Detection of tumor DNA in the blood of patients receiving standard therapy for hormone receptorpositive (HR+) non-HER2 expressing (HER2-) metastatic breast cancer as a tool to select those who may benefit from the next course of fulvestrant in combination with alpelisib or ribociclib.

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]

Trial duration

19 Oct 2023 → 24 Nov 2025

Decision date (initial)

2023-07-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis · BCRF (Breast Cancer Research Foundation)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenetic, Safety, Efficacy

This randomised study aims to compare the efficacy of alpelisib-fulvestrant to ribociclib-fulvestrant, in terms of PFS, for the treatment of women and men with persistent mutations on exon 4, 9 or 20* of PIK3CA ctDNA after 4 weeks of treatment with any CDK4/6 inhibitor-fulvestrant in first-line setting.

Secondary objectives 8

1. To evaluate and compare the Overall Survival (OS) in the study groups.
2. To evaluate and compare the objective response rates (ORR) in the study groups.
3. To evaluate and compare the duration of response (DoR) in the study groups.
4. To evaluate and compare the clinical benefit rate (CBR) in the study groups.
5. To evaluate and compare time to response (TTR) in the study groups.
6. To validate that randomised patients with residual PIK3CA on ctDNA present a poor outcome compare to non-randomised patient.
7. To evaluate the safety in each study groups.
8. To describe the non-randomised patients in terms of: disease characteristics, PFS, and OS.

Conditions and MedDRA coding

Metastatic Breast Cancer HR+, HER2-

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 24

1. Screening Program : Patient must have signed a written informed consent prior to any study-specific screening procedures (the consent form specifically for the screening phase must be signed).
2. Screening Program : Patient is ≥18 years of age.
3. Screening Program : Patient has an histologically or cytologically confirmed metastatic breast cancer.
4. Screening Program : Patient has a HER2- breast cancer
5. Screening Program : Patient has hormone receptor-positive (HR+) breast cancer, defined as having oestrogen receptor (ER) and/or progesterone receptor (PR) expression in ≥10% of tumour cells.
6. Screening Program : Patient had a metastatic relapse during or within 1 year after termination of the adjuvant endocrine therapy.
7. Screening Program : Patient has not yet been treated in the metastatic breast cancer setting.
8. Screening Program : Patient is eligible for a first-line treatment with a marketed CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) in combination with fulvestrant, according to its marketing authorisation.
9. Screening Program : Eastern Cooperative Oncology Group (ECOG) performance status is ≤1.
10. Screening Program : Patient has an adequate bone marrow and organ function.
11. Screening Program : Patient has an adequate bone marrow and organ function.
12. Screening Program : Patients must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures.
13. Screening Program : Patient must be affiliated to the national social security (or equivalent).
14. Randomised study phase : Patient must have signed a written informed consent prior to any procedures for the randomised study phase (the consent form specifically for the randomised study phase must be signed).
15. Randomised study phase : Patient has a persistent mutations on exon 4, 9 or 20* of PIK3CA ctDNA determined by circulating tumour DNA (ctDNA) assay after 4 weeks of treatment with any CDK4/6 inhibitor combined with fulvestrant.
16. Randomised study phase : Patient must have discontinued CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) at least 7 days before randomisation.
17. Randomised study phase : ECOG performance status is ≤1.
18. Randomised study phase : Patient’s life expectancy is deemed ≥3 months.
19. Randomised study phase : Patient has an adequate bone marrow and organ function as defined
20. Randomised study phase : Participant must have the following laboratory values within normal limits or corrected to within normal limits with supplements before randomisation
21. Randomised study phase : Participant must have the following laboratory values within normal limits or corrected to within normal limits with supplements before randomisation : QTcF interval <450ms (using Fridericia’s correction), Resting heart rate between 50-90 bpm.
22. Randomised study phase : Women of childbearing potential must have a negative serum pregnancy test result within 14 days of enrolment in the randomised trial phase.
23. Randomised study phase : Men or Women of childbearing potential must agree to the use of effective contraceptive for the study duration and for at least 2 year after the last dose of study treatment for women, and at least 21 days for men.
24. Randomised study phase : Patients must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion criteria 27

1. Screening Program : Prior exposure to PIK3CA-AKT or CDK4/6 inhibitors.
2. Screening Program : Patient that has initiated the CDK4/6 inhibitor treatment.
3. Screening Program : Patient with spinal cord compression and/or symptomatic or progressive brain metastases (unless asymptomatic or treated and stable off steroids for ≥30 days before initiating the study treatment).
4. Screening Program : Participant with an established diagnosis of diabetes mellitus type I or not controlled type II (based on FG and HbA1c).
5. Screening Program : Patient unable to swallow tablets.
6. Screening Program : Patient with known hypersensitivity to any of the study treatment excipients, in particular patients with allergies to soya or peanuts.
7. Screening Program : Patients with a history of malabsorption syndrome or other condition that may interfere with enteral absorption: including but not limited to active intestine inflammation (e.g., Crohn’s disease or ulcerative colitis) requiring immunosuppressive therapy.
8. Screening Program : Patient with any condition/disease for which the investigator considers that participating in the study is inappropriate or that may jeopardize treatment and protocol compliance.
9. Screening Program : Patient deprived of liberty or under the authority of a tutor.
10. Randomised study phase : Patient is eligible to chemotherapy because of visceral crisis.
11. Randomised study phase : Pregnant or lactating women.
12. Randomised study phase : Patient has received more than 2 cycles of the ongoing CDK4/6 inhibitor treatment combined with fulvestrant before randomisation.
13. Randomised study phase : Patient has interrupted the ongoing CDK4/6 inhibitor treatment for more than 14 days before randomisation.
14. Randomised study phase : Patient has evidence of clinical or radiological disease progression before randomisation.
15. Randomised study phase : Patient has unresolved adverse events (grade ≥1), except alopecia and grade ≥2 unresolved adverse events related to fulvestrant or the LH-RH analogue which are acceptable to randomisation.
16. Randomised study phase : Patient is considered at high medical risk because of severe or uncontrolled systemic disease, including but not limited to diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, chronic pancreatitis, chronic active hepatitis, active untreated/uncontrolled fungal, bacterial, or viral infections, as well as known active viral infections with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
17. Randomised study phase : Participant has currently documented pneumonitis/interstitial lung disease (the chest CT scan performed before start of study treatment for the purpose of tumour assessment should be reviewed to confirm that there are no relevant pulmonary complications present).
18. Randomised study phase : Participant has a history of severe cutaneous reaction, such as Stevens-Johnson Syndrome (SJS), Erythema Multiforme (EM), Toxic Epidermal Necrolysis (TEN), or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
19. Randomised study phase : Participant with unresolved osteonecrosis of the jaw.
20. Randomised study phase : Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities
21. Randomised study phase : Patient who has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 weeks prior to starting study drug, or who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom ≥ 25% of the bone marrow was irradiated
22. Randomised study phase : Patient is currently consuming any of the following foods, supplements, herbal preparations or medications that cannot be discontinued within 7 days of initiating the study treatment: Known strong inducers or inhibitors of CYP3A4/5 (including grapefruits), Medications predominantly metabolised through CYP3A4/5, with a narrow therapeutic window
23. Randomised study phase : Patient has known hypersensitivity to any of the study treatment excipients, in particular patients with allergies to soya or peanuts.
24. Randomised study phase : Patient is or plans to participate in another interventional therapeutic clinical trial. Concurrent participation in an observational study is acceptable.
25. Randomised study phase : Patient has malignancies, other than that under study, except for adequately treated conebiopsied in situ carcinoma of the cervix and basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, with no evidence of relapse/recurrence within ≥5 years, and at negligible risk for recurrence are eligible for the study.
26. Randomised study phase : Patient has any condition/disease, for which the investigator considers that participating in the trial is inappropriate or that may jeopardize treatment and protocol compliance.
27. Randomised study phase : Patient deprived of liberty or under the authority of a tutor.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the progression free survival (PFS).

Secondary endpoints 8

1. Efficacy endpoint for randomised patients - Overall survival (OS): OS is defined as the time interval between the date of randomisation and the date of death, from any cause. Patients still alive at the cut-off time (including lost to follow-up) will be censored at the last known alive date.
2. Efficacy endpoint for randomised patients - Objective response Rate (ORR): ORR will be assessed by the investigators using RECIST V1.1and is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) during treatment.
3. Efficacy endpoint for randomised patients - Duration of response (DoR) is defined as the time interval from the date of first documented CR or PR to the date of first documented disease progression or death, from any cause. Patients without progression at the cut-off date will be censored at the last tumour assessment date.
4. Efficacy endpoint for randomised patients - Clinical Benefit Rate (CBR): CBR will be and assessed by the investigators using RECIST v1.1. and is defined as the proportion of patients with a best overall response of complete response (CR), partial response (PR) or stable disease during treatment.
5. Efficacy endpoint for randomised patients - Time to Response (TTR): TTR is defined, for subjects with an OR according to RECIST v1.1, as the time from randomisation to the first documentation of OR which is subsequently confirmed.
6. Efficacy endpoint for non-randomised patients - Overall survival (OS): OS is defined as the time interval between the date of initiation of standard of care and the date of death, from any cause. Patients still alive at the cut-off time (including lost to follow-up) will be censored at the last known alive date.
7. Efficacy endpoint for non-randomised patients - Progression Free Survival (PFS): PFS is defined as the time interval between the date of initiation of standard of care to the date of the first documented disease progression or death, whatever the cause. The tumour assessments are made by the investigators and based on RECIST 1.1
8. Safety endpoint is the assessment of the incidences of adverse events, graded by NCI CTC-AE v5.

Investigational products

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

Test 5

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris Cedex 13

Postcode

75654

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Director of Regulatory Affairs, Quality and Pharmacovigilance

Public contact point

Organisation

Unicancer

Contact name

Director of Regulatory Affairs, Quality and Pharmacovigilance

Locations

1 EU/EEA country · 45 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 7 files

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

Application history

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