Overcoming Therapy Resistance in ER+ Breast Cancer Patients: a Translational Project (OVERTuRE)

Breast Cancer Clinical Trial

— OVERTuRE  

Official title:

Overcoming Therapy Resistance in ER+ Breast Cancer Patients: a Translational Project (OVERTuRE)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06129786
• Other study ID #: CRO-2023-10
• Status: Recruiting
• Start date: May 18, 2023
• Est. completion date: May 18, 2026

Study information

• Verified date: November 2023
• Source: Centro di Riferimento Oncologico - Aviano
• Contact: Fabio Puglisi, MD, PhD
• Phone: +39 0434 659253
• Email: fabio.puglisi[@]cro.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Patients presenting with a de novo diagnosis of luminal-like advanced breast cancer (ABC) or with disease recurrence after >12 months from the end of adjuvant ET, are generally candidate to a first line therapy with an aromatase inhibitor in association with a CDK4/6i. Disease recurrence in <12 months from the end of adjuvant ET defines the disease as "endocrine resistant" and identifies patients that should receive a first line therapy with the selective estrogen receptor degrader (SERD) Fulvestrant in association with the CDK4/6i Ribociclib, according to the results of the MONALEESA-3 trial. A significant percentage of ABC patients develops a primary resistance with disease progression within the first 6 months from the beginning of the treatment. Furthermore, another relevant percentage of patients initially responding to the therapy, will later develop a secondary resistance, thus progressing after a median of 2 years from the beginning of the treatment. Thereby, it is crucial to identify biomarkers that could be predictive of a response or a resistance to ET and/or CDK4/6i, to provide the best therapeutic strategy, tailored upon both clinico-pathological and molecular characteristics. Numerous pathways associated with resistance to CDK4/6i have been investigated by means of liquid biopsy analysis. The aim of this study is to identify potential biomarkers predictive of a clinical benefit in patients receiving a first line therapy with AI/fulvestrant (+/- LH-RH analogue) in association with a CDK4/6i for luminal-like advanced breast cancer.

Description:

Patients presenting with a de novo diagnosis of luminal-like advanced breast cancer (ABC) or with disease recurrence after >12 months from the end of adjuvant ET, are generally candidate to a first line therapy with an aromatase inhibitor (+/- LH-RH analogue depending from the menopausal status) in association with a CDK4/6i. Disease recurrence in <12 months from the end of adjuvant ET defines the disease as "endocrine resistant" and identifies patients that should receive a first line therapy with the selective estrogen receptor degrader (SERD) Fulvestrant in association with the CDK4/6i Ribociclib, according to the results of the MONALEESA-3 trial. The choice of the endocrine backbone and of the CDK4/6i is mostly influenced by the patient's clinical characteristics and by disease factors. However, a significant percentage of ABC patients develops a primary resistance with disease progression within the first 6 months from the beginning of the treatment. Furthermore, another relevant percentage of patients initially responding to the therapy, will later develop a secondary resistance, thus progressing after a median of 2 years from the beginning of the treatment. Thereby, it is crucial to identify biomarkers that could be predictive of a response or a resistance to ET and/or CDK4/6i, to provide the best therapeutic strategy, tailored upon both clinico-pathological and molecular characteristics. Numerous pathways associated with resistance to CDK4/6i have been investigated by means of liquid biopsy analysis. The aim of this study is to identify potential biomarkers predictive of a clinical benefit in patients receiving a first line therapy with AI/fulvestrant (+/- LH-RH analogue) in association with a CDK4/6i for luminal-like advanced breast cancer.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 74
• Est. completion date: May 18, 2026
• Est. primary completion date: May 18, 2026
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically proven diagnosis of adenocarcinoma of the breast with evidence of metastatic disease.
• ER positive tumor = 1%
• HER2 negative breast cancer by FISH or IHC (IHC 0,1+, 2+ and/or FISH HER2: CEP17 ratio < 2.0)
• Females, 18 years of age or older
• Candidate to first-line endocrine therapy (LH-RH analogue for pre-menopausal women is allowed)
• Signed and dated informed consent document indicating that the subject (or legally acceptable representative) has been informed of all the pertinent aspects of the trial prior to enrollment.
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria:

• Diagnosis of any secondary malignancy within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
• Prior endocrine therapy for metastatic disease
• Prior chemotherapy for metastatic disease
• Patients unwilling to or unable to comply with the protocol.
• Known CNS metastases

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Locations

Country	Name	City	State
Italy	Centro di Riferimento Oncologico (CRO) di aviano-IRCCS	Aviano	Pordenone
Italy	Azienda Sanitaria Universitaria del Friuli Centrale(ASUFC)	Udine

Sponsors (1)

Lead Sponsor	Collaborator
Centro di Riferimento Oncologico - Aviano

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To identify potential biomarkers predictive of a clinical benefit in patients receiving a first line therapy with AI/fulvestrant (+/- LH-RH analogue) in association with a CDK4/6i for luminal-like ABC.	Mean difference in mean VAF in most frequently mutated gene found at baseline, with respect to first evaluation after 15 days between responders (CR-PR-SD, Complete Response - Partial Response - Stable Disease) and non-responders (PD, Progressive Disease)	up to 3 years
Primary	To identify potential biomarkers predictive of a clinical benefit in patients receiving a first line therapy with AI/fulvestrant (+/- LH-RH analogue) in association with a CDK4/6i for luminal-like ABC.	Mean difference in mean VAF in most frequently mutated gene found at baseline, with respect to 6 months evaluation between responders (CR-PR-SD, Complete Response - Partial Response - Stable Disease) and non-responders (PD, Progressive Disease)	up to 3 years
Secondary	To explore the impact of ctDNA-based biomarkers in terms of treatment resistance	Differences in time-to-progression (TTP) probability between patients with or without selected ctDNA-based biomarkers. TTP will be defined as the time from first biomarker assessment until objective PD or end of follow-up, whichever comes first.	from first biomarker assessment until objective PD or end of follow-up, up to 3 years
Secondary	To explore the impact of ctDNA-based biomarkers in terms of survival	Differences in progression-free survival (PFS) between patients with or without selected ctDNA-based biomarkers. PFS will be defined as time from beginning of the therapy until objective PD, death or end of follow-up, whichever comes first.	from beginning of the therapy until objective PD, death or end of follow-up, up to 3 years
Secondary	To explore the impact of ctDNA-based biomarkers in terms of survival	Differences in Overall survival (OS) between patients with or without selected ctDNA-based biomarkers. OS will be defined as time from beginning of the therapy until death from any cause or end of follow-up, whichever comes first.	from beginning of the therapy until death from any cause or end of follow-up, up to 3 years
Secondary	Mean difference in mean VAF in most frequently mutated gene found at baseline, between baseline and progression in non-responders (PD, Progressive Disease)	Mean difference in mean VAF in most frequently mutated gene found at baseline, between baseline and progression in non-responders (PD, Progressive Disease)	up to 3 years