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Biomarker study in patients receiving standard treatment

Everolimus 10mg, oral, daily; exemestane 25 mg, oral, daily. Number of Cycles: until progression or unacceptable toxicity develops. From all patients, 4 additional blood samples, 6ml each, will be collected and an optional tumor biopsy will be taken, if eligible.

Everolimus plus Exemestane

Epie Boven, Prof.dr. MD

The purpose of this study is to determine whether biomarkers could be found to gain more insight in tumor characteristics in order to predict which patients will have a high chance of a long progression-free survival. Postmenopausal patients with advanced metastatic breast cancer who have progressed on anastrozole or letrozole will be eligible for this study.

Rationale of study:

Everolimus combined with exemestane has shown to improve progression-free survival compared to exemestane monotherapy in patients with hormone receptor-positive breast cancer previously treated with non-steroidal aromatase inhibitors. Since January 1st, 2013, everolimus is being reimbursed for this category of patients. For many patients this means, that an interesting treatment possibility has become available. However, some patients do not benefit from everolimus and exemestane, while others have to deal with side-effects requiring adjustment of the dose or even discontinuation of treatment.

In this study proposal the investigators plan to gain more insight in tumor characteristics in order to predict which patients will have a high chance of a long progression-free survival.

Study objectives:

1. It is proposed to compare progression-free survival on the combination of everolimus and exemestane between patients whose metastatic tumor expresses markers of phosphatidylinositol 3-kinase (PI3K) pathway activation versus patients whose metastatic tumor does not express PI3K pathway activation.
2. It is proposed to carry out immunohistochemistry on activated members of the PI3K pathway in primary tumor tissue of patients treated with everolimus and exemestane and compare the findings with the outcome of treatment and more specifically, with the results from other studies.
3. It is proposed to associate protein expression/ phosphorylation by proteomics in tumor biopsies to cancer mutations, PI3K pathway activation and progression-free survival on the exemestane and everolimus combination.
4. It is proposed to establish the incidence of mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and protein kinase B (AKT) in peripheral blood of advanced breast cancer patients amenable for treatment with everolimus and exemestane and to explore whether the presence of such mutations is associated with outcome to treatment in these patients.

Study population:

Postmenopausal women with hormone receptor-positive locally advanced or metastatic breast cancer whose disease is refractory to non steroidal aromatase inhibitors (NSAIs) and have a documented recurrence or progression on last therapy for breast cancer.

Number of patients and centers:

* 175 patients for blood samples and archived tumor tissue, 50 for fresh tumor biopsy, another 30 for fresh tumor biopsy upon progressive disease
* 30 hospitals in the Netherlands.

Treatment phase:

Patients will be treated with 10 mg daily doses of everolimus (either 2 x 5 mg or 1 x 10 mg tablets) in combination with exemestane (25 mg daily tablets).

Dose adjustment (reduction, interruption) according to safety findings will be allowed.

Treatment will continue until one of the following conditions apply and whichever comes first: tumor progression, unacceptable toxicity according to investigator's judgment, patient's wish, death, discontinuation from the study for any other reason. Further treatment after progression will be at the investigator's discretion.

Physicians will collect data on demographics, previous treatments, efficacy of everolimus and exemestane as well as on toxic effects of this combination according to good clinical practice (GCP) in the patient's file.

Statistical considerations:

Since the majority of the studies involve the use of new techniques, the study will be mainly explorative in design. For blood sample analysis and analysis of archival tumor tissue at least 175 patients will be required. For tumor tissue biopsies a number of 50 patients is expected to give insight in differences between patients with clinical benefit ant those with early progressive disease; from 30 of these patients a tumor biopsy will be collected upon progressive disease.

Analysis of Tumor Tissue and Circulating Genetic Material in the Blood to Obtain Further Insight in the Effectiveness of Everolimus When Combined With Exemestane

Phosphatidylinositol 3-kinase (PI3K) Pathway Analysis in Tumor Tissue and Circulating DNA to Obtain Further Insight in the Efficacy of Everolimus When Combined With Exemestane: A Side-study Protocol Attached to Standard Treatment With Everolimus and Exemestane for Postmenopausal Patients With Hormone Receptor-positive Advanced Metastatic Breast Cancer, Who Have Progressed on Anastrozole or Letrozole

Biomarker evaluation to gain more insight in tumor characteristics in order to predict which patients will have a high chance of a long progression-free survival. For biomarker evaluation, primary tumor tissue, new tumor tissue Biopsies and blood samples will be analysed for activated members of the PI3K pathway by immunohistochemistry and phosphoproteomics, and for the incidence of mutations in the PI3K pathway. The findings will be compared with the outcome of treatment and with the results from other studies.

Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression. Progressive disease will be assessed by radiological assessment or, if clearly stated in the patient's file, by clear clinical signs.

Adverse Events related to Everolimus will be recorded according to Common Toxicity Criteria for Adverse Effects (CTCAE) v4.03. Number of events and worst grades will be recorded, as well as reasons for dose reduction and discontinuation.

Borstkanker Onderzoek Groep

Novartis

Amsterdam UMC, location VUmc

Prof dr Verheul, MD

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Analysis of Tumor Tissue and Circulating Genetic Material in the Blood to Obtain Further Insight in the Effectiveness of Everolimus When Combined With Exemestane	NCT02109913	Hormone Recepto... Metastatic Brea...	Everolimus plus...	18 Years -	Amsterdam UMC, location VUmc
Analysis of Tumor Tissue and Circulating Genetic Material in the Blood to Obtain Further Insight in the Effectiveness of Everolimus When Combined With Exemestane	NCT02109913	Hormone Recepto... Metastatic Brea...	Everolimus plus...	18 Years -	Amsterdam UMC, location VUmc

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