Breast Cancer Stage IV
Conditions
Keywords
metastatic Breast Cancer, HER2-, RH+, PIK3CA mutated
Brief summary
After an initial screening phase (SAFIR 03 - SCREENING) to identify patients with blood circulating mutated-PIK3CA tumours persistent, patients will be enrolled in the treatment phase of SAFIR 03 (SAFIR 03 - ARRIBA) that was designed as a randomised, open-label, multicentre, phase II study, for comparison of alpelisib to ribociclib in combination with fulvestrant (as the continuation of the CDK4/6 inhibitor-fulvestrant strategy) in terms of progression-free survival (PFS).
Detailed description
INDICATION The population eligible to the screening phase is composed of all women or men with HR+, HER2- metastatic breast cancer who are eligible for first-line treatment with a cyclin-dependent kinases (CDK) 4/6 inhibitor combined with fulvestrant (and a luteinizing hormone realeasing hormone (LH-RH) analogue in men and premenopausal women) in the context of the standard healthcare management. The screening will identify patients with high risk of relapse on any CDK4/6 inhibitor thanks to ctDNA kinetic between baseline and 4 weeks of treatment. The purpose is to early adapt the therapeutic intervention for ctDNA no drop patient to prevent from relapse. This study will propose an intervention for PIK3CA mutated patients with alpelisib vs. ribociclib. Other therapeutic approaches might be proposed to patients with wild type PIK3CA through other protocols. The randomised study phase will include patients with persistent mutations on exons 4, 9 or 20\* of PIK3CA ctDNA after 4 weeks of treatment with any CDK4/6 inhibitor-fulvestrant in first-line setting.
Interventions
DRUGAlpelisib
Alpelisib 300 mg once daily + fulvestrant 500 mg every 28 days
DRUGRibociclib
Ribocilcib 600 mg once daily 3 weeks on/1 week off + fulvestrant 500 mg every 28 days
Sponsors
Novartis
Breast Cancer Research Foundation
UNICANCER
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
After an initial screening phase (SAFIR 03 - SCREENING) to identify patients with blood circulating mutated-PIK3CA tumours persistent, patients will be enrolled in the treatment phase of SAFIR 03 (SAFIR 03 - ARRIBA) that was designed as a randomised, open-label, multicentre, phase II study, for comparison of alpelisib to ribociclib in combination with fulvestrant (as the continuation of the CDK4/6 inhibitor-fulvestrant strategy)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
SCREENING PHASE (SAFIR 03 - SCREENING) Inclusion Criteria: 1. 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. Patient is ≥18 years of age. 3. Patient has an histologically or cytologically confirmed metastatic breast cancer. 4. Patient has a HER2- breast cancer (without HER2 overexpression according to the ASCO-CAP 2018 guidelines). 5. 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. Patient had a metastatic relapse during or within 1 year after termination of the adjuvant endocrine therapy. 7. Patient has not yet been treated in the metastatic breast cancer setting. 8. 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. Eastern Cooperative Oncology Group (ECOG) performance status is ≤1. 10. Patient has an adequate bone marrow and organ function. 11. Measurable or evaluable disease according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1). 12. 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. Patient must be affiliated to the national social security (or equivalent).
Exclusion criteria
1. Prior exposure to PIK3CA-AKT or CDK4/6 inhibitors. 2. Patient that has initiated the CDK4/6 inhibitor treatment. 3. 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. Participant with an established diagnosis of diabetes mellitus type I or not controlled type II (based on FG and HbA1c). 5. Patient unable to swallow tablets. 6. Patient with known hypersensitivity to any of the study treatment excipients, in particular patients with allergies to soya or peanuts. 7. 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. 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. Patient deprived of liberty or under the authority of a tutor. RANDOMISED PHASE ( SAFIR 03 -ARRIBA) Inclusion Criteria: 1. 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). 2. Patient has a circulating PIK3CA level of exon 4, 9 or 20 mutant\* of PIK3CA ctDNA determined by circulating tumour DNA (ctDNA) assay after 4 weeks of treatment with any CDK4/6 inhibitor combined with fulvestrant. 3. Patient must have discontinued CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) at least 7 days before randomisation. 4. ECOG performance status is ≤1. 5. Patient's life expectancy is deemed ≥3 months. 6. Patient has an adequate bone marrow and organ function as defined by the following laboratory values: * Absolute neutrophil count (ANC) ≥1500/mm³, * Platelet count ≥100,000/mm³, * Haemoglobin ≥9.0 g/dL, * International normalised ratio (INR) ≤1.5 (unless the participant is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study drug), * Serum creatinine ≤1.5 × upper limit of normal (ULN) or creatinine clearance ≥50 mL/min, * Total bilirubin ≤2× ULN (\<3 ULN with documented Gilbert's disease) or direct bilirubin ≤ 1.5 × ULN, * aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN, or \<5.0 x ULN if patient has liver metastasis, * Fasting Serum amylase ≤ 2 × ULN, * Fasting Serum lipase ≤ ULN, * Fasting plasma glucose (FPG) ≤140 mg/dL (or ≤7.7 mmol/L) and glycosylated haemoglobin (HbA1c) ≤6.4%. 7. Participant must have the following laboratory values within normal limits or corrected to within normal limits with supplements before randomisation * Potassium * Magnesium * Total Calcium (corrected for serum albumin) 8. Patient with parameters of standard 12-lead ECG (defined as the mean of triplicate ECGs performed) as follows, before randomisation: * QTcF interval \<450ms (using Fridericia's correction), * Resting heart rate between 50-90 bpm. 9. Women of childbearing potential must have a negative serum pregnancy test result within 14 days of enrolment in the randomised trial phase. 10. 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. 11. 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. * Also numbered exon 5, 10 and 21 according to recent classification: Ensembl Transcript ID: ENST00000263967.4, RefSeq: NM\_006218.4.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival in the study groups | From randomization to disease progression or death, up to 5 years | The PFS is the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate in the study groups | 5 years | Clinical benefit rate (CBR) is defined as the proportion of patients with a best overall response of CR, PR, or stable disease during treatment. |
| Overall Survival in the study groups | From randomization to death, up to 5 years | Overall survival (OS) is the length of time from randomization that patients enrolled in the study are still alive. |
| Objective response Rate (ORR) in the study groups | 5 years | Objective response rate (ORR) is the percentage of patients with a best response during treatment being either complete response (CR) or partial response (PR). |
| Time to Response in the study groups | From randomization to death, up to 5 years | Time to response (TTR) is defined, for subjects with an objective response (OR), as the time from randomisation to the first documentation of OR which is subsequently confirmed. |
| Duration of response in the study groups | 5 years | 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. |
| Safety in each study groups. | Throughout study completion, up to 5 years | The National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, and 5 = death) determined by the investigator, will make it possible to assess the severity of the disorders. |
| Overall Survival (OS) in non-randomised patients | From the date of initiation of standard of care to death of any cause, up to 5 years | For non-randomised patients, OS is the length of time from the date of initiation of standard of care that patients enrolled in the study are still alive. |
| Progression Free Survival (PFS) in non-randomised patients | From randomization to death, up to 5 years | For non-randomised patients, PFS is the length of time during and after the treatment of a disease with the standard of care that a patient lives with the disease but it does not get worse. |
| To validate that randomised patients with residual PIK3CA on ctDNA present a poor outcome compare to non-randomised patient | From the date of initiation of standard of care to death, up to 5 years | For this outcome, 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. |
Countries
France
Outcome results
None listed