A study on the effectiveness (how well the treatment works) of the investigational drug Alpelisib in patients with advanced HER2+ breast cancer and a specific mutation (change) in the PIK3CA gene, who have received prior treatment

Austria, France, Italy, Netherlands, Spain, Switzerland (ICTRP)

ICTRP Studien-ID
NCT05063786 (ICTRP)

Offizieller Titel (Genehmigt von der Ethikkommission)
A randomized phase III trial of trastuzumab + ALpelisib +/- fulvestrant versus trastuzumab + chemotherapy in patients with PIK3CA mutated previously treated HER2+ Advanced BrEasT cancer. “ALPHABET Study” (BASEC)

Wissenschaftlicher Titel
A Randomized Phase III Trial of Trastuzumab + ALpelisib +/- Fulvestrant Versus Trastuzumab + Chemotherapy in Patients With PIK3CA Mutated Previously Treated HER2+ Advanced BrEasT Cancer. "ALPHABET Study". (ICTRP)

Öffentlicher Titel
Trastuzumab + Alpelisib +/- Fulvestrant vs Trastuzumab + CT in Patients With PIK3CA Mutated Previously Treated HER2+ Advanced BrEasT Cancer (ALPHABET) (ICTRP)

Untersuchte Krankheit(en)
Advanced Breast Cancer (ICTRP)

Untersuchte Intervention
Biological: TrastuzumabDrug: AlpelisibDrug: FulvestrantDrug: VinorelbineDrug: CapecitabineDrug: Eribulin (ICTRP)

Studientyp
Interventional (ICTRP)

Studiendesign
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Ein-/Ausschlusskriterien
Inclusion Criteria:

Patients are eligible to be enrolled for randomization in the study only if they meet all
of the following criteria:

1. Written informed consent prior to any specific study procedures, showing patient
willingness to comply with all study procedures.

2. Histologically or cytologically documented locally recurrent inoperable or
metastatic breast cancer with HER2+ status based on local laboratory determination,
preferably on the most recent available FFPE tumor sample, and according to American
Society of ClinicalOncology (ASCO)/College of American Pathologists (CAP)
international guidelines valid at the time of the assay. In case of discordance in
HER2+ status in different biopsies, we will consider the result from the most recent
biopsy one will be used.

3. Documented HR status based on local laboratory, preferably on the most recent
available FFPE tumor sample, and according to ASCO/CAP international guidelines
valid at the time of the assay. In case of discordance in HR status in different
biopsies, the result from the most recent biopsy will be used. HR+ will be defined
as =1% positive cells by immunohistochemistry for Estrogen Receptor (ER) and/or
Progesterone Receptor (PgR). HR- will be defined as <1% positive cells by
immunohistochemistry for both ER and PgR. Considering that there are limited data on
endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive,
for the purpose of this study, patients with ER and PgR expression between 1 and 10%
(considered to be HR low by the most recent ASCO/CAP guidelines) will be eligible
for inclusion in the HR- cohort.

4. Patients with a PIK3CA tumor mutation at central laboratory determination,
preferably on the most recent available FFPE tumor sample.

5. At least 1 but no more than 5 prior lines of anti-HER2 based therapy for metastatic
breast cancer (MBC). Maintenance therapy will not count as an additional line of
therapy.

6. At least 1 prior line of trastuzumab in the metastatic setting, or in the
(neo)adjuvant setting (provided the patient relapsed while on therapy or within 6
months after completing adjuvant trastuzumab).

7. Female or male patient is at least 18 years of age.

8. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.

9. Patients can be either males or premenopausal/perimenopausal or postmenopausal
females. In the HR+ cohort, males and females who are not post-menopausal must have
been on a gonadotropin-releasing hormone (GnRH) agonist (e.g. goserelin or
leuprorelin) for at least 28 days prior to starting study treatment.

Premenopausal status is defined as either:

- Last menstrual period occurred within the last 12 months, or

- If on tamoxifen: last menstrual period occurred within the past 14 days, plasma
estradiol is = 10 pg/mL and follicle-stimulating hormone (FSH) = 40 IU/l or in
the premenopausal range, according to local laboratory definition, or

- In case of therapy induced amenorrhea: plasma estradiol is = 10 pg/mL and FSH =
40 IU/l or in the premenopausal range, according to local laboratory
definition.

Postmenopausal status is defined as either:

- Natural (spontaneous) amenorrhea lasting more than 12 months and either age from49
to 59 years and/or history of vasomotor symptoms (e.g., hot flush) in the absence of
other medical justification, or Levels of plasma estradiol = 20 pg/mL and
follicle-stimulating hormone (FSH) = 40 IU/l or in the postmenopausal range,
according to local laboratory definition, or Surgical bilateral oophorectomy.

Perimenopausal status is defined as neither premenopausal nor postmenopausal.

10. Measurable disease or at least one evaluable bone lesion, lytic or mixed
(lytic+blastic), which has not been previously irradiated and is assessable by
computer tomography (CT)/magnetic resonance imaging (MRI) in the absence of
measurable disease according to RECIST 1.1 criteria.

11. Life expectancy = 12 weeks.

12. Adequate organ and marrow function defined as follows:

- Absolute neutrophil count (ANC) = 1,500/mm3 (1.5x109/L).

- Platelets = 100,000/mm3 (100x109/L).

- Hemoglobin = 9g/dL (90g/L).

- Calcium (corrected for serum albumin) and magnesium within normal limits or =
grade 1 according to NCI-CTCAE version 5.0 if judged clinically not significant
by the investigator.

- Creatinine <1.5 x upper limit of normal (ULN) or creatinine Clearance = 35
mL/min using Cockcroft-Gault formula (if creatinine is =1.5 ULN).

- Total bilirubin < 2 x ULN (any elevated bilirubin should be asymptomatic at
enrollment) except for patients with Gilbert's syndrome who may only be
included if the total bilirubin is = 3.0 x ULN or direct bilirubin = 1.5 x ULN.

- Potassium within normal limits, or corrected with supplements.

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 3.0 x
ULN.

If patient has liver metastasis, AST and ALT = 5.0 x ULN (elevated AST or AST values
must be stable for 2 weeks, without evidence of biliary obstruction by imaging).

- Fasting serum amylase = 2.0 x ULN.

- Fasting serum lipase = ULN.

- Fasting plasma glucose (FPG) < 140 mg/dL (7.7 mmol/L) and glycosylated
hemoglobin (HbA1c) < 6.5%.

13. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical
procedures to NCI-CTCAE version 5.0 grade = 1 (except alopecia or other toxicities
not considered a safety risk for the patient at investigators discretion).

14. Adequate cardiac function as defined by left ventricular ejection fraction (LVEF) of
= 50% measured by echocardiography or multi-gated acquisition (MUGA) scans.

Exclusion Criteria:

Patients will be excluded from the study if they meet any of the following criteria:

1. Have received more than 5 previous lines of anti-HER2 based therapy for MBC, or
prior fulvestrant.

2. Symptomatic visceral disease or any disease burden that makes the patient ineligible
for experimental therapy per the investigator's best judgment.

3. Symptomatic central nervous system (CNS) metastases. However, patients with CNS
metastases who have been adequately treated, are asymptomatic and do not require
corticosteroid or anti-epileptic medication are eligible.

4. Presence of leptomeningeal carcinomatosis.

5. Other invasive malignancy (different from the current breast cancer) at the time of
enrollment or previous diagnosis of a completely removed malignancy within 3 years
prior to randomization except for adequately treated (including complete surgical
removal) of International Federation of Gynecology and Obstetrics (FIGO) stage I
grade 1 endometrial cancer, basal or squamous cell carcinoma of the skin, thyroid
cancer limited to thyroid gland, in situ carcinoma of the cervix, and grade 1-2
early stage bladder cancer defined as T1 or less, without nodal involvement (N0).

6. Patients with an established diagnosis of diabetes mellitus type I or not controlled
type II (FPG = 140 mg/dL (ICTRP)

nicht verfügbar

Primäre und sekundäre Endpunkte
Progression Free Survival (PFS) (ICTRP)

Overall Survival (OS);Objective Response (OR);Safety and tolerability (ICTRP)

Registrierungsdatum
nicht verfügbar

Einschluss des ersten Teilnehmers
nicht verfügbar

Sekundäre Sponsoren
ETOP IBCSG Partners Foundation;Breast International Group;Novartis Pharmaceuticals (ICTRP)

Weitere Kontakte
Study Director;Study Director;Study Director, H. Cl?nico Universitario Valencia. Valencia, Spain.,Istituto Europeo di Oncologia. Milan, Italy.,Princess Margaret Cancer Center. Toronto, Canada (ICTRP)

Sekundäre IDs
2020-005639-65, GEICAM/2017-01_IBCSG 62-20_BIG (ICTRP)

Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
nicht verfügbar

Weitere Informationen zur Studie
https://clinicaltrials.gov/study/NCT05063786 (ICTRP)