ALPHABET (BIG 18-04)

Intro text: 

A randomised phase III trial of trastuzumab + ALpelisib +/- fulvestrant versus trastuzumab + chemotherapy in patients with PIK3CA mutated previously treated HER2+ Advanced BrEasT cancer

ALPHABET aims to assess the efficacy and safety of the PI3K inhibitor alpelisib given in combination with trastuzumab (an anti-HER2 therapy) compared to chemotherapy with trastuzumab.
This treatment will be tested in patients with advanced HER2-positive breast cancer that is also positive for a PIK3CA mutation.

In some tumours, the PIK3CA gene, which contains the information needed to produce the PI3K protein, is abnormal (or mutated) and linked to cancer growth. Previous research suggests that mutations in the PIK3CA gene might lead to resistance to anti-HER2 therapy. Treatment resistance is a common problem in patients with advanced HER2-positive breast cancer, and it can lead to the cancer coming back or continuing to grow. There is a lot of interest in developing strategies to overcome this resistance. One approach is to combine anti-HER2 therapy with drugs that block the PI3K protein, such as alpelisib, which is what is known as a “PI3K inhibitor”.

Alpelisib has already been approved for use in some cancer patients by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA). Currently, alpelisib can be used in combination with a hormone therapy drug called fulvestrant for the treatment of postmenopausal women and men with hormone receptor (HR)-positive, HER2-negative, locally advanced breast cancer with a PIK3CA mutation.

The aim of ALPHABET is to assess whether alpelisib given in combination with trastuzumab is better than chemotherapy and trastuzumab in patients with advanced HER2-positive breast cancer that has a PIK3CA mutation.

Researchers will also evaluate side effects and quality of life.

Depending on the tumour’s hormone receptor (HR) status, patients will be assigned to one of two groups: the HR-negative cohort or the HR-positive cohort. 

In each cohort, there will be an experimental group (also referred to as ‘treatment arm A’), which will receive alpelisib (plus fulvestrant in the HR-positive cohort) and a control group (also referred to as ‘treatment arm B’), which will not receive alpelisib but instead standard chemotherapy. Alpelisib is a drug that is taken orally at home.

All patients will receive the drug trastuzumab since their tumour is HER2-positive.

Study design

Patients will receive the assigned treatment until the cancer continues to grow (this is called ‘disease progression’), or until side effects become too difficult to manage. The total duration of the study is estimated to be approximately 5 years from the time the first patient is enrolled.

The study will enrol approximately 300 patients with previously treated advanced HER2-positive breast cancer that has a PIK3CA mutation.

This study is being conducted and sponsored by GEICAM (the Spanish Breast Cancer Group) in collaboration with IBCSG (the International Breast Cancer Study Group) and BIG Headquarters.

Recruitment opened in July 2021 and is ongoing.

Approximately 110 hospitals from 6 European countries are participating.

Not at present.

ALPHABET is made possible by a research grant and provision of the study drug (alpelisib) by Novartis. The study is an investigator-initiated trial and is being run according to BIG’s Principles of Research Conduct.