A phase II randomised study to evaluate alpelisib plus fulvestrant versus capecitabine in oestrogen receptor positive, HER2-negative advanced breast cancer patients with PIK3CA mutant circulating DNA.

Trial summary:

Women or men with oestrogen receptor positive, HER2 negative advanced breast cancer and PIK3CA mutant circulating DNA will be randomised to evaluate treatment with alpelisib plus fulvestrant compared with capecitabine on progression free survival.

Receptor status / problem studied:

Oestrogen receptor positive, HER2 negative

Inclusion criteria

1. Female or Male, >= 18 years.
2. Advanced (locoregionally recurrent not amenable to curative therapy, or metastatic) ER-positive, HER2-negative breast cancer, histologically defined as:
a. ER positive: Locally assessed oestrogen receptor status based on assessment of primary or metastatic disease. ER-positive is defined as >=10% (any PR expression) by immunohistochemistry irrespective of staining intensity.
b. HER2 negative:
i. IHC 1+, as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of invasive tumour cells; OR
ii. IHC 0, as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within <= 10% of the invasive tumour cells; OR
iii. ISH (FISH or SISH) negative based on:
* Single-probe average HER2 copy number < 4.0 signals/cell, OR
* Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell.
3. ECOG performance status of 0–1.
4. No more than two prior lines of endocrine therapy for treatment of advanced disease setting (no prior fulvestrant).
5. No more than one line of chemotherapy for treatment of advanced breast cancer (no prior capecitabine).

In addition to the above listed pre-screening inclusion criteria, participants must fulfil all of the following criteria prior to randomisation:
1. PIK3CA mutation (PIK3CA E542K, E545K, H1047L or H1047R mutation) identified through ctDNA testing.
2. Progression of disease during or after CDK4/6 inhibitor (i.e. ribociclib, palbociclib, abemaciclib) AND AI therapy (i.e. letrozole, anastrozole, exemestane) in the (neo) adjuvant OR advanced disease setting.
3. Evaluable disease (i.e. at least one measurable or non-measurable lesion as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

Exclusion criteria

1. Any disease burden that makes participants ineligible for endocrine therapy as per the investigator’s best judgement.
2. Prior treatment with capecitabine, fulvestrant, any PI3K, mTOR or AKT inhibitor.
3. Known hypersensitivity or contra-indication to alpelisib, fulvestrant or capecitabine.
4. Concurrently using other anti-cancer therapy. Exception: goserelin.
5. Previous or concomitant invasive malignancy. The exceptions are:
a. participants with non-breast malignancy >= 3 years ago, treated with curative intent and without evidence of recurrence;
b. basal or squamous cell carcinoma of the skin or non-melanomatous skin cancer;
c. in situ carcinoma without invasion (includes in situ breast carcinoma);
d. curatively resected cervical cancer.
6. Radiotherapy <= 2 weeks prior to randomisation, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia).
7. Prior endocrine therapy <= 2 weeks prior to randomisation. Exception: goserelin.
8. Prior chemotherapy <= 2 weeks prior to randomisation.
9. Surgery <= 2 weeks prior to randomisation or has not recovered from major side effects.
10. Not recovered from all toxicities related to prior anticancer therapy to NCI-CTCAE V5.0 Grade <= 1. Exception: patients with any grade of alopecia or menopausal symptoms.

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Open for recruitment

Trial Title



Breast cancer

Type of trial


Type of treatement

Medical Oncology





Principal Investigator
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