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Spots Global Cancer Trial Database for Overcoming Endocrine Resistance in Metastatic Breast Cancer

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Trial Identification

Brief Title: Overcoming Endocrine Resistance in Metastatic Breast Cancer

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

Study ID: NCT02394496

Study Description

Brief Summary: 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.

Detailed Description: 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.

Eligibility

Minimum Age: 18 Years

Eligible Ages: ADULT, OLDER_ADULT

Sex: FEMALE

Healthy Volunteers: No

Locations

A.S.U.R. Zona Territoriale 6 Fabriano U.O. Oncologia Medica, Fabriano, Ancona, Italy

Azienda Ospedaliera Treviglio-Caravaggio U.O. Oncologia Medica, Treviglio, Bergamo, Italy

Ospedale Civile Renzetti U.O. Oncologia Medica, Lanciano, Chieti, Italy

Ospedale S. Francesco da Paola U.O. Oncologia Medica, Paola, Cosenza, Italy

IRCCS - 'Casa Sollievo della Sofferenza' U.O. Oncologia Medica, San Giovanni Rotondo, Foggia, Italy

Ospedale 'SS. Trinità' U.O. Oncologia Medica, Sora, Frosinone, Italy

Ospedale Unico Versilia U.O. Oncologia Medica, Lido Di Camaiore, Lucca, Italy

Ospedale Civico San Vincenzo U.O. Oncologia Medica, Taormina, Messina, Italy

Ospedale 'Felice Lotti' - Azienda USL 5 di Pisa U.O. di Oncologia Medica, Pontedera, Pisa, Italy

Centro di Riferimento Oncologico S.O.C. di Oncologia Medica C, Aviano, Pordenone, Italy

Ospedale Oncologico Regionale - Centro di Riferimento Oncologico di Basilicata U.O. di Oncologia Medica, Rionero in vulture, Potenza, Italy

Ospedale San Sebastiano Day Hospital Oncologico - Divisione Medicina Acuti, Correggio, Reggio Emilia, Italy

Azienda Ospedaliera - Ospedale Umberto I U.O. di Medicina e Oncoematologia, Nocera Inferiore, Salerno, Italy

Presidio Ospedaliero di Vallo della Lucania U.O. Oncologia Medica, Vallo Della Lucania, Salerno, Italy

AOVV - Ospedale E. Morelli S.O.C. Medicina Interna - D.H. Oncologico-Ematologico-Internistico, Sondalo, Sondrio, Italy

Fondazione del Piemonte per l'Oncologia - Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.) Direzione di Oncologia Medica, Candiolo, Torino, Italy

Ospedale 'S. Antonio Abate' U.O. Oncologia, Gallarate, Varese, Italy

Azienda Ospedaliera Busto Arsizio - Presidio Ospedaliero Saronno S.C. Oncologia Medica, Saronno, Varese, Italy

Ospedale Sacro Cuore - Don Calabria U.O.C. Oncologia Medica, Negrar, Verona, Italy

Istituto Tumori 'Giovanni Paolo II' - IRCCS Ospedale Oncologico U.O. Oncologia Medica e Sperimentale, Bari, , Italy

Azienda Ospedaliera G. Rummo U.O. di Oncologia Medica, Benevento, , Italy

Ospedale Fatebenefratelli 'Sacro Cuore di Gesù' U.O. Oncologia, Benevento, , Italy

Presidio Ospedaliero 'Antonio Perrino' U.O.C. di Oncologia, Brindisi, , Italy

dazione di Ricerca e Cura 'Giovanni Paolo II' U.O. di Ginecologia Oncologia, Campobasso, , Italy

Ospedale Civile di Campobasso - A. Cardarelli U.O.C. Oncologia Medica, Campobasso, , Italy

Azienda Ospedaliera 'Sant'Anna e San Sebastiano' U.O.C. di Oncologia, Caserta, , Italy

Presidio Ospedaliero Garibaldi - Nesima S.C. di Oncologia Medica, Catania, , Italy

A.O.U. Ospedale Vittorio Emanuele e Ferrarotto U.O. di Oncologia Medica, Catania, , Italy

Humanitas Centro Catanese di Oncologia U.O. Oncologia Medica, Catania, , Italy

Azienda Ospedaliera S. Anna U.O. di Oncologia Medica, Como, , Italy

Arcispedaliera S. Anna di Ferrara U.O. Oncologia Clinica, Ferrara, , Italy

I.R.C.C.S. A.O.U. San Martino - I.S.T. S.C. Oncologia Medica A, Genova, , Italy

ASRM - Ospedale F. Veneziale - Zona di Isernia U.O. Oncologia, Isernia, , Italy

A.S.L. LT - Ospedale Santa Maria Goretti U.O.C. di Oncologia Medica, Latina, , Italy

Ospedale Vito Fazzi U.O. di Oncologia, Lecce, , Italy

Istituto Europeo di Oncologia (IRCCS) Dipartimento di Medicina - Unità Cure Mediche, Milano, , Italy

Azienda Ospedaliera Cardarelli Divisione Di Oncologia, Napoli, , Italy

Istituto Nazionale dei Tumori - Fondazione G. Pascale U.O. Oncologia Medica Senologica, Napoli, , Italy

Università di Napoli Federico II - Facoltà di Medicina Dipartimento di Medicina Clinica e Chirurgia - Oncologia, Napoli, , Italy

A.O.U. 'Maggiore della Carità' S.C. Oncologia, Novara, , Italy

Istituto Oncologico Veneto - I.R.C.C.S. U.O. di Oncologia Medica II, Padova, , Italy

A.O.U.P. 'Paolo Giaccone' U.O.C. di Oncologia Medica, Palermo, , Italy

A.R.N.A.S - Ospedale Civico e Benfratelli G. Di Cristina e M. Ascoli Divisione di Oncologia Medica, Palermo, , Italy

Fondazione S. Maugeri IRCCS U.O. Oncologia Medica II, Pavia, , Italy

IRCCS Policlinico S. Matteo S.C. di Oncologia Medica, Pavia, , Italy

Ospedale S. Maria della Misericordia S.C. Oncologia Medica, Perugia, , Italy

AUSL di Piacenza - Ospedale U.O. Oncologia Medica, Piacenza, , Italy

Azienda Ospedaliera Santa Maria degli Angeli U.O. Oncolgia Medica, Pordenone, , Italy

Azienda Ospedaliera Bianchi - Melacrino - Morelli U.O. di Oncologia Medica, Reggio Calabria, , Italy

Arcispedale S.Maria Nuova Servizio di Oncologia, Reggio Emilia, , Italy

Istituto Regina Elena per lo studio e la cura dei tumori S.C. Oncologia Medica A, Roma, , Italy

Azienda Ospedaliera San Camillo - Forlanini Day Hospital Oncologia Mammella, Roma, , Italy

Policlinico Universitario 'Agostino Gemelli' U.O.C. Ginecologia Oncologica, Roma, , Italy

Ospedale Fatebenefratelli San Giovanni Calibita - Isola Tiberina U.O. Oncologia, Roma, , Italy

Azienda Ospedaliera S. Andrea - Università La Sapienza U.O.C. Oncologia, Roma, , Italy

Ospedale San Pietro Fatebenefratelli Dipartimento di Oncologia - Day Hospital Oncologico, Roma, , Italy

Ospedale G. Da Procida - ASL SA U.O. di Oncologia, Salerno, , Italy

Azienda Ospedaliera 'San Giovanni di Dio e Ruggi D'Aragona' Struttura Complessa di Oncologia, Salerno, , Italy

Azienda Ospedaliera n. 1 - Annunziata Oncologia Medica, Sassari, , Italy

Università di Sassari U.O. di Oncologia Medica, Sassari, , Italy

Ospedale Civile di Sondrio - Azienda Ospedaliera Valtellina e Valchiavenna S.C. Oncologia Medica, Sondrio, , Italy

Ospedale Evangelico Valdese - ASL TO1 U.O. di Oncologia Medica, Torino, , Italy

Presidio San Lazzaro - A.O.U. San Giovanni Battista di Torino (Molinette) S.C. Oncologia Medica II, Torino, , Italy

Università degli Studi di Torino - Ospedale S. Anna U.O. di Oncologia Medica, Torino, , Italy

Ospedale Mauriziano Umberto I S.C.D.U. Ginecologia e Ostetricia, Torino, , Italy

Centro Oncologico A.S.S. N°1 Triestina Centro Sociale Oncologico, Trieste, , Italy

A.O.U. ´S. Maria della Misericordia´ Dipartimento di Oncologia, Udine, , Italy

Azienda Ospedaliera Circolo e Fondazione Macchi U.O. di Oncologia Medica, Varese, , Italy

Presidio Ospedaliero 'Belcolle' U.O.C. Oncologia Medica, Viterbo, , Italy

Contact Details

Name: Sabino De Placido, MD

Affiliation: Dipartimento di Medicina Clinica e Chirurgia Oncologia Università degli Studi di Napoli "Federico II"

Role: PRINCIPAL_INVESTIGATOR

Name: Michelino De Laurentiis, MD

Affiliation: Istituto Nazionale dei Tumori - Fondazione G. Pascale

Role: STUDY_CHAIR

Useful links and downloads for this trial

Clinicaltrials.gov

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