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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Neoplasm, Breast; Congenital, Familial and Genetic Disorders
• Intervention / Treatment: Drug: Alpelisib 150 MG Oral Tablet [Piqray]; Drug: Fulvestrant

• Study Type: Interventional
• Enrollment (Estimated): 130
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Jeroen Bosch Ziekenhuis
  • Alkmaar, Netherlands
    • Noordwest Ziekenhuisgroep
  • Almelo, Netherlands
    • Ziekenhuisgroep Twente
  • Amersfoort, Netherlands
    • Meander Medisch Centrum
  • Amstelveen, Netherlands
    • Ziekenhuis Amstelland
  • Amsterdam, Netherlands
    • Amsterdam UMC
  • Amsterdam, Netherlands
    • Antoni van Leeuwenhoek
  • Apeldoorn, Netherlands
    • Gelre Ziekenhuizen
  • Arnhem, Netherlands
    • Rijnstate
  • Breda, Netherlands
    • Amphia
  • Delft, Netherlands
    • Reinier de Graaf Gasthuis
  • Deventer, Netherlands
    • Deventer Ziekenhuis
  • Eindhoven, Netherlands
    • Maxima Medisch Centrum
  • Enschede, Netherlands
    • Medisch Spectrum Twente
  • Goes, Netherlands
    • Admiraal De Ruyter Ziekenhuis
  • Groningen, Netherlands
    • Martini Ziekenhuis
  • Hoofddorp, Netherlands
    • Spaarne Gasthuis
  • Leeuwarden, Netherlands
    • Medisch Centrum Leeuwarden
  • Nieuwegein, Netherlands
    • St. Antonius ziekenhuis
  • Nijmegen, Netherlands
    • Canisius Wilhelmina Ziekenhuis
  • Rotterdam, Netherlands
    • Maasstad Ziekenhuis
  • Schiedam, Netherlands
    • Franciscus Gasthuis & Vlietland
  • The Hague, Netherlands
    • HagaZiekenhuis
  • Tilburg, Netherlands
    • Elisabeth-TweeSteden Ziekenhuis
  • Venlo, Netherlands
    • VieCuri Medisch Centrum

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine circulating tumor DNA (ctDNA) in plasma before and during treatment	Exploratory endpoint; determine circulating tumor DNA (ctDNA) in plasma before and during treatment, to investigate the prognostic and possibly predictive values of these measures	At baseline, 2 weeks of treatment, 8 weeks of treatment and every 8 weeks until disease progression. Assessed up to 36 months

Collaborators and Investigators

• Sponsor: Borstkanker Onderzoek Groep
• Collaborators: Novartis Pharma B.V.; BOOG Study Center
• Investigators: Principal Investigator: Vincent V.O. Dezentjé, MD PhD, NKI-AvL; Principal Investigator: Monique M.E.M.M. Bos, MD PhD, Erasmuc Mc; Principal Investigator: Inge I.R. Konings, MD PhD, Amsterdam UMC

Study record dates

Study Major Dates

• Study Start (Actual): June 2, 2022
• Primary Completion (Actual): May 7, 2026
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: May 16, 2022
• First Submitted That Met QC Criteria: May 23, 2022
• First Posted (Actual): May 26, 2022

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Hormone receptor positive HER2 negative breast cancer; PIK3CA-activated mutation
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin and Connective Tissue Diseases; Breast Neoplasms; Genetic Diseases, Inborn; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pharmaceutical Preparations; Dosage Forms; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estradiol; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Fulvestrant; Tablets; Alpelisib
• Other Study ID Numbers: BOOG 2021-01 SEQUEL-Breast

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No