Informations générales (source: ClinicalTrials.gov)
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 (SAFIR 03)
Interventional
Phase 2
UNICANCER (Voir sur ClinicalTrials)
octobre 2023
juin 2030
05 avril 2025
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).
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT GUSTAVE ROUSSY | Joana Mourato RIBEIRO | 16/04/2024 07:02:14 | Contacter | ||
| HOPITAL NOVO | NGUEFACK Rolande | 14/02/2025 09:03:20 | Contacter | ||
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| CH DE VERSAILLES SITE ANDRE MIGNOT | Sophie BARTHIER, Dr | Contact (sur clinicalTrials) | |||
| GRPE HOSP DIACONESSES-CROIX ST-SIMON | Laura HIRSCH, Dr | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Antoine Lacassagne - 06189 - Nice - France | Caroline BAILLEUX, Dr | Contact (sur clinicalTrials) | |||
| Centre Eugène Marquis - 35042 - Rennes Cedex - France | Fanny LE DU, Dr | Contact (sur clinicalTrials) | |||
| Centre François Baclesse - 14000 - Caen - France | George EMILE, Dr | Contact (sur clinicalTrials) | |||
| Centre Hospitalier Alpes Léman - 74130 - Contamine-sur-Arve - France | Mansour RASTKHAH, Dr | Contact (sur clinicalTrials) | |||
| Centre Hospitalier d'Auxerre - 89000 - Auxerre - France | Adina MARTI, Dr | Contact (sur clinicalTrials) | |||
| Centre Hospitalier de Beauvais - 60021 - Beauvais - France | Hanifa AMMARGUELLAT, Dr | Contact (sur clinicalTrials) | |||
| Centre Hospitalier de Boulogne-sur-Mer - 62321 - Boulogne-sur-Mer - France | Abeer NAJEM, Dr | Contact (sur clinicalTrials) | |||
| Centre Hospitalier de Cholet - 49300 - Cholet - France | Victor SIMMET, Dr | Contact (sur clinicalTrials) | |||
| Centre Hospitalier de la Côte Basque - 64100 - Bayonne - France | Thomas GRELLETY, Dr | Contact (sur clinicalTrials) | |||
| Centre Hospitalier de Pau - 64046 - Pau - France | Kévin BOURCIER, Dr | Contact (sur clinicalTrials) | |||
| Centre Hospitalier William Morey - 71100 - Chalon-sur-Saône - France | Thomas COLLOT, Dr | Contact (sur clinicalTrials) | |||
| Centre Jean Perrin - 63011 - Clermont-Ferrand - France | Xavier DURANDO, Pr | Contact (sur clinicalTrials) | |||
| Centre Léon Bérard - 69008 - Lyon - France | Thomas BACHELOT, Dr | Contact (sur clinicalTrials) | |||
| CHD Vendée - 85925 - La Roche-sur-Yon - France | Céline BIHAN, Dr | Contact (sur clinicalTrials) | |||
| CHI Fréjus-Saint-Raphaël - 83608 - Fréjus - France | Jean-François PAITEL, Dr | Contact (sur clinicalTrials) | |||
| CHP Saint-Grégoire - Groupe Vivalto Santé - 35760 - Saint-Grégoire - France | Romuald LE SCODAN, Dr | Contact (sur clinicalTrials) | |||
| CHRU Morvan - 29200 - Brest - France | Laura DEIANA, Dr | Contact (sur clinicalTrials) | |||
| CHU Amiens Picardie - 80054 - Amiens Cedex 1 - France | Aurélie MOREIRA, Dr | Contact (sur clinicalTrials) | |||
| Clinique de Flandre - 59210 - Coudekerque Branche - France | Jean-Baptiste AISENFARB, Dr | Contact (sur clinicalTrials) | |||
| Clinique de la Sauvegarde - 69009 - Lyon - France | Yann MOLIN, Dr | Contact (sur clinicalTrials) | |||
| Clinique de l'Europe Amiens - CTHE - 80090 - Amiens - France | David DEFEVER, Dr | Contact (sur clinicalTrials) | |||
| Clinique Hartmann - 92200 - Neuilly-sur-Seine - France | Jean-Michel VANNETZEL, Dr | Contact (sur clinicalTrials) | |||
| Clinique Pasteur Lanroze - CFRO - Groupe Vivalto Santé - 29200 - Brest - France | Matthieu CHASSERAY, Dr | Contact (sur clinicalTrials) | |||
| Clinique Sainte-Anne - GH Saint-Vincent - 67000 - Strasbourg - France | Youssef TAZI, Dr | Contact (sur clinicalTrials) | |||
| Groupe Hospitalier Mutualiste de Grenoble (GHMG) - 38028 - Grenoble Cedex 1 - France | Elise BONNET, Dr | Contact (sur clinicalTrials) | |||
| Hôpital Privé des Côtes-d'Armor (HPCA) - Cario - 22190 - Plérin - France | Jérôme MARTIN-BABAU, Dr | Contact (sur clinicalTrials) | |||
| Hôpital privé Jean Mermoz - 69008 - Lyon - France | Olfa DERBEL MILED, Dr | Contact (sur clinicalTrials) | |||
| Hôpital Saint-Louis - 75010 - Paris - France | Delphine COCHEREAU, Dr | Contact (sur clinicalTrials) | |||
| Hôpital Simone Veil de Blois - 41000 - Blois - France | Olivier ARSENE, Dr | Contact (sur clinicalTrials) | |||
| Hôpitaux du Léman - 74200 - Thonon-les-Bains - France | Fanny POMMERET, Dr | Contact (sur clinicalTrials) | |||
| ICM Val d'Aurelle - 34298 - Montpellier - France | William JACOT, Pr | Contact (sur clinicalTrials) | |||
| Institut Bergonié - 33000 - Bordeaux - France | Monica ARNEDOS, Dr | Contact (sur clinicalTrials) | |||
| Institut Claudius Regaud - IUCT-O - 31059 - Toulouse - France | Florence DALENC, Dr | Contact (sur clinicalTrials) | |||
| Institut de Cancérologie de Lorraine - 54519 - Vandœuvre-lès-Nancy - France | Vincent MASSARD, Dr | Contact (sur clinicalTrials) | |||
| Institut Godinot - 51100 - Reims - France | Pauline SOIBINET-OUDOT, Dr | Contact (sur clinicalTrials) | |||
| Institut Paoli Calmettes - 13009 - Marseille - France | Anthony GONCALVES, Pr | Contact (sur clinicalTrials) | |||
| Medipôle de Nancy - COG-ILC (Polyclinique de Gentilly) - 54100 - Nancy - France | Laurene GAVOILLE, Dr | Contact (sur clinicalTrials) | |||
| Pôle Santé République (ELSAN) - 63000 - Clermont-Ferrand - France | Pierre DALLOZ, Dr | Contact (sur clinicalTrials) | |||
| Polyclinique de Limoges - Site François Chénieux - 87000 - Limoges - France | Dominique GENET, Dr | Contact (sur clinicalTrials) | |||
| Sainte Catherine Institut du Cancer Avignon Provence - 84918 - Avignon - France | Bertrand BILLEMONT, Dr | Contact (sur clinicalTrials) | |||
Critères
Tous
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.
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.