Clinical trial NCT05625087: Detection of Tumor DNA in the Blood of Patients Receiving Standard Therapy for Hormone Receptor-positive (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
Official title: A ctDNA Screening Program in Patients With HR+, HER2- Metastatic Breast Cancer for Detection of High-risk Relapse Patients on Any CDK4/6 Inhibitor and a Randomised Phase II Study Comparing Alpelisib Combined With Fulvestrant to Ribociclib Combined With Fulvestrant, in Patients With Persistent Targetable PIK3CA Mutations
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Breast Cancer Stage IV
Keywords: metastatic Breast Cancer
HER2-
RH+
PIK3CA mutated
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: Novartis
name: Breast Cancer Research Foundation
First posted: 2022-11-22
Enrollment: 162
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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)
Primary purpose: TREATMENT

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.

Eligibility 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.

Exclusion Criteria:

1. Patient is eligible to chemotherapy because of visceral crisis.
2. Pregnant or lactating women.
3. Patient has received more than 2 cycles of the ongoing CDK4/6 inhibitor treatment combined with fulvestrant before randomisation.
4. Patient has interrupted the ongoing CDK4/6 inhibitor treatment for more than 14 days before randomisation.
5. Patient has evidence of clinical or radiological disease progression before randomisation.
6. 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.
7. 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).
8. 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).
9. 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)
10. Participant with unresolved osteonecrosis of the jaw.
11. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormalities including any of the following:

    * Uncontrolled hypertension,
    * Symptomatic congestive heart failure: New York Heart Association (NYHA) class ≥2,
    * Unstable angina pectoris,
    * Stroke or myocardial infarction within the 6 months before randomisation,
    * Serious cardiac arrhythmia requiring treatment, except treated atrial fibrillation and paroxysmal supraventricular tachycardia, or conduction abnormality for which the patient is no longer at risk of serious arrhythmia (e.g., Patient with Wolff-Parkinson-White syndrome treated with surgical ablation),
    * Left ventricular ejection fraction (LVEF) \<50% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) before randomisation.
    * Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following before randomisation:

      * Presence of risk factors for Torsades de Pointe, including uncorrected hypokalaemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia,
      * Concomitant use of medication(s) known to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued (within 5 half-lives or 7 days prior to initiating the study treatment) or cannot be replaced by a safe alternative,
      * Unable to determine the QTcF (using Fridericia's correction),
    * Systolic blood pressure (SBP) \>160 mmHg or \<90 mmHg.
12. 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
13. 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,
14. Patient has known hypersensitivity to any of the study treatment excipients, in particular patients with allergies to soya or peanuts.
15. Patient is or plans to participate in another interventional therapeutic clinical trial. Concurrent participation in an observational study is acceptable.
16. Patient has malignancies, other than that under study, except for adequately treated cone-biopsied 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.
17. 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.
18. Patient deprived of liberty or under the authority of a tutor.

Primary outcomes:
measure: Progression-Free Survival in the study groups
timeFrame: From randomization to disease progression or death, up to 5 years
Secondary outcomes:
measure: Overall Survival in the study groups
timeFrame: From randomization to death, up to 5 years
measure: Objective response Rate (ORR) in the study groups
timeFrame: 5 years
measure: Duration of response in the study groups
timeFrame: 5 years
measure: Clinical Benefit Rate in the study groups
timeFrame: 5 years
measure: Time to Response in the study groups
timeFrame: From randomization to death, up to 5 years
measure: To validate that randomised patients with residual PIK3CA on ctDNA present a poor outcome compare to non-randomised patient
timeFrame: From the date of initiation of standard of care to death, up to 5 years
measure: Safety in each study groups.
timeFrame: Throughout study completion, up to 5 years
measure: Overall Survival (OS) in non-randomised patients
timeFrame: From the date of initiation of standard of care to death of any cause, up to 5 years
measure: Progression Free Survival (PFS) in non-randomised patients
timeFrame: From randomization to death, up to 5 years
Other outcomes:
Locations:
city: Amiens Cedex 1
country: France
facility: CHU Amiens Picardie
city: Amiens
country: France
facility: Clinique de l'Europe Amiens - CTHE
city: Auxerre
country: France
facility: Centre Hospitalier d'Auxerre
city: Avignon
country: France
facility: Sainte Catherine Institut du Cancer Avignon Provence
city: Bayonne
country: France
facility: Centre Hospitalier de la Côte Basque
city: Beauvais
country: France
facility: Centre Hospitalier de Beauvais
city: Blois
country: France
facility: Hôpital Simone Veil de Blois
city: Bordeaux
country: France
facility: Institut Bergonié
city: Boulogne-sur-Mer
country: France
facility: Centre Hospitalier de Boulogne-sur-Mer
city: Brest
country: France
facility: CHRU Morvan
city: Brest
country: France
facility: Clinique Pasteur Lanroze - CFRO - Groupe Vivalto Santé
city: Caen
country: France
facility: Centre François Baclesse
city: Cergy-Pontoise Cedex
country: France
facility: Hôpital NOVO
city: Chalon-sur-Saône
country: France
facility: Centre Hospitalier William Morey
city: Cholet
country: France
facility: Centre Hospitalier de Cholet
city: Clermont-Ferrand
country: France
facility: Pôle Santé République (ELSAN)
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Contamine-sur-Arve
country: France
facility: Centre Hospitalier Alpes Léman
city: Coudekerque Branche
country: France
facility: Clinique de Flandre
city: Fréjus
country: France
facility: CHI Fréjus-Saint-Raphaël
city: Grenoble Cedex 1
country: France
facility: Groupe Hospitalier Mutualiste de Grenoble (GHMG)
city: La Roche-sur-Yon
country: France
facility: CHD Vendée
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles - Hôpital André Mignot
city: Limoges
country: France
facility: Polyclinique de Limoges - Site François Chénieux
city: Lyon
country: France
facility: Centre Léon Bérard
city: Lyon
country: France
facility: Hôpital privé Jean Mermoz
city: Lyon
country: France
facility: Clinique de la Sauvegarde
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Montpellier
country: France
facility: ICM Val d'Aurelle
city: Nancy
country: France
facility: Medipôle de Nancy - COG-ILC (Polyclinique de Gentilly)
city: Neuilly-sur-Seine
country: France
facility: Clinique Hartmann
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Paris
country: France
facility: Groupe Hospitalier Diaconesses Croix Saint-Simon
city: Pau
country: France
facility: Centre Hospitalier de Pau
city: Plérin
country: France
facility: Hôpital Privé des Côtes-d'Armor (HPCA) - Cario
city: Reims
country: France
facility: Institut Godinot
city: Rennes Cedex
country: France
facility: Centre Eugène Marquis
city: Saint-Grégoire
country: France
facility: CHP Saint-Grégoire - Groupe Vivalto Santé
city: Strasbourg
country: France
facility: Clinique Sainte-Anne - GH Saint-Vincent
city: Thonon-les-Bains
country: France
facility: Hôpitaux du Léman
city: Toulouse
country: France
facility: Institut Claudius Regaud - IUCT-O
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Gustave Roussy
Study officials:
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
name: Fabrice ANDRE
role: PRINCIPAL_INVESTIGATOR
References: