NCT05063786

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

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".

• Status: Active Not Recruiting
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 27 (actual)
• Sponsor: Spanish Breast Cancer Research Group · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Randomized phase III trial of trastuzumab + Alpelisib +/- fulvestrant versus trastuzumab + chemotherapy in patients with PIK3CA mutated previously treated HER2+ Advanced Breast cancer.

Detailed description

This is an international, multicenter, open-label, controlled phase III randomized clinical trial in HER2+ advanced breast cancer (ABC) patients harboring PIK3CA mutation. Approximately 300 patients (144 in the Hormone Receptor (HR)- cohort and 156 in the HR+ cohort) will be enrolled. Central screening of PIK3CA mutations on the most recent available formalin-fixed paraffinembedded (FFPE) tumor sample is required for the purpose of eligibility. Investigators will be encouraged to send the most recent tumor tissue, preferably from a metastatic lesion. However, if this is not possible, archived tissue samples either from primary tumor or metastatic lesion will be acceptable. Local screening of HR and HER2 status is required (although there will be a central confirmation done retrospectively). Once the screening process (locally at each site and at the central laboratory) is completed, fully eligible patients will be randomized in a 1:1 fashion to the control arm with trastuzumab plus chemotherapy (CT) or to the experimental arm with trastuzumab + alpelisib +/- fulvestrant (depending on HR status). The two patient cohorts defined according to HR status will be randomized separately, with randomization in each cohort stratified by prior treatment with pertuzumab (yes vs no) and number of prior anti-HER2 based therapy lines for MBC (≤2 vs \>2). In both cohorts patients will continue to receive their assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first. After objective disease progression, patients in both treatment arms will be followed until death or withdrawal of consent. In order to perform exploratory biomarker analysis, pre-treatment tumor and sequential blood samples (at baseline, at week 9, at the end of treatment (EOT), and at progressive disease (PD)) will be obtained. Additionally, blood samples from approximately 100 patients (50 HR+ and 50 HR-) screened and without PIK3CA mutation will be collected.

Conditions

• Advanced Breast Cancer

Interventions

Type	Name	Description
BIOLOGICAL	Trastuzumab	6 mg/kg IV every 3 weeks (3-weekly schedule), or 4 mg/kg IV loading dose, followed by 2mg/kg IV weekly (weekly schedule)\*, or 600 mg SC every 3 weeks. \* If using trastuzumab IV, a loading dose of 8 mg/kg (for the 3-weekly schedule), or 4 mg/kg (for the weekly schedule) is necessary if more than 6 weeks have passed since the previous trastuzumab dose.
DRUG	Alpelisib	300 mg oral once daily.
DRUG	Fulvestrant	500 mg intramuscular every 4 weeks plus loading dose on day 15 cycle 1.
DRUG	Vinorelbine	Oral (60 mg/m2) or IV (25 or 30 mg/m2 per investigator preference) on days 1 and 8, every 3 weeks.
DRUG	Capecitabine	1250 or 1000 mg/m2 (per investigator preference) twice a day (BID) oral, 2 weeks on, 1 week off, every 3 weeks.
DRUG	Eribulin	1.23 mg/m2 IV on days 1 and 8, every 3 weeks.

Timeline

• Start date: 2021-09-14
• Primary completion: 2026-06-01
• Completion: 2026-06-01
• First posted: 2021-10-01
• Last updated: 2025-09-08

Locations

106 sites across 6 countries: Austria, France, Italy, Netherlands, Spain, Switzerland