TAILORswitch (PADA-2): rising ctDNA to tailor endocrine therapy switch in patients with ER+/HER2- metastatic breast cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-07-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Astrazeneca · Natera · PHRC

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To demonstrate the efficacy of the switch to camizestrant and abemaciclib in ER+ HER2- mBC participants receiving first line CDK4/6i and aromatase inhibitor who have displayed rising ctDNA with no evidence of disease progression

Secondary objectives 6

1. To assess the feasibility of imaging de-escalation in arm B (related to Step 1)
2. To assess the safety of imaging de-escalation (Related to step 1)
3. To assess the efficacy of the treatment switch in terms of PFS, PFS2, time to chemotherapy and overall survival (OS) in all the participants randomized in Step 2 and in predefined subgroups (subgroups of stratification factors) - (Related to Step 2)
4. To assess the efficacy of Step #2 treatments in the per-protocol population (Related to Step 2)
5. To assess the safety and tolerability of the treatment switch (Related to Step 2)
6. To evaluate the health-related quality of life trajectories in both arms (Related to Step 2)

Conditions and MedDRA coding

Patients with advanced or metastatic ER+ HER2- breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 23

1. First written informed consent (ICF#1) prior to any trial specific procedures. When the participant is physically unable to give his written consent, an impartial witness, independent from the investigator and the sponsor, can confirm in signing the participant’s consent (Related to step 1)
2. Women of childbearing potential must have a negative serum or urine pregnancy test done within 28 days before inclusion
3. Minimum life expectancy of at least 6 months
4. Participants must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan and other study procedures including follow-up
5. Participants must be affiliated with a social security scheme or a beneficiary of such a scheme (or equivalent)
6. Additional written informed consent (ICF#2). When the participant is physically unable to give his written consent, an impartial witness, independent from the investigator and the sponsor, can confirm in signing the participant’s consent (Sub Study)
7. Participants must have received at least 6 months (from 22 weeks authorized) of treatment with AI + CDK4/6 inhibitor, with no evidence of ctDNA rising in STEP #1 (at the current visit or, if current results are pending, at the previous visit), and no disease progression on imaging at the current visit as per RECIST v1.1 (Sub study)
8. No history of venous thrombo-embolic event, interstitial lung disease or any pre-existing condition that may impair participant’s respiratory function (per investigator assessment) (Sub study)
9. Men or women ≥ 18 years of age
10. Additional written informed consent (ICF#3). When the participant is physically unable to give his written consent, an impartial witness independent from the investigator and the sponsor, can confirm in signing the participant’s consent (Related to step 2)
11. Rising ctDNA (as defined in the protocol) detected during Step #1 (centrally determined);
12. Eastern Cooperative Oncology Group performance status of 0 or 1
13. Having received at least 6 months of AI + CDK4/6i (Related to step 2)
14. Adequate bone marrow reserve and organ function as follows: a) Hemoglobin ≥9.0g/dL (90 g/L). b) Absolute neutrophil count ≥1000/mm3 (1.0×10^9/L) or documented institutional normal range for starting abemaciclib. c) Total bilirubin ≤1.5×ULN or ≤3×ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia). d) ALT and AST ≤3×ULN; for participants with hepatic metastases, ALT and AST ≤5×ULN. e) Alkaline phosphatase ≤2.5×ULN (≤ 5.0×ULN if bone or liver metastases present). f) Serum creatinine ≤ 1.5×ULN or calculated creatinine clearance ≥ 30 mL/min as determined by Cockcroft-Gault (using actual body weight). (Related to step 2)
15. Female participants must have a negative highly sensitive serum pregnancy test during the screening period if they are of childbearing potential and agree to use highly effective contraceptive methods to prevent pregnancy during the study and for 4 weeks following the last dose of camizestrant (if applicable) and/or for 3 weeks after the last dose of CDK4/6inhibitor or must have evidence of nonchildbearing potential. In addition, female participants must refrain from egg cell donation and breastfeeding during this same period. a. Non-sterilized male partners of a participant who is a woman of childbearing potential must use a male condom plus spermicide from the time of screening throughout the total duration of the study until 28 days after last dose of camizestrant. b. Non-sterilised male participants (including males sterilised by a method other than bilateral orchidectomy, eg, vasectomy) who intend to be sexually active with a Female OfChildBearing Potential (FOCBP) must be using an acceptable method of contraception, such as male condom plus spermicide (condom alone in countries where spermicides are not approved), from enrolment throughout the study until at least 1 week to avoid conception during treatment. Male participants must not donate or bank sperm during this same period. c. Female partners (of child-bearing potential) of male participants enrolled in this study must also use a highly effective method of contraception from the time of study enrolment of their male partner, throughout their participation in the study, and until at least 1 week after their male partners last dose of camizestrant
16. ER+ HER2- advanced (metastatic or locally advanced inoperable) breast adenocarcinoma (ERpositivity threshold: ≥10% tumor cells; HER2-negative tumour is defined as an immunohistochemical (IHC) score of 0 or 1+, or an IHC score of 2+ with negative in situ hybridization (ISH) (HER2/CEP17 ratio <2 or, for single probe assessment, HER2 copy number <4, according to the most recent available results), not amenable to resection or radiation therapy with curative intent;
17. Eligible to (per investigator assessment) or currently receiving for up to 3 years, AI (+/- LH RH agonist) and CDK4/6i (palbociclib or ribociclib) as first line therapy with adequate cardiac, renal, hematological and hepatic functions per investigator assessment
18. Evaluable disease (RECIST v1.1) before the start of AI+CDK4/6i and, in participants currently receiving AI and CDK4/6i, no evidence of clinical or radiological progression since AI+CDK4/6i initiation
19. Must have an adequate archival tumor tissue sample available (with a cellularity > 30%) for centralized WGS analysis to design the ctDNA test. Requirements: • Sample age: Less than 10 years old. Preferably less than 2 years when possible • Preferred sample types (in order of priority): a) b) c) Most recent resected tumor tissue sample from primary breast site Affected lymph node with adequate cellularity. Metastatic tissue samples, including brain, lung, or other organs. Avoid bone samples.
20. Pre/perimenopausal women and fertile men must agree to use adequate contraception methods during the study
21. Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception until at least one week after the last treatment administration.
22. Willingness and ability to comply with scheduled visits
23. ctDNA detected at study entry and no rising ctDNA

Exclusion criteria 19

1. Systemic antineoplastic therapy (except adjuvant therapies) received prior to AI and CDK4/6i
2. Participants with synchronous disease progression per local assessment (tumor imaging performed within 28 days prior to entry in Step #2 RECIST v1.1) (Related to step 2)
3. Participants with a contraindication to abemaciclib, as assessed by the investigator
4. Participants presenting any of the following cardiovascular conditions or findings a) unexplained syncope, symptomatic hypotension, or systolic blood pressure < 90 mmHg. b) second- and third-degree heart block, or clinically significant sinus pause or sinoatrial block (participants with pacemakers or medically controlled atrial fibrillation are not excluded). c) known left ventricular ejection fraction <50% with congestive heart failure NYHA Grade ≥ 2. d) experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, any other structural heart disease interventions (e.g., cardiac valve repair or replacement surgery or transcatheter valve intervention), severe aortic regurgitation (Grade 3 and 4), myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack. e) any clinically important abnormalities in rhythm, conduction or morphology that might impact resting ECG, such as third-degree heart block and any factors that increase the risk of QTc prolongation or the risk of arrhythmic events such as symptomatic heart failure, congenital long QT syndrome, immediate family history of long QT syndrome, unexplained sudden death at <40 years of age, hypertrophic cardiomyopathy and clinically significant stenotic valve disease, or clinically significant electrolyte abnormalities with potential QT-prolonging effect including hypokalaemia, hyperkalaemia, hypo- and hyper-magnesaemia, hypo- and hyper-calcaemia. Note: correction of electrolyte abnormalities to within normal ranges can be performed during screening). mean resting QTcF interval > 480 ms obtained from ECG performed at screening. g) resting heart rate < 55 beats per minute. Repeat measurements are permitted during the screening period. h) uncontrolled hypertension. Blood pressure systolic > 160 and diastolic > 90 mmHg. Hypertensive participants may be eligible, but blood pressure must be adequately controlled at baseline. Participants may be rescreened regarding blood pressure requirement.
5. Participants treated within the last 2 weeks before randomization with medications that are sensitive substrates (e.g. omeprazole) or substrates with narrow therapeutic index of CYP2C9 and/or CYP2C19 (e.g. warfarin and phenytoin). Strong CYP3A4/5 inducers should be stopped at least 2 weeks before randomization (3 weeks for St John’s Wort).
6. Participant who was treated within the timeframe indicated in the CSP with drugs that are known to prolong the QT interval.
7. Participant taking medications known to prolong the QT interval and associated with a known risk of Torsades de Pointes
8. Participant with a known active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), HBV (known positive HBsAg result), and HCV. 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 is negative for HCV RNA
9. Participants known to be positive for HIV can be enrolled if they fulfil the criteria recommended by Food and Drug Administration (FDA) and ASCO guidelines (FDA Guidance, Uldrick et al 2017):  CD4+ T-cell (CD4+) counts ≥350 cells/µL, AND No history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections within the past 12 months (prophylactic antimicrobials allowed if no DDI or overlapping toxicities), AND  On established anti-retroviral therapy (ART) for at least 4 weeks and have an HIV viral load less than 400 copies/mL before enrolment. Effective ART is defined as a drug, dosage and schedule associated with reduction and control of the viral load
10. Known leptomeningeal metastasis and/or brain metastasis
11. Known contraindication to camizestrant and abemaciclib, per investigator assessment
12. Prior exposure to camizestrant, other SERD or investigational endocrine therapy agents
13. History of another malignancy, except (i) those treated with curative intent and with no known active disease ≥3 years; (ii) adequately treated non-melanoma cutaneous and in-situ cervix cancer
14. Pregnant women or women who are breast-feeding or participants not willing to apply highly effective contraception as defined in the protocol
15. Participants unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
16. Participation in another clinical study whose procedures interfere with those of the study (within 28 days prior to participant enrolment and for the duration of the study)
17. Persons deprived of their liberty or under protective custody or guardianship
18. History of bone marrow transplantation
19. Patients relapsing while on or during the year after the discontinuation of adjuvant CDK4/6 inhibitor

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-free survival (PFS), defined as the time from randomization in step #2 until the date of objective disease progression per RECIST 1.1 as assessed by local investigator or death due to any cause, whichever occurs first. Participants without events will be censored at their date of last assessment. (Step 2)

Secondary endpoints 6

1. Number of imaging assessments received per participant and per year Percentage of participants who followed the planned schedule of no more than one imaging assessment per year among participants enrolled in arm B.
2. Rates of randomized participants in Step #1 (arm A & B) who experience a disease progression: - with no ctDNA detected prior to disease progression, - - - with visceral assessment), crisis (per investigator with altered general condition (ECOG PS ≥2), treated with chemotherapy as 2nd line of treatment, reported by randomization arm. Rates of randomized participants in Step #1 (arm A & B) - experiencing a venous thrombo-embolic event, adherent to the allocated imaging schedule
3. PFS (as defined in the primary endpoint) ; PFS2, (time to second tumor progression), defined as the time from randomization to the earliest progression after the 1st progression, or death from any cause; Time to chemotherapy, defined as the time from randomization until the start date of the 1st subsequent chemotherapy treatment after discontinuation treatment; of randomized OS, defined as the time from randomization to death from any cause.
4. PFS, PFS2, Time to chemotherapy and OS, as defined above, reported in the per protocol population
5. Rate of AEs (per CTCAE v5.0) and SAEs, reported by treatment arm in Step #2 (arm C & D)
6. Change from baseline in Quality of life, measured by EORTC QLQ-C30 and EORTC BR42 questionnaires

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 32 investigational sites

By country

Investigational sites

Results and documents

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

Documents 11 files

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

Application history

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