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*
- Conditions
- previously treated HER2+ advanced PIK3CA mutated breast cancer10006291
- Registration Number
- NL-OMON53690
- Lead Sponsor
- GEICAM (Fundación Grupo Español de Investigación en Cáncer de Mama)
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 24
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 Clinical Oncology (ASCO)/Collegue of American Pathologists (CAP)
international guidelines valid at the time of the assay. In case of discordance
in HER2+ status in different biopsies, the result from the most recent biopsy
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. 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 on the most representative
archival FFPE tumor sample (ie, a block with sufficient tumor surface and
cellularity) from the primary tumor or a metastatic lesion. If the tumor
analysis is not informative or inconclusive for the mutation analysis,
detection of PIK3CA mutations by the central laboratory on ctDNA extracted from
a blood sample will be allowed. 5. At least 1 prior line of anti-HER2 based
therapy for metastatic breast cancer (MBC). 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. 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. -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 enrollme
1.Have recently received study agent(s) in any of the following scenarios:
-Fulvestrant within 12 months prior to the start of the study treatment (HR+
cohort only). -All the chemotherapy options, vinorelbine, capecitabine and
eribulin within 12 months prior to start the study treatment. Patients that
have received one or more of these chemotherapies more than 12 months prior can
receive them again as study therapy. 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 [7.7 mmol/L] or
HbA1c >= 6.5%), or history of gestational diabetes (as per ACOG guidelines) or
documented steroid-induced diabetes mellitus. 7.Prior treatment with any mTOR,
AKT or PI3K inhibitor. 8.Patients treated within the last 7 days prior to
treatment initiation with: -Drugs that are strong inducers of CYP3A4. -Drugs
that are inhibitors of BCRP (Breast Cancer Resistance Protein). 9.Patients who
received before randomization: -Any investigational agent or other anti-cancer
therapy not listed in the protocol within 4 weeks prior to starting study
treatment (all acute toxic effects, including peripheral neurotoxicity must be
resolved to NCI-CTCAE version 5.0 grade <=1, except toxicities not considered a
safety risk for the patient at the investigator*s discretion). -Chemotherapy
within a period of time that is shorter than the cycle duration used for that
treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicine or < 1
week for weekly chemotherapy). -Biologic therapy (e.g., antibodies, other than
trastuzumab which is permitted): within 4 weeks prior to starting study
treatment. -Endocrine therapy: tamoxifen or aromatase inhibitor (AI) within 2
weeks prior to starting study treatment. -Corticosteroids within 2 weeks prior
to starting study treatment. -Radiotherapy within 2 weeks prior to starting
study treatment. Patients who received prior radiotherapy to >25% of bone
marrow are not eligible regardless of when it was administered. -Major surgery
within 4 weeks prior to starting study treatment and/or if patient has not
recovered from major side effects. 10.Patient has clinically significant,
uncontrolled heart disease and/or recent cardiac events. 11.Bleeding diathesis
(i.e., disseminated intravascular coagulation [DIC], clotting factor
deficiency) or lon
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>PFS: Time from randomization to objective disease progression based on the<br /><br>investigator*s assessment according to the response evaluation criteria for<br /><br>solid tumors (RECIST) version 1.1., or death from any cause.</p><br>
- Secondary Outcome Measures
Name Time Method <p>OS: time from randomization to death from any cause.<br /><br>OR: complete or partial response as best overall response based on the<br /><br>investigator*s assessment according to RECIST version 1.1.<br /><br>Safety and tolerability: adverse events (AEs) grades will be defined by the<br /><br>National Cancer Institute common terminology criteria for adverse events<br /><br>(NCI-CTCAE) version 5.0. AE terms will be coded according to the MedDRA<br /><br>dictionary.</p><br>