Trial Title:
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
NCT ID:
NCT05625087
Condition:
Breast Cancer Stage IV
Conditions: Official terms:
Breast Neoplasms
Fulvestrant
Conditions: Keywords:
metastatic Breast Cancer
HER2-
RH+
PIK3CA mutated
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
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
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Alpelisib
Description:
Alpelisib 300 mg once daily + fulvestrant 500 mg every 28 days
Arm group label:
ALPELISIB ARM
Other name:
Fulvestrant
Intervention type:
Drug
Intervention name:
Ribociclib
Description:
Ribocilcib 600 mg once daily 3 weeks on/1 week off + fulvestrant 500 mg every 28 days
Arm group label:
RIBOCICLIB ARM
Other name:
Fulvestrant
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.
Criteria for 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.
Gender:
All
Gender based:
Yes
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
CHU Amiens Picardie
Address:
City:
Amiens Cedex 1
Zip:
80054
Country:
France
Status:
Recruiting
Contact:
Last name:
Aurélie MOREIRA, Dr
Facility:
Name:
Clinique de l'Europe Amiens - CTHE
Address:
City:
Amiens
Zip:
80090
Country:
France
Status:
Recruiting
Contact:
Last name:
Khadija KALAI, Dr
Facility:
Name:
Centre Hospitalier d'Auxerre
Address:
City:
Auxerre
Zip:
89000
Country:
France
Status:
Recruiting
Contact:
Last name:
Adina MARTI, Dr
Facility:
Name:
Sainte Catherine Institut du Cancer Avignon Provence
Address:
City:
Avignon
Zip:
84918
Country:
France
Status:
Recruiting
Contact:
Last name:
Bertrand BILLEMONT, Dr
Facility:
Name:
Centre Hospitalier de la Côte Basque
Address:
City:
Bayonne
Zip:
64100
Country:
France
Status:
Recruiting
Contact:
Last name:
Thomas GRELLETY, Dr
Facility:
Name:
Centre Hospitalier de Beauvais
Address:
City:
Beauvais
Zip:
60021
Country:
France
Status:
Recruiting
Contact:
Last name:
Hanifa AMMARGUELLAT, Dr
Facility:
Name:
Hôpital Simone Veil de Blois
Address:
City:
Blois
Zip:
41000
Country:
France
Status:
Recruiting
Contact:
Last name:
Olivier ARSENE, Dr
Facility:
Name:
Institut Bergonié
Address:
City:
Bordeaux
Zip:
33000
Country:
France
Status:
Recruiting
Contact:
Last name:
Monica ARNEDOS, Dr
Facility:
Name:
Centre Hospitalier de Boulogne-sur-Mer
Address:
City:
Boulogne-sur-Mer
Zip:
62321
Country:
France
Status:
Recruiting
Contact:
Last name:
Abeer NAJEM, Dr
Facility:
Name:
CHRU Morvan
Address:
City:
Brest
Zip:
29200
Country:
France
Status:
Recruiting
Contact:
Last name:
Laura DEIANA, Dr
Facility:
Name:
Clinique Pasteur Lanroze - CFRO - Groupe Vivalto Santé
Address:
City:
Brest
Zip:
29200
Country:
France
Status:
Recruiting
Contact:
Last name:
Brigitte LUCAS, Dr
Facility:
Name:
Centre François Baclesse
Address:
City:
Caen
Zip:
14000
Country:
France
Status:
Recruiting
Contact:
Last name:
George EMILE, Dr
Facility:
Name:
Hôpital NOVO
Address:
City:
Cergy-Pontoise Cedex
Zip:
95303
Country:
France
Status:
Recruiting
Contact:
Last name:
Rolande NGUEFACK, Dr
Facility:
Name:
Centre Hospitalier William Morey
Address:
City:
Chalon-sur-Saône
Zip:
71100
Country:
France
Status:
Recruiting
Contact:
Last name:
Thomas COLLOT, Dr
Facility:
Name:
Centre Hospitalier de Cholet
Address:
City:
Cholet
Zip:
49300
Country:
France
Status:
Recruiting
Contact:
Last name:
Victor SIMMET, Dr
Facility:
Name:
Pôle Santé République (ELSAN)
Address:
City:
Clermont-Ferrand
Zip:
63000
Country:
France
Status:
Recruiting
Contact:
Last name:
Pierre DALLOZ, Dr
Facility:
Name:
Centre Jean Perrin
Address:
City:
Clermont-Ferrand
Zip:
63011
Country:
France
Status:
Recruiting
Contact:
Last name:
Xavier DURANDO, Pr
Facility:
Name:
Centre Hospitalier Alpes Léman
Address:
City:
Contamine-sur-Arve
Zip:
74130
Country:
France
Status:
Recruiting
Contact:
Last name:
Mansour RASTKHAH, Dr
Facility:
Name:
CHI Fréjus-Saint-Raphaël
Address:
City:
Fréjus
Zip:
83608
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Jean-François PAITEL, Dr
Facility:
Name:
Groupe Hospitalier Mutualiste de Grenoble (GHMG)
Address:
City:
Grenoble Cedex 1
Zip:
38028
Country:
France
Status:
Recruiting
Contact:
Last name:
Elise BONNET, Dr
Facility:
Name:
CHD Vendée
Address:
City:
La Roche-sur-Yon
Zip:
85925
Country:
France
Status:
Recruiting
Contact:
Last name:
Céline BIHAN, Dr
Facility:
Name:
Centre Hospitalier de Versailles - Hôpital André Mignot
Address:
City:
Le Chesnay
Zip:
78150
Country:
France
Status:
Recruiting
Contact:
Last name:
Sophie BARTHIER, Dr
Facility:
Name:
Polyclinique de Limoges - Site François Chénieux
Address:
City:
Limoges
Zip:
87000
Country:
France
Status:
Recruiting
Contact:
Last name:
Dominique GENET, Dr
Facility:
Name:
Centre Léon Bérard
Address:
City:
Lyon
Zip:
69008
Country:
France
Status:
Recruiting
Contact:
Last name:
Thomas BACHELOT, Dr
Facility:
Name:
Hôpital privé Jean Mermoz
Address:
City:
Lyon
Zip:
69008
Country:
France
Status:
Recruiting
Contact:
Last name:
Olfa DERBEL MILED, Dr
Facility:
Name:
Clinique de la Sauvegarde
Address:
City:
Lyon
Zip:
69009
Country:
France
Status:
Recruiting
Contact:
Last name:
Yann MOLIN, Dr
Facility:
Name:
Institut Paoli Calmettes
Address:
City:
Marseille
Zip:
13009
Country:
France
Status:
Recruiting
Contact:
Last name:
Anthony GONCALVES, Pr
Facility:
Name:
ICM Val d'Aurelle
Address:
City:
Montpellier
Zip:
34298
Country:
France
Status:
Recruiting
Contact:
Last name:
William JACOT, Pr
Facility:
Name:
Medipôle de Nancy - COG-ILC (Polyclinique de Gentilly)
Address:
City:
Nancy
Zip:
54100
Country:
France
Status:
Recruiting
Contact:
Last name:
Laurene GAVOILLE, Dr
Facility:
Name:
Clinique Hartmann
Address:
City:
Neuilly-sur-Seine
Zip:
92200
Country:
France
Status:
Recruiting
Contact:
Last name:
Jean-Michel VANNETZEL, Dr
Facility:
Name:
Centre Antoine Lacassagne
Address:
City:
Nice
Zip:
06189
Country:
France
Status:
Recruiting
Contact:
Last name:
Caroline BAILLEUX, Dr
Facility:
Name:
Hôpital Saint-Louis
Address:
City:
Paris
Zip:
75010
Country:
France
Status:
Recruiting
Contact:
Last name:
Luis TEIXEIRA, Pr
Facility:
Name:
Groupe Hospitalier Diaconesses Croix Saint-Simon
Address:
City:
Paris
Zip:
75020
Country:
France
Status:
Recruiting
Contact:
Last name:
Laura HIRSCH, Dr
Facility:
Name:
Centre Hospitalier de Pau
Address:
City:
Pau
Zip:
64046
Country:
France
Status:
Recruiting
Contact:
Last name:
Kévin BOURCIER, Dr
Facility:
Name:
Hôpital Privé des Côtes-d'Armor (HPCA) - Cario
Address:
City:
Plérin
Zip:
22190
Country:
France
Status:
Recruiting
Contact:
Last name:
Jérôme MARTIN-BABAU, Dr
Facility:
Name:
Institut Godinot
Address:
City:
Reims
Zip:
51100
Country:
France
Status:
Recruiting
Contact:
Last name:
Pauline SOIBINET-OUDOT, Dr
Facility:
Name:
Centre Eugène Marquis
Address:
City:
Rennes Cedex
Zip:
35042
Country:
France
Status:
Recruiting
Contact:
Last name:
Fanny LE DU, Dr
Facility:
Name:
CHP Saint-Grégoire - Groupe Vivalto Santé
Address:
City:
Saint-Grégoire
Zip:
35760
Country:
France
Status:
Recruiting
Contact:
Last name:
Romuald LE SCODAN, Dr
Facility:
Name:
Clinique Sainte-Anne - GH Saint-Vincent
Address:
City:
Strasbourg
Zip:
67000
Country:
France
Status:
Recruiting
Contact:
Last name:
Youssef TAZI, Dr
Facility:
Name:
Hôpitaux du Léman
Address:
City:
Thonon-les-Bains
Zip:
74200
Country:
France
Status:
Recruiting
Contact:
Last name:
Fanny POMMERET, Dr
Facility:
Name:
Institut Claudius Regaud - IUCT-O
Address:
City:
Toulouse
Zip:
31059
Country:
France
Status:
Recruiting
Contact:
Last name:
Florence DALENC, Dr
Facility:
Name:
Institut de Cancérologie de Lorraine
Address:
City:
Vandœuvre-lès-Nancy
Zip:
54519
Country:
France
Status:
Recruiting
Contact:
Last name:
Vincent MASSARD, Dr
Facility:
Name:
Gustave Roussy
Address:
City:
Villejuif
Zip:
94805
Country:
France
Status:
Recruiting
Contact:
Last name:
Joana MOURATO-RIBEIRO, Dr
Start date:
October 19, 2023
Completion date:
June 2030
Lead sponsor:
Agency:
UNICANCER
Agency class:
Other
Collaborator:
Agency:
Novartis
Agency class:
Industry
Collaborator:
Agency:
Breast Cancer Research Foundation
Agency class:
Other
Source:
UNICANCER
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05625087
