Studieoverzicht - 2021-01 SEQUEL-Breast

Multicenter, single arm phase II trial

To investigate the efficacy of the combination of fulvestrant and alpelisib directly after progression on 1st or 2nd line therapy with fulvestrant in patients pretreated with a CDK 4/6 inhibitor (in first or second line) in pre- or postmenopausal women and men with HR+HER2- advanced breast cancer with tumors harboring an activating PIK3CA mutation. Primary endpoint is PFS. The aim is to determine a clinically meaningful median PFS of at least six months.

Primary endpoint:

To determine 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.

Secondary endpoints:

- to determine Progression-free survival (PFS) ‘on treatment’, 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;

- to determine the Objective Response Rate, described as complete response (CR) or partial response (PR);

- to determine the Clinical Benefit Rate, described as stable disease (SD), PR, or CR;

- to determine the Duration of Response (DoR);

- to evaluate safety and tolerability;

- to determine risk factors for alpelisib-induced hyperglycaemia;

- to determine which management is needed in patients with alpelisib-induced hyperglycae-mia, and time till resolvement;

- to assess Quality of Life (QoL);

- to evaluate Patient Reported Outcome Measures (PROMs);

- to compare PFS in patients with the 11 most frequent activating PIK3CA mutations with PFS in patients with unselected activating PIK3CA mutations (including rare mutations);

- to determine Overall Survival (OS);

- to determine circulating tumor DNA (ctDNA) in plasma before and during treatment, to investigate the prognostic and possibly predictive values of these measures;

- to explore mechanisms of resistance using tumor DNA and ctDNA;

- to determine pharmacokinetics of alpelisib.

The most important inclusion criteria are:  

1. Adult women (≥ 18 years of age) and men with proven diagnosis of adenocarcinoma of the breast with locoregional recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated.

2. Documentation of histologically or cytologically confirmed diagnosis of estrogen receptor (ER) expression >10% and/or progesterone receptor (PR) expression >10% breast cancer based on local laboratory results. In case ER ≤ 10% and PR >10% the ER and PR expression need to be confirmed in a referral center. Tumor must be HER2-negative as defined by ASCO-CAP guidelines. If HER2 status is unavailable then testing must be performed/repeated.

3. Patients must have progressed on fulvestrant as a preceding treatment line (as first or second line therapy). In case fulvestrant plus a CDK4/6 inhibitor has been given in 1st line as last treatment, the patient must have progressed during or shortly (<12 months) after stopping adjuvant treatment with an (NS)AI.

4. Previous treatment with a CDK4/6 inhibitor in the advanced setting is mandatory.

5. The presence of an activating PIK3CA mutation; preferably detected in a metastasis as PIK3CA mutation status may change during the course of the disease. In case a biopsy from a metastasis is not obtainable, mutation analysis may be performed on the primary tumor or archival tumor material.

6. Evaluable disease* as defined per RECIST v.1.1. Tumor lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented.

* Evaluable disease in this study is defined as measurable and non-measurable disease according to RECIST, with the exception of truly non-measurable disease only (i.e. ascites or pleural effusion as only site of disease). In case of truly non-measurable disease only, a patient is NOT considered evaluable according to RECIST. Bone only disease is considered evaluable.

Centra open voor inclusie:

Admiraal de Ruyter Ziekenhuis, Goes

Amphia, Breda

Amstelland, Amstelveen

Amsterdam UMC, Amsterdam

Antoni van Leeuwenhoek ziekenhuis, Amsterdam

Deventer ziekenhuis, Deventer

Franciscus Gasthuis & Vlietland, Schiedam

Gelre Ziekenhuizen, Apeldoorn

Jeroen Bosch Ziekenhuis, Den Bosch

Maasstad Ziekenhuis, Rotterdam

Martini Ziekenhuis, Groningen

Máxima Medisch Centrum, Eindhoven

Meander MC, Amersfoort

Medisch Centrum Leeuwarden, Leeuwarden

Medisch Spectrum Twente, Enschede

Noordwest Ziekenhuisgroep, Alkmaar

Reinier de Graaf Gasthuis, Delft

Rijnstate, Arnhem 

Spaarne Gasthuis, Hoofddorp

St. Antonius Ziekenhuis, Nieuwegein

Viecuri Medisch Centrum, Venlo

Ziekenhuisgroep Twente, Almelo