Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Fulvestrant

Aromatase Inhibitors

Lapatinib

Antineoplastic Agents, Hormonal

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Fulvestrant + Aromatase Inhibitors + Placebo Lapatinib

Fulvestrant + Lapatinib + Aromatase Inhibitors

Fulvestrant 500mg (2 x 5ml) im injections as a loading dose on Day 0, followed by 500mg (2x5ml) on Day 14 (+/- 3 days) , Day 28 (+/- 3 days) and every 28 Days (+/- 3 days) thereafter.

as indicated in the Summary Product Characteristic

Placebo Lapatinib

Clinical Research Technology

ROSA RITA SILVA, Md

Sandro Barni, Md

ANTONIO NUZZO, Md

EVARISTO MAIELLO, Md

TERESA GAMUCCI, Md

Domenico Amoroso, Md

FRANCESCO FERRAÙ, Md

Giacomo Allegrini, MD

SIMON SPAZZAPAN, Md

Michele Aieta, MD

ALESSANDRA ZOBOLI, Md

ALFONSO MARIA D'ARCO, Md

PIETRO MASULLO, Md

GIUSEPPE VALMADRE, Md

Massimo Aglietta, MD

CLAUDIO VERUSIO, Md

STEFANIA GORI, Md

GIUSEPPE COLUCCI, Md

BRUNO DANIELE, Md

ANTONIO FEBBRARO, Md

SAVERIO CINIERI, Md

GABRIELLA MARIA FERRANDINA, Md

FRANCESCO CARROZZA, Md

LUIGI DE LUCIA, Md

ROBERTO BORDONARO, Md

CALOGERO BUSCARINO, Md

MICHELE CARUSO, Md

MONICA GIORDANO, Md

MONICA INDELLI, Md

LUCIA DEL MASTRO, Md

LIBERATO DI LULLO, Md

ENZO VELTRI, Md

ROSACHIARA FORCIGNANÒ, Md

FRANCO NOLÈ, Md

GIACOMO CARTENÌ, Md

MICHELINO DE LAURENTIIS, Md

SABINO DE PLACIDO, Md

Oscar Alabisio, MD

ANTONIO JIRILLO, Md

ANTONIO RUSSO, Md

VITA LEONARDI, Md

ANTONIO BERNARDO, Md

CARLO BASURTO, Md

LUIGI CAVANNA, Md

SILVANA SARACCHINI, Md

MARIO NARDI, Md

CORRADO BONI, Md

FRANCESCO COGNETTI, mD

ANNA MARIA PARISI, Md

GIOVANNI SCAMBIA, Md

ANGELO FEDELE SCINTO, Md

PAOLO MARCHETTI, Md

IDA PAVESE, Md

MARIA LUISA BARZELLONI, Md

CLEMENTINA SAVASTANO, Md

ANTONIO CONTU, Md

MARIA GIUSEPPA SAROBBA, Md

ALESSANDRO BERTOLINI, Md

ANNA TURLETTI, Md

Mario Airoldi, MD

ANTONIO DURANDO, Md

NICOLETTA BIGLIA, Md

FABIO PUGLISI, Md

GRAZIELLA PINOTTI, Md

LUCA MOSCETTI, Md

Sabino De Placido, MD

Michelino De Laurentiis, MD

Based on these results it can be envisioned that the majority of endocrine-responsive post-menopausal breast cancer patients will be treated with an AI as adjuvant therapy (front-line, switching or extending) and/or as first-line management of metastatic breast cancer.

In presence of ER hypersensitivity even a small amount of ER may be sufficient for sustained growth signalling. On the other hand, ER disruption operated by fulvestrant is not complete, particularly in the initial phase of treatment. From phase III trials, indeed, The invertigators know that with the standard 250mg monthly dose the steady state of circulating drug is reached only after 5-6 injections. This may play a role since, as long as ER downregulation is concerned, a clear dose-response relationship has been reported. In such a situation, fulvestrant efficacy may be partial, particularly because the concomitant AI discharge yields a restoration of physiologic postmenopausal levels of circulating oestrogens. New dosing schedule are currently under investigation both to accelerate the achievement of the steady state (loading dose) and to achieve higher circulating drug levels (high dose) (86).

In this trial the investigators will be using the so-called 'loading dose'.

Further potential strategies to improve fulvestrant efficacy in this setting are:

A) avoid the restoration of circulating oestrogens; B) interfere with molecular mechanisms that produce ER hypersensitivity by targeting the EGFR/ERBB2/ERB3 system.

A) avoid the restoration of circulating oestrogens: this should be achieved by holding the AI treatment. Because some cases of progression upon AIs may be related to an inefficient inhibition of the aromatase it is a logical step to test whether changing AI class (from type I, steroidal, to type II, non steroidal, and vice-versa) (87), may improve fulvestrant efficay. In this view, pts in this trial will be randomized to receive fulvestrant (loading dose) with or without the alternate class AI treatment. Circulating oestrogens levels will be tracked to verify inhibition of aromatase for pts assigned to concurrent AI treatment.

B) Interfere with growth factors-mediated ER hypersensitivity: although fulvestrant is able to overcome the ER hypersensitivity of LTED (88) and produce a growth arrest, this activity may not be complete because of incomplete ER disruption, but also because of a direct stimulation of growth by the hyperactivated EGFR/ERBB2/ERB3 system. Laboratory evidence support this hypothesis. Indeed, breast cancer cell lines exposed to long-term treatment with fulvestrant became insensitive to the drug and restore growth (89). This growth does not appear, however, related to the development of direct resistance to the drug, since ER mediated signalling continue to be efficiently suppressed in these cells; rather it may be driven by the use of alternative growth-stimulating pathway, including the EGFR system. Indeed, it can be abrogated by the EGFR-tyrosine Kinase inhibitor Gefitinib (IRESSA™) and by an MAPK-inhibitor (90). Lapatinib (GW572016) is an orally active small molecule that reversibly inhibits ErbB1 and ErbB2 tyrosine kinases, which in turn blocks phosphorylation and activation of Erk1/2 (p-Erk1/2) and Akt (p-Akt) in ErbB1- and/ or ErbB2-expressing tumor cell lines and xenografts (91-94). Lapatinib elicits cytostatic or cytotoxic antitumor effects depending on the cell type (95;96). Because ErbB2-containing heterodimers exert potent mitogenic signals, simultaneously interrupting both ErbB1 and ErbB2 signaling is an appealing therapeutic approach. Moreover, ErbB3 signaling is also involved in lapatinib action. Indeed ErbB3 is kinase-dead and relies on ErbB2 for transactivation: ErbB2-ErbB3 heterodimers are potent activators of the PI3K-Akt survival pathway (97;98), which can, in turn, inhibited by lapatinib.

Based on its molecular mechanism of action, on its fair toxicity profile and on its promising, although preliminary, activity data, Lapatinib appears an ideal candidate to combine with Fulvestrant in the attempt to improve its efficacy in patients progressing on AIs.

Overcoming Endocrine Resistance in Metastatic Breast Cancer

A Randomized Trial With Factorial Design Comparing Fulvestrant ± Lapatinib ± Aromatase Inhibitor in Metastatic Breast Cancer Progressing After Aromatase Inhibitor Therapy

Progression free survival (PFS): it is defined as the time between the first study dose administration and the date of progression of the disease or death from any cause, whichever occurs first.

Time to Progression (TTP): it is defined as the time between the first study dose administration and the date of progression of the disease or cancer-related death, whichever occurs first.

Overall survival. (OS): it is defined as the time between the first study dose administration and the date death from any cause.

Response Rate: It will be classified according to the RECIST criteria.

Clinical Benefit Rate: it is defined as the sum of rates of PR, CR and SD lasting ≥ 6 months.

To evaluate expected and Non-expected toxicity events that occur in more than 5% of patients in any of the study group, as reported by the CTC.

Withdrawals from the treatment plan (causes of withdrawals will be compared per each study group).

Consorzio Oncotech

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Overcoming Endocrine Resistance in Metastatic Breast Cancer	NCT02394496	Metastatic Brea...	Fulvestrant Lapatinib Aromatase Inhib... Placebo Lapatin...	18 Years -	Consorzio Oncotech
Overcoming Endocrine Resistance in Metastatic Breast Cancer	NCT02394496	Metastatic Brea...	Fulvestrant Lapatinib Aromatase Inhib... Placebo Lapatin...	18 Years -	Consorzio Oncotech
Overcoming Endocrine Resistance in Metastatic Breast Cancer	NCT02394496	Metastatic Brea...	Fulvestrant Lapatinib Aromatase Inhib... Placebo Lapatin...	18 Years -	Consorzio Oncotech

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