SEQUence of Endocrine Therapy in Advanced Luminal Breast Cancer (SEQUEL-Breast)

Study Overview
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Brief Summary
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The study is a nationwide, multicenter single-arm phase 2 study. The current phase 2 study investigates the efficacy of the combination of fulvestrant and alpelisib directly after progression on fulvestrant (either in first or second line, with or without previous use of CDK4/6-inhibitor) in patients with HR+ HER2- advanced breast cancer with PIK3CA mutated tumors. All eligible patients must have progressive disease on fulvestrant as latest treatment line. Previous treatment with a CDK4/6 inhibitor in first or second line is obligatory. After progressive disease is confirmed, it is important to continue fulvestrant (without CDK4/6 inhibition) during the screening period awaiting study enrollment. After study enrollment all participants will be treated with alpelisib and fulvestrant beyond progression. Follow-up time will be until progression or death or until a different oncolytic treatment has started (in case no progressive disease during previous fulvestrant and alpelisib treatment has been documented). Should participants discontinue due to reasons other than progression or death (e.g. toxicity), then they should still be evaluated for disease progression every 8 weeks as per protocol until progression, unless they do not wish to proceed with these screenings, or receive a different oncolytic treatment.

Official Title
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SEQUence of Endocrine Therapy in Advanced Luminal Breast Cancer (SEQUEL-Breast): A Phase 2 Study on Fulvestrant Beyond Progression in Combination With Alpelisib for PIK3CA-mutated, Hormone-receptor Positive HER2 Negative Advanced Breast Cancer

Conditions
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Neoplasm, Breast, Congenital, Familial and Genetic Disorders

Intervention / Treatment
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* Drug: Alpelisib 150 MG Oral Tablet [Piqray]
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult women and men (≥ 18 years of age) with proven diagnosis of adenocarcino-ma of the breast withlocoregional recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent andfor whom chemotherapy is not clinically indicated Estrogen receptor (ER) expression >10% and/or progesterone receptor (PR) expression >10% breast cancerbased on local la-boratory results. Tumor must be HER2- as defined by ASCO-CAP guidelines Patients must have progressed on fulvestrant as a preceding treatment line (as first or second line therapy) Previous treatment with a CDK4/6 inhibitor in the advanced setting The presence of an activating PIK3CA mutation Evaluable disease* as defined per RECIST v.1.1 Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 Exclusion Criteria: Patients with advanced, symptomatic, visceral spread, who are at risk of life-threatening complications in theshort term Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningealdisease as indicated by clinical symptoms, cerebral edema, and/or progressive growth Prior treatment with a PI3K /AKT/mTOR inhibitor Type 1 diabetes or uncontrolled type 2 diabetes (Hba1C > 68 mmol/mol) Clinically significant, uncontrolled heart disease and/or recent cardiac events

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (one-arm study)<br>Alpelisib plus fulvestrant beyond progression | Drug: Alpelisib 150 MG Oral Tablet [Piqray]<br>* Alpelisib 300mg once daily (may be reduced to 1dd250 or 1dd200mg in case of toxicity)<br>* Other names: Piqray;Drug: Fulvestrant<br>* Fulvestrant 300mg 1x/four weeks<br>* Other names: Faslodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Defined as time from study enrollment to disease progression or death from any cause, with censoring when fulvestrant and alpelisib are stopped and another treatment is initiated without confirmed disease progression. | From registration to progression, assessed up to 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 'On treatment' Progression-free survival (PFS) | Defined as time from study enrollment to disease progression or death from any cause, with censoring when fulvestrant and alpelisib are stopped earlier than disease progression | From registration to progression, assessed up to 36 months | 
| Objective Response Rate | Described as complete response (CR) or partial response (PR) | From registration to progression, assessed up to 36 months | 
| Clinical Benefit Rate | Described as stable disease (SD), PR, or CR | From registration to progression, assessed up to 36 months | 
| Duration of Response (DoR) | Duration of Response | From registration to progression, assessed up to 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hormone receptor positive HER2 negative breast cancer, PIK3CA-activated mutation