECIST 1.1 (either measurable or non-measurable).
Key exclusion criteria (2 listed)
- Patients with metastatic disease isolated to the central nervous system (CNS) without metastatic involvement of any other site, unless surgical excision of CNS metastasis has been performed and the tumor tissue is available for the study.
- Previous or current non-breast malignancies within the last 5 years, with the exception of in situ carcinoma of the cervix and/or adequately treated basal cell or squamous cell carcinoma of the skin
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 |
|---|---|---|
| Thymidine kinase activityAlso: DivitumDiviTum® assay determines the enzymatic activity of TK in serum samples | Diagnostic test | Women with ER+/Her2 negative metastatic breast cancer |
Primary outcome
Progression free survival
Time frame: 5 years
time from inclusion date to date of first documentation of progression or death due to any cause, whichever occurs first
1 secondary outcome
Clinical benefit rate
Time frame: 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Sep 2026.
- Background: PubMed 35172272Malorni L, Tyekucheva S, Hilbers FS, Ignatiadis M, Neven P, Colleoni M, Henry S, Ballestrero A, Bonetti A, Jerusalem G, Papadimitriou K, Bernardo A, Seles E, Duhoux FP, MacPherson IR, Thomson A, Davies DM, Bergqvist M, Migliaccio I, Gebhart G, Zoppoli G, Bliss JM, Benelli M, McCartney A, Kammler R, De Swert H, Ruepp B, Fumagalli D, Maibach R, Cameron D, Loi S, Piccart M, Regan MM; International Breast Cancer Study Group; Breast International Group and PYTHIA Collaborators. Serum thymidine kinase activity in patients with hormone receptor-positive and HER2-negative metastatic breast cancer treated with palbociclib and fulvestrant. Eur J Cancer. 2022 Mar;164:39-51. doi: 10.1016/j.ejca.2021.12.030. Epub 2022 Feb 13.
- Individual participant dataSharing planned: Undecided
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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.
Luca Malorni principal investigator
Azienda USL Toscana Centro - Prato
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Metastatic Breast Cancer and ER Positive Breast Cancer, run by Fondazione Sandro Pitigliani at 1 site 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 8 inclusion and 2 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: looking for participants now, as of the sponsor's last update on 14 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Luca Malorni (+390574802523, luca.malorni@uslcentro.toscana.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression free survival (time frame: 5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04660435, which also lists 1 linked publication.
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 14 Sep 2026; AzTrials last refreshed its copy on 26 Oct 2026.