A proof of concept study to evaluate treatments´efficacy by monitoring Minimal Residual Disease using ctDNA in HR-positive/HER2-negative early breast cancer population

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medica Scientia Innovation Research S.L.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Dec 2025 → ongoing

Decision date (initial)

2025-12-08

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Hoffmann-La Roche

External identifiers

EU CT number

2023-505661-89-00

EudraCT number

2022-002616-24

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

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

Secondary objectives 9

1. To assess the incidence of ctDNA detection in participants with HRpositive/ HER2-negative BC
2. To evaluate the efficacy – in terms of a 90% decrease in baseline ctDNA at six, nine, and 12 months – of the different arms.
3. To evaluate the efficacy –in terms of a 90% decrease in baseline ctDNA at three months and maintained at six months and 12 months- of the different arms
4. To evaluate the efficacy –in terms of a 50% and 70% decrease in baseline ctDNA at three, six, nine, and 12 months- of the different arms.
5. To evaluate the efficacy –in terms of time to rising ctDNA during the study follow-up- of the different arms
6. To evaluate the duration of efficacy -in terms of time with at least a 90% decrease in baseline ctDNA- of the different arms
7. To evaluate the efficay - in terms of ctDNA decrease relative to baseline -at three, six, nine, and 12 months- of the different arms
8. To evaluate the safety and tolerability of the different study treatments
9. The exploratory analyses within the MiRaDor study may include, but are not limited to, the following objectives: •To conduct exploratory analyses of the primary and secondary objectives by grouping patients based on the Study treatment actually received, including (i) Arm A patients after switching treatment at month 3, and (ii) the overall Study population. • To evaluate predictive and/or prognostic and/or pharmacodynamic biomarkers associated with disease activity status, patient outcome or response to Study treatments on archival and/or liquid biopsy samples. • To determine the association of treatment efficacy and/or safety outcomes with radiological imaging biomarkers. • To assess the ability of SignateraTM Genome assay to measure ctDNA in the blood of patients with early stage HR-positive/HER2- negative breast cancer at high risk of relapse but with no evidence of locoregional, contralateral, or distant disease.

Conditions and MedDRA coding

Early-stage, Hormone Receptor (HR)-positive / Human Epidermal Growth Factor Receptor 2 (HER2)-negative, breast cancer (BC)

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 37

1. Surveillance phase: Signed surveillance phase informed consent form (ICF) prior to participation in any Study-related activities.
2. Surveillance phase: 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.
3. Surveillance phase: Prior treatment with cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) in the adjuvant setting will be allowed in the case of an interval of at least 12 months between the last dose and inclusion in the trial.
4. Surveillance phase: No prior treatment with selective estrogen receptor degraders (SERDs) will be allowed.
5. Surveillance phase: Availability and willingness to provide the most recently available (archival formalin-fixed paraffin-embedded [FFPE]) tumor tissue sample (either from diagnostic biopsy, primary surgery, or where available from a residual disease post-neoadjuvant therapy) at the time of Study inclusion. Note I: Participants with multifocal BC may be enrolled, if archival tissue samples from at least two tumors are available and after histopathological examination, all tumors meet pathologic criteria for HR-positive and HER2-negative BC. Note II: Participants with bilateral carcinoma of the breast may be included as long as at least one of the tumors meets the criteria established by the protocol and both are HR-positive and HER2- negative tumors.
6. Direct-to-treatment phase: Signed treatment phase ICF prior to participation in any Studyrelated activities.
7. Direct-to-treatment phase: Male or female participants aged 18 years or older.
8. Direct-to-treatment phase: Histologically proven primary HR-positive according to the updated ASCO/CAP 2020 guidelines and HER2-negative BC as per ASCO/CAP 2018 criteria based on local testing on the most recent analyzed biopsy.
9. Direct-to-treatment phase: Availability and willingness to provide the most recently available (archival FFPE) tumor tissue sample (either from diagnostic biopsy, primary surgery, or where available from a residual disease post-neoadjuvant therapy) at the time of Study inclusion. Note I: Participants with multifocal BC may be enrolled, if archival tissue samples from at least two tumors are available and after histopathological examination, all tumors meet pathologic criteria for HR-positive and HER2-negative BC. Note II: Participants with bilateral carcinoma of the breast may be included as long as at least one of the tumors meets the criteria established by the protocol and both are HR-positive and HER2- negative tumors.
10. Direct-to-treatment phase: Successful ctDNA assay designability, defined as the ability to generate a personalized, tumor-informed ctDNA assay based on sequencing of tumor tissue and matched germline DNA, enabling longitudinal ctDNA assessment.
11. Direct-to-treatment phase: Confirmation of ctDNA positivity by the Study test. Note: Only participants who are confirmed as ctDNA-positive by the SignateraTM Genome test will be eligible to enter the treatment phase. External ctDNA results may be used to identify potential candidates, but eligibility will be based solely on the ctDNA status determined by the SignateraTM Genome test.
12. Surveillance phase: Successful ctDNA assay designability, defined as the ability to generate a personalized, tumor-informed ctDNA assay based on sequencing of tumor tissue and matched germline DNA, enabling longitudinal ctDNA assessment.
13. Direct-to-treatment phase: Participants must have had surgery for their primary BC with documented clear margins (as per local guidelines), and they must have received radiotherapy if indicated (as per local guidelines).
14. Direct-to-treatment phase: Fulfillment of all general treatment phase eligibility criteria listed below.
15. Direct-to-treatment phase: No participation in another interventional clinical trial within 28 days prior to screening or concurrent participation in another interventional clinical trial.
16. Treatment phase: Signed treatment phase ICF prior to participation in any Study treatment phase-related activities.
17. Surveillance phase: Absence of metastatic disease by routine clinical assessment (computed tomography [CT] scan of the thorax and abdomen, and bone scan or positron emission tomography [PET] scan) confirmed no longer than three months prior to Study inclusion.
18. Surveillance phase: Participants must have had surgery for their primary BC with documented clear margins (as per local guidelines), and they must have received radiotherapy if indicated (as per local guidelines).
19. Surveillance phase: Participants must be able and willing to adhere to Study procedures.
20. Surveillance phase: Male or female participants aged 18 years or older.
21. Surveillance phase: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
22. Surveillance phase: 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.
23. Surveillance phase: Participants with high-risk early-stage BC according to at least one of the following criteria: a. If no previous neoadjuvant chemotherapy: i. pN2-N3, or ii. pN1 (including micrometastasis – pN1mi) if: 1. pT3/T4, or 2. 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: 1. cT3/T4, or 2. cT2 and high genomic risk, and/or histological grade III, and/or Ki67 ≥ 30%. Note: Genomic risk using platforms such as Oncotype Dx, Prosigna or Mammaprint won’t be assessed for the screening to participate in the Study. However, participants with the detailed scores assessed prior to Study inclusion, may be eligible.
24. Treatment phase: ctDNA positivity with no evidence of locoregional or contralateral clinical or radiologic recurrence by standard assessments (breast staging scans, e.g.: mammogram, breast ultrasound, breast magnetic resonance imaging [MRI]).
25. Treatment phase: ECOG performance status 0 or 1.
26. Treatment phase: 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. Participants must have received the same ET treatment with AI or tamoxifen during at least the last six months. A temporary discontinuation of < 90 days during the surveillance phase is allowed.
27. Treatment phase: Receiving LHRH agonist therapy alongside the same ET treatment for at least 90 days prior to initiation of one of the available Study treatments if male or premenopausal female participant.
28. Treatment phase: Prior treatment with CDK4/6i in the adjuvant setting will be allowed in the case of an interval of at least 12 months between the last CDK4/6i dose and Study inclusion in the trial.
29. Treatment phase: No prior treatment with SERDs will be allowed.
30. Treatment phase: Female of reproductive potential and male participants with female partners of childbearing potential, must remain abstinent and truly abstain from sexual activity (refrains from heterosexual intercourse) or use locally recognized adequate methods of contraception (described as that with a failure rate < 1%) for the duration of trial treatment. In addition, participants must follow these guidelines for a certain period of time after the last dose of trial treatment, specified in the protocol depending on which treatment arm the participant is allocated in. During this period of time, female and male participants must as well refrain from donating eggs or sperm. Note: Female participants will be deemed not of childbearing potential if they are postmenopausal or have had irreversible sterilization. Well-defined premenopausal status refers to women who have not reached the postmenopausal state because they are not permanently infertile due to prior bilateral oophorectomy, age ≥ 60 years or age < 60 years with amenorrhea for ≥ 12 months and estradiol and follicle-stimulating hormone (FSH) levels in the postmenopausal range.
31. Treatment phase: Resolution of all acute toxic effects of prior anti-cancer therapy to Grade ≤ 1 as determined by the National Cancer Institute - Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v.5.0) (except for alopecia, or other toxicities not considered a safety risk for the participant at investigator's discretion). Adverse events (AEs) of current ET treatment are not included.
32. Treatment phase: Adequate hematologic and organ function within 14 days before the first Study treatment on Day 1 of Cycle 1, defined by the following: • Hematological (without platelet, red blood cell (RBC) transfusion, and/or granulocyte colony-stimulating factor support within seven days before first Study treatment dose): White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 9.0 g/dL (≥ 5.6 mmol/L). • Hepatic: Serum albumin ≥ 3 g/dL; Bilirubin ≤ 1.5x the upper limit of normal (ULN) (≤ 3x ULN in the case of Gilbert’s disease); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5x ULN; alkaline phosphatase (ALP) ≤ 2 × ULN. • Renal: serum creatinine level ≤ 1.5x the ULN or an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m², as calculated using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation (National Kidney Foundation [NKF], 2021). Note: eGFR should be determined using the recommended standardized 2021 CKD-EPI Creatine Equation (without race adjustment): eGFR (mL/min/1.73 m²) = 142 × min (Scr/κ, 1) ^α × max (Scr/κ, 1) ^–1.200 × 0.9938^Age × 1.012 [if female]. Scr = serum creatinine in mg/dL, κ = 0.7 for females; 0.9 for male; α = –0.241 for females; –0.302 for males; min (Scr/κ, 1) = the lesser of Scr/κ or 1; max (Scr/κ, 1) = the greater of Scr/κ or 1; Age = age in years; The multiplication factor 1.012 is applied only for females.
33. Treatment phase: Participants who are able and willing to swallow, retain, and absorb oral medication.
34. Treatment phase: Participants must be able and willing to adhere to Study procedures.
35. Treatment phase (arm C): Participants with prior diagnosis of thrombosis might be included as long as they are under stable anti-coagulation regimen therapy 28 days prior to starting treatment with abemaciclib.
36. Treatment phase (arm D): Central confirmation of biomarker eligibility (detection of specified PIK3CA mutation(s) via Qiagen therascreen® PIK3CA RGQ PCR kit [CE-IVD]) in tumor tissue sample.
37. Treatment phase (arm D): No prior treatment with any phosphatidylinositol 3-kinase (PI3K), Akt, or mammalian target of rapamycin (mTOR) inhibitors, or any agent whose mechanism of action is to inhibit the PI3K/Akt/mTOR pathway.

Exclusion criteria 31

1. Surveillance phase: Participants with pathological complete response (pCR) after neoadjuvant treatment.
2. Surveillance phase: Creatinine clearance < 30mL/min.
3. Surveillance phase: Participants with renal dysfunction who require dialysis.
4. Surveillance phase: 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.
5. Surveillance phase: Females who are known to be breastfeeding or pregnant as determined by a serum pregnancy test, Human chorionic gonadotropin (β-HCG), prior to the administration of any trial treatment (once during the treatment phase). Since β-HCG over expression can be also elevated in some tumor types, a positive result should be confirmed with a validated alternative test (e.g., ultrasound).
6. Surveillance phase: Female or male participants planning a pregnancy.
7. Surveillance phase: Participation in another interventional clinical trial within 28 days prior to screening or concurrent participation in another interventional clinical trial.
8. Surveillance phase: 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).
9. Surveillance phase: Diagnosis of an alternative cancer in the five years prior to primary BC diagnosis, other than for non-melanoma carcinoma of the skin or cervical carcinoma in situ. Other stage I tumors will be discussed case by case prior to inclusion with the Medical Monitor of the Study.
10. Surveillance phase: 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.
11. Surveillance phase: 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, moderateto- 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.
12. Surveillance phase: History of pneumonitis, interstitial lung disease (ILD), or pulmonary fibrosis.
13. Surveillance phase: Known history of Human Immunodeficiency Virus (HIV) infection.
14. Surveillance phase: 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.
15. Surveillance phase: 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.
16. Treatment phase: Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances.
17. Treatment phase: Undergoing any concurrent anti-cancer treatment for the current BC diagnosis, other than permitted adjuvant ET and/or bonemodifying agents (denosumab or bisphosphonates).
18. Treatment phase: Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 28 days of start of Study drug, or participants who have not recovered from the side effects of any major surgery.
19. Treatment phase: Treatment with strong Cytochrome P450 3A4 (CYP3A4) inhibitors or strong CYP3A4 inducers within 14 days or five drug-elimination half-lives, whichever is longer, prior to initiation of Study treatment.
20. Treatment phase: 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.
21. Treatment phase: History of pneumonitis, ILD, or pulmonary fibrosis.
22. Treatment phase: Known history of HIV infection.
23. Treatment phase: Clinically significant liver disease consistent with Child-Pugh C, including current known infection with HBV or HCV, current alcohol abuse, or cirrhosis. Participants with past HBV infection or resolved HBV infection (defined as having a negative HBsAg test and a positive HBcAb test, accompanied by a negative HBV DNA test) are eligible. Participants positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
24. Treatment phase: Diagnosis of an alternative cancer in the five years prior to primary BC diagnosis, other than for non-melanoma carcinoma of the skin or cervical carcinoma in situ. Other stage I tumors will be discussed case by case prior to inclusion with the Medical Monitor of the Study.
25. Treatment phase: Females who are known to be breastfeeding or pregnant as determined by a serum pregnancy test (β-HCG) prior to the administration of any trial treatment (once during the treatment phase). Since β-HCG over expression can be also elevated in some tumor types, a positive result should be confirmed with a validated alternative test (e.g., ultrasound).
26. Treatment phase: 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.
27. Treatment phase: Participant has a history of non-compliance to medical regimen.
28. Treatment phase (arm D): Type 2 diabetes requiring ongoing systemic treatment at the time of Study entry; or any history of Type 1 diabetes.
29. Treatment phase (arm D): Fasting glucose ≥ 126 mg/dL or ≥ 7.0 mmol/L and hemoglobin A1c (HbA1c) ≥ 6.0%.
30. Treatment phase (arm D): Any concurrent ocular or intraocular condition excluding cataracts (e.g., diabetic retinopathy) that, in the opinion of the investigator, would require medical or surgical intervention during the Study period to prevent or treat vision loss that might result from that condition.
31. Treatment phase (arm D): Active inflammatory (e.g., uveitis or vitritis) or severe infectious conditions (e.g., keratitis, scleritis, or endophtalmitis) in either eye or history of idiopathic or autoimmune-associated uveitis in either eye.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Treatment phase: Proportion of participants with at least a 90% decrease or clearance in baseline ctDNA at three months after initiation of study treatment

Secondary endpoints 9

1. Surveillance phase: Total ctDNA detection and breakdown by incidence at first ctDNA test versus incidence at subsequent ctDNA tests.
2. Treatment phase: Proportion of participants with at least a 90% decrease in baseline ctDNA at six, nine, and 12 months after initiation of study treatment
3. Treatment phase: 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.
4. Treatment phase: Proportion of participants with 50% and 70% decrease in baseline ctDNA at three, six, nine, and 12 months after initiation of study treatment.
5. Treatment phase: Time to rising ctDNA defined as time to first ctDNA increase compared to baseline
6. Treatment phase: Duration of at least a 90% decrease in baseline ctDNA after initiation of study treatment.
7. Treatment phase: Best percentage of ctDNA decrease relative to baseline at six, nine, and 12 months after initiation of study treatment
8. Treatment phase: Safety and toxicity profile according to the NCI-CTCAE v.5.0.
9. Evaluation of the primary and secondary outcomes based on the actual Study treatment received, including analyses within Arm A patients after switching treatment at month 3 and in the overall Study population. • Association of clinical outcomes, safety and/or tolerability profile with mutation profiling, copy number variability, gene expression, multiplex assays, proteomic analyses, digital pathology, immunohistochemistry, taxonomic o

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medica Scientia Innovation Research S.L.

Sponsor organisation

Medica Scientia Innovation Research S.L.

Address

Torre Glories 27th Floor, Avinguda Diagonal 211 Avinguda Diagonal 211

City

Barcelona

Postcode

08018

Country

Spain

Scientific contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Alicia García Sanz

Public contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Alba Meya

Third parties 4

Locations

4 EU/EEA countries · 62 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 1 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 47 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications