A PoC Study to Evaluate Treatments' Efficacy by Monitoring MRD Using ctDNA in HR-positive/HER2-negative EBC Population

NCT05708235 | Active Not Recruiting Phase 2 DMC

• 3 other identifiers: MedOPP4852023-505661-89-002023
• Study Type: interventional
• Target: 976
• Locations: 2 countries
• Sites: 41

Brief Summary

This trial is a multicenter, open-label, non-comparative, phase II, biomarker-driven adjuvant treatment study involving the periodic collection and analysis of blood samples from patients with HR-positive/HER2-negative early-stage BC at higher risk of relapse, who have undergone surgery within the previous five years, with no evidence of locoregional, contralateral, or distant disease. The study design is composed by an initial pre-screening phase, a molecular follow-up phase (ctDNA surveillance phase), and an interventional therapeutic phase (treatment phase). After informed consent is obtained, a total of 976 eligible patients will enter a ctDNA surveillance in which primary tumor tissue and matched normal blood will be collected from each patient to obtain a patient-specific somatic mutations panel (tumor signature). At the event of ctDNA positivity, patients will be screened to enter the treatment phase of the study. Upon confirmed eligibility, a total of 40 patients will be allocated in one of the following trial's arms adopting a sequential recruitment strategy: Arm A: Control Arm (N=10) Arm B: Experimental Arm with giredestrant (N=10) Arm C: Experimental Arm with giredestrant + abemaciclib (N=10) Arm D: Experimental Arm with giredestrant + inavolisib (N=10) If the strategy of ctDNA monitoring enables physicians to identify patients at high risk of relapse and assess whether treatment at molecular relapse can improve outcome, new cohorts may be added to the study.

Conditions

Breast Cancer

Keywords

ctDNA; Early breast cancer; HR-positive/HER2-negative; MRD; Minimal Residual Disease

Outcome Measures

Primary Outcomes (1)

• Evaluation of decrease or clearance in baseline ctDNA at three months after initiation of study treatment

  To evaluate the efficacy - in terms of rate of participants with a 90% decrease or clearance in baseline ctDNA at three months - of the different arms

  Treatment phase (three months after Study treatment initiation)

Secondary Outcomes (8)

• Total ctDNA detection and breakdown by incidence at first ctDNA test versus incidence at subsequent ctDNA tests.

  Surveillance phase (up to two years after study start date)

• Proportion of participants with at least a 90% decrease in baseline ctDNA at six, nine, and 12 months after initiation of study treatment.

  Treatment phase (at six, nine, and 12 months after study treatment initiation)

• Proportion of participants with at least a 90% decrease in baseline ctDNA at three months maintained at six months and 12 months after initiation of study treatment.

  Treatment phase (at six and 12 months after study treatment initiation)

• Proportion of participants with 50% and 70% decrease in baseline ctDNA at three, six, nine, and 12 months after initiation of study treatment.

  Treatment phase (at three, six, nine, and 12 months after study treatment initiation)

• Time to rising ctDNA defined as time to first ctDNA increase compared to baseline

  Treatment phase (up to five years after study treatment initiation)

Study Arms (4)

Arm A: Control Arm

ACTIVE COMPARATOR

Participants assigned to this arm will continue receiving the same standard ET that was prescribed during the surveillance phase for a period of 90 days. This will be done in accordance with standard clinical practice and until the analysis of the primary endpoint. After this 90-day period, participants will be eligible to receive one of the other three predefined treatments (giredestrant, giredestrant plus abemaciclib or giredestrant plus inavolisib if a detectable PIK3CA mutation is present and the participant also meets all additional eligibility criteria for Arm D). as determined by the investigator´s choice. No changes to the prescribed ET are permitted during the 90-day period.

Drug: Standard ET followed by change in treatment

Arm B: Experimental Arm with giredestrant

EXPERIMENTAL

Giredestrant: 30 mg will be taken orally (PO) once a day (QD) on Days 1 to 28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first).

Drug: Giredestrant

Arm C: Experimental Arm with giredestrant + abemaciclib

EXPERIMENTAL

Giredestrant: 30 mg will be taken PO QD on Days 1 to 28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first). Abemaciclib 150 mg will be taken PO twice daily (BID) (two intakes for a total daily dose of 300 mg) during each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first). Note: Participants who have previously received adjuvant abemaciclib at a reduced dose (100 mg BID or 50 mg BID) due to toxicity may initiate study treatment at the same reduced dose level, at the investigator's discretion. Dose re-escalation is not permitted.

Drug: Giredestrant; Drug: Abemaciclib

Arm D: Experimental Arm with giredestrant + inavolisib

EXPERIMENTAL

Giredestrant: 30 mg will be administered PO QD on Days 1-28 of each 28-day cycle up to five years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first). Inavolisib: 9 mg will be administered PO QD on Days 1-28 of each 28-day cycle up to two years or until disease recurrence, unacceptable toxicity, or treatment/Study discontinuation (whichever occurs first).

Drug: Giredestrant; Drug: Inavolisib

Interventions

Standard ET followed by change in treatment DRUG

90-day period of standard ET in accordance with standard clinical practice, followed by one of the other three predefined treatments (giredestrant, giredestrant plus abemaciclib or giredestrant plus inavolisib if a detectable PIK3CA mutation is present and the participant also meets all additional eligibility criteria for Arm D).

Arm A: Control Arm

Giredestrant DRUG

Giredestrant is a highly potent, non-steroidal, oral selective ER antagonist and degrader (SERD)

Also known as: GDC-9545

Arm B: Experimental Arm with giredestrant; Arm C: Experimental Arm with giredestrant + abemaciclib; Arm D: Experimental Arm with giredestrant + inavolisib

Abemaciclib DRUG

Abemaciclib is an orally administered CDK4/6 inhibitor

Also known as: LY2835219

Arm C: Experimental Arm with giredestrant + abemaciclib

Inavolisib DRUG

Inavolisib is a potent, selective inhibitor of the Class I phosphatidylinositol 3-kinase α (PI3K-alpha isoform (p110-alpha)

Also known as: GDC-0077

Arm D: Experimental Arm with giredestrant + inavolisib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed surveillance phase ICF prior to participation in any Study-related activities.
• Male or female participants aged 18 years or older.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Histologically proven primary HR-positive according to the updated American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2020 guidelines and HER2-negative BC as per ASCO/CAP 2018 criteria based on local testing on the most recent analyzed biopsy.
• Participants with high-risk early-stage BC according to at least one of the following criteria:
• If no previous neoadjuvant chemotherapy:
• i. pN2-N3, or ii. pN1 (including micrometastasis - pN1mi) if:
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• pT3/T4, or
• pT2 and high genomic risk, and/or histological grade III, and/or Ki 67 ≥ 30%. b. If participants have received previous neoadjuvant chemotherapy, they must have had residual invasive disease defined as at least one of the following: i. Residual invasive disease in lymph nodes (ypN+, including ypN1mi) ii. ypN0 with residual invasive disease in breast if:
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• cT3/T4, or
• \. On adjuvant treatment with ET for at least two years and no more than seven years at the time of Study enrolment with an additional three years of ET planned, and at least six months prior to enrolment on the same ET treatment with AI or tamoxifen (LHRH agonist is mandatory for male and premenopausal participants receiving AI or tamoxifen, except in cases of bilateral oophorectomy).
• Note: Premenopausal and male participants treated with tamoxifen alone are excluded.
• \. No prior treatment with selective estrogen receptor degraders (SERDs) will be allowed.

You may not qualify if:

• Participants with pathological complete response (pCR) after neoadjuvant treatment.
• Receiving or planning to receive any concurrent anti-cancer treatment for the current BC diagnosis, other than permitted adjuvant ET and/or bone-modifying agents (denosumab or biphosphonates).
• Active or prior documented inflammatory bowel disease (i.e. Crohn's disease, ulcerative colitis, or a preexisting chronic condition resulting in baseline grade ≥ 1 diarrhea) that may significantly alter the absorption of oral drugs.
• Active cardiac disease or history of cardiac dysfunction including any of the following:
• a. History (within two years from screening) or presence of idiopathic bradycardia or resting heart rate \< 50 beats per minute at screening.
• b. History of angina pectoris or symptomatic coronary heart disease within 12 months prior to Study entry.
• c. QT interval corrected through use of Fridericia's formula (QTcF) \> 450 ms for women and \> 470 ms for men by at least three electrocardiograms (ECGs) \> 30 minutes apart.
• d. History or presence of an abnormal ECG that is clinically significant in the investigator's opinion, e. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g. severe left ventricular systolic dysfunction, left ventricular hypertrophy cardiomyopathy, infiltrative cardiomyopathy, moderate-to-severe valve disease), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g. hypokalemia, hypomagnesemia, hypocalcemia), or family history of long QT syndrome within 12 months.
• History of pneumonitis, interstitial lung disease (ILD), or pulmonary fibrosis.
• Known history of Human Immunodeficiency Virus (HIV) infection.
• Clinically significant liver disease consistent with Child-Pugh C, including current known infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), current alcohol abuse, or cirrhosis. Participants with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen \[HBsAg\] test and a positive hepatitis B core antibody \[HBcAb\] test, accompanied by a negative HBV DNA test) are eligible. Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
• Active bleeding diathesis venous thrombo-embolism, previous history of bleeding diathesis or chronic anti-coagulation treatment, or any indications or history of Disseminated Intravascular Coagulation (DIC) or Deep vein thrombosis (DVT). Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel are permitted.
• Creatinine clearance \< 30mL/min.
• Participants with renal dysfunction who require dialysis.
• Participant who has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator' opinion cause unacceptable safety risks, contraindicate participation in the clinical trial or compromise compliance with the protocol.

Sponsors & Collaborators

• MedSIR: lead

Study Sites (41)

Complejo Hospitalario Universitario A Coruña (CHUAC)

A Coruña, Spain

Location

Hospital General Universitario Dr. Balmis

Alicante, Spain

Location

Hospital Marina Salud de Denia

Alicante, Spain

Location

Hospital Virgen de los Lirios

Alicante, Spain

Location

Fundació Althaia

Barcelona, Spain

Location

Hospital Clínic i Provincial de Barcelona

Barcelona, Spain

Location

Hospital Universitari Dexeus

Barcelona, Spain

Location

Hospital Universitario de Basurto

Bilbao, Spain

Location

Hospital Provincial de Castellón

Castellon, Spain

Location

Hospital Universitario Reina Sofía

Córdoba, Spain

Location

Hospital del Vinalopó

Elche, Spain

Location

Institut Català d' Oncologia Girona (ICO)

Girona, Spain

Location

Hospital Universitario Clínico San Cecilio de Granada

Granada, Spain

Location

Complejo Hospitalario de Jaén

Jaén, Spain

Location

Hospital Universitario de León

León, Spain

Location

Hospital Universitario Arnau de Vilanova de Lleida

Lleida, Spain

Location

Clínica Universidad de Navarra

Madrid, Spain

Location

Hospital Beata María Ana

Madrid, Spain

Location

Hospital Universitario de Torrejón

Madrid, Spain

Location

Hospital Universitario Doce de Octubre

Madrid, Spain

Location

Hospital Universitario La Paz

Madrid, Spain

Location

Hospital Universitario Sanchinarro-START-CIOCC

Madrid, Spain

Location

Hospital Regional Universitario de Málaga (Hospital Carlos Haya)

Málaga, Spain

Location

Hospital Universitario Virgen de la Victoria

Málaga, Spain

Location

Hospital Clínico Universitario Virgen de la Arrixaca

Murcia, Spain

Location

Hospitalario Universitario de Navarra

Pamplona, Spain

Location

Hospital de Sagunto

Sagunto, Spain

Location

Hospital Quirónsalud Sagrado Corazón

Seville, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, Spain

Location

Hospital Universitari Sant Joan de Reus

Tarragona, Spain

Location

Hospital Arnau de Vilanova de Valencia

Valencia, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, Spain

Location

Hospital Universitari i Politècnic La Fe

Valencia, Spain

Location

Hospital Universitario La Ribera, Alzira

Valencia, Spain

Location

Complejo Hospitalario Universitario de Vigo

Vigo, Spain

Location

Hospital de Xativa

Xàtiva, Spain

Location

Hospital Universitario Miguel Servet

Zaragoza, Spain

Location

University Hospital Coventry

Coventry, United Kingdom

Location

Royal Surrey County Hospital NHS Foundation Trust

Guildford, United Kingdom

Location

Barts Cancer Institute

London, United Kingdom

Location

Imperial College Healthcare NHS Trust

London, United Kingdom

Location

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm, Residual

Interventions

giredestrant; abemaciclib; inavolisib; Therapeutics

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Antonio Llombart, MD

  Arnau de Vilanova Hospital, Valencia (Spain)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 976 HR+, HER2-, early BC participants on ET adjuvant treatment will be screened; 40 participants with ctDNA positivity will be allocated to one of four arms: 1. Arm A (participants with PIK3CAwt tumors, or participants with PIK3CAmut tumors that do not fulfill the specific criteria to enter arm D) and arm D (participants with PIK3CAmut tumors that fulfill the specific criteria to enter arm D). 2. Once arm A is closed, participants will be included in arm B (\*). 3. Once arms A and B are closed, participants will be included in arm C (\*). * Participants with PIK3CAwt tumors, or participants with PIK3CAmut tumors that do not fulfill the specific criteria to enter arm D. Also, participants with PIK3CAmut tumors that fulfill the specific criteria to enter arm D, once arm D is completed.

Study Record Dates

• First Submitted: January 12, 2023
• First Posted: February 1, 2023
• Study Start: April 1, 2024
• Primary Completion (Estimated): June 30, 2028
• Study Completion (Estimated): June 30, 2028
• Last Updated: September 24, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

GB (4); ES (37)