Condition médicale (spécialité visée)
Choix aire thérapeutique
Cancérologie / Radio-oncologie/ tumeurs solides
Stades de cancer
Avancé
Biomarqueur
Autre :
PIK3CA
Profil des participants
Sexe(s) des participants
Tous
Critères de sélection
Critères d'inclusion
1. Adults ≥18 years of age and meet one of the following criteria:
a. Women who are postmenopausal, defined as one of the following:
i. Women 18–59 years of age (at the time of consent) with cessation of regular menses for at least 12 consecutive months with no alternative
pathological or physiological cause, and serum estradiol and follicle-stimulating hormone (FSH) level within the laboratory’s reference range
for postmenopausal females
ii. Women ≥60 years of age (at the time of consent) with cessation of menses for at least 12 consecutive months
iii. Documented bilateral oophorectomy
iv. Medically confirmed ovarian failure
b. Pre/perimenopausal women with medically-induced menopause by treatment with the luteinizing hormone-releasing hormone (LHRH)
agonist goserelin, the gonadotropin releasing hormone (GnRH) agonist leuprolide (Lupron Depot), or equivalent agents to induce chemical
menopause
c. Male subjects must use an effective and/or acceptable contraceptive method from screening until 1 year after the last dose of study
treatment
2. Negative pregnancy test for women of childbearing potential. Female subjects of childbearing potential must use an effective and/or acceptable
contraceptive method from screening until 1 year after the last dose of study treatment
3. Histologically or cytologically confirmed diagnosis of metastatic or locally advanced breast cancer
4. Confirmed diagnosis of estrogen receptor positive and/or progesterone receptor positive, as per American Society of Clinical Oncology/College
of American Pathologists (ASCO-CAP) guidelines (2020), based on most recent tumor biopsy utilizing an assay consistent with local standards
5. Documented HER2 immunohistochemistry (IHC) negative as per ASCO-CAP 2018 guidance (Wolff 2018); if result by IHC is +2 (equivocal), an in
situ hybridization test must be performed
6. Adequate archival or fresh tumor tissue for the analysis of PIK3CA mutational status by Therascreen®PIK3CA RGQ PCR test and identified
PIK3CA status (mutant or non-mutant)
a. If archival tissue is not available and a tumor biopsy is not possible, a liquid biopsy will be used in consultation with the Sponsor’s Medical
Monitor or designee
b. Patients with confirmed PIK3CA MT are eligible for treatment with alpelisib in combination with fulvestrant (per PIQRAY® USPI, SmPC) and will
be assigned to Study 2
c. All other patients who do not have confirmed PIK3CA MT will be assigned to Study 1
7. Subject must have documentation of radiological disease progression on or after the last prior treatment and also have radiologically evaluable
disease (measurable and/or non-measurable) according to RECIST v1.1, per local assessment
a. Prior radiotherapy ≤3 months before randomization; the lesion must either be outside the field of prior radiotherapy or have documented
progression following radiation therapy
b. Subjects with bone only disease must have lytic or mixed lytic/blastic lesions that can be accurately assessed; bone only blastic lesions with
no soft tissue component is not allowed
c. Completely necrotic or cavitated lesions are not allowed
d. Truly non-measurable disease as per RECIST v1.1 criteria (e.g., effusion/ascites) is not allowed
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0–1
9. Life expectancy of at least 3 months
10. Progressed during or after CDK4/6 inhibitor combination treatment with non-steroidal aromatase inhibitor (AI)
11. Resolution of all toxicities related to prior therapies or surgical procedures to NCI CTCAE v.5.0 Grade ≤1 (except alopecia)
12. Left ventricular ejection fraction ≥50% at baseline
13. At least 2 weeks beyond treatment with a targeted therapy or major surgery and at least 3 weeks beyond immunotherapy and/or radiation
therapy and recovered from all acute toxicities prior to randomization (adverse events [AEs] from prior anticancer agents recovered to Grade ≤1
or lower; except alopecia)
14. Adequate bone marrow, hepatic, renal and coagulation function as defined by the following:
a. Absolute neutrophil count ≥1.5 × 109/L
b. Hemoglobin ≥9.0 g/dL (90 g/L)
c. Platelets ≥100 × 109/L
d. HbA1c ≤6.4% and fasting plasma glucose (FPG) ≤140 mg/dL
e. Potassium within normal limits, or corrected with supplements
f. Calcium (corrected for serum albumin) and magnesium within normal limits or Grade ≤1 if judged clinically not significant by the Investigator
g. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) (if no hepatic metastases); if hepatic
tumor involvement, AST and ALT ≤5 × ULN
h. Total bilirubin ≤1.5 × ULN (total bilirubin≤3.0 × ULN and direct bilirubin ≤1.5 × ULN in patients with Gilbert’s Syndrome)
i. Serum amylase ≤1.5 × ULN (subjects with values >1.5 × ULN may be allowed if there are no clinical and radiological signs of pancreatitis)
j. Serum lipase ≤ 1.5 × ULN (subjects with values >1.5 × ULN may be allowed if there are no clinical and radiological signs of pancreatitis)
k. Prothrombin time (PT)/International Normalized Ratio (INR) ≤1.5 × ULN if not on anticoagulants
l. Calculated creatinine clearance (CrCL) >50 mL/min using the Cockcroft and Gault equation:
15. Must be willing and able to comply with protocol-specified schedules of assessments, treatment plans, laboratory tests, and other study
procedures
16. Ability to understand the investigational nature of the study and sign the informed consent
Critères d'exclusion
1. History of malignancies other than adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid
tumors curatively treated with no evidence of disease for ≥3 years
2. Prior treatment with a phosphoinositide 3 kinase (PI3K) inhibitor, a protein kinase B (Akt) inhibitor, or a mechanistic target of rapamycin (mTOR)
inhibitor
3. Prior treatment with chemotherapy and antibody drug conjugates (e.g., Enhertu®) for advanced disease is not permitted (prior adjuvant or
neoadjuvant chemotherapy is permitted)
4. More than 2 lines of prior endocrine therapy treatment
5. Bone only disease that is only blastic with no soft tissue component
6. Subjects with type 1 diabetes or uncontrolled type 2 diabetes
7. Active human immunodeficiency virus (HIV) infection (testing not mandatory).
a. Subjects with well controlled HIV infection may be allowed if CD4+ T-cell (CD4+) counts >350 cells/μL
b. Subjects without a history of AIDS-defining opportunistic infections may be eligible for enrollment
8. Known seropositive for or active viral infection with hepatitis B virus (testing not mandatory)
a. Hepatitis B surface antigen (HBsAg) positive
b. HBsAg negative, hepatitis B surface antibody (anti-HBs) positive and/or hepatitis B core antibody (anti-HBc) positive and detectable viral DNA
by PCR
[Note: Subjects who are HBsAg negative and viral DNA PCR negative are eligible.]
9. Known seropositive for, or active infection with hepatitis C virus (testing not mandatory)
a. Subjects with positive hepatitis C virus (HCV) antibodies are eligible with negative PCR test for HCV
10. Known and untreated, or active, brain or leptomeningeal metastases
a. Subjects with previously treated central nervous system (CNS) metastases may be enrolled in the study if they meet the following criteria: do
not require supportive therapy with steroids; do not have seizures and do not exhibit uncontrolled neurological symptoms; stable disease
confirmed by radiographic assessment within at least 4 weeks prior to enrollment
11. Patients with advanced, symptomatic, visceral spread that are at risk of life-threatening complication in the short-term
12. History of clinically significant cardiovascular abnormalities such as:
a. Congestive heart failure (New York Heart Association (NYHA) classification ≥ II [NYHA 1994]) within 6 months of study entry
b. Myocardial infarction within 12 months of study entry
c. History of any uncontrolled (or untreated) clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle
branch block, high grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block), supraventricular, nodal arrhythmias, or
conduction abnormality in the previous 12 months
d. Uncontrolled hypertension defined by systolic blood pressure (SBP) ≥160 mmHg and/or diastolic blood pressure (DBP) ≥100 mmHg, with or
without antihypertensive medication (initiation or adjustment of antihypertensive medication[s] is allowed prior to screening)
e. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
i. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, or history of clinically
significant/symptomatic bradycardia
ii. On screening, inability to determine the corrected QT interval using Fridericia’s formula (QTcF) on the ECG (i.e., unreadable or not
interpretable) or QTcF >480 msec (determined by mean of triplicate ECGs at screening)
13. Gastrointestinal tract disease resulting in an inability to absorb oral medication
14. History of acute pancreatitis within 12 months of screening or past medical history of chronic pancreatitis
15. Unable to swallow oral medication tablets/capsules
16. Known hypersensitivity to the study drugs or their components
17. History of pulmonary embolus or deep vein thrombosis diagnosed and/or treated within the previous 6 months
18. History of drug induced pneumonitis or interstitial lung disease
19. Current uncontrolled medical conditions that, in the opinion of the Investigator, could limit a subject’s ability to undertake study therapy or
comply with study requirements
20. Pregnant or breast-feeding women
21. Concurrent participation in another interventional clinical trial
a. Subjects must agree not to participate in another clinical trial (other than observational trials) at any time during participation in VIKTORIA-1