Clinical trial NCT02394496: 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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Metastatic Breast Cancer
Keywords: Fulvestrant
Lapatinib
Aromatase Inhibitor
metastatic breast cancer
Lead sponsor: Consorzio Oncotech
Sponsor class: OTHER
First posted: 2015-03-20
Enrollment: 396
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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 criteria: Inclusion Criteria:

1. Provision of written informed consent
2. Histological/cytological confirmation of breast cancer
3. Documented positive hormone receptor status (ER+ve and/or PgR+ve) of primary or metastaic tumor issue, according to the local laboratory parameters
4. Postmenopausal women
5. Confirmed progression of disease after an adjuvant therapy or a therapy for metastatic disease with an aromatase inhibitors
6. Patients demonstrating prior response to AI therapy
7. Patients with measurable disease as per RECIST criteria /Patients with bone lesions, lytic or mixed (lytic + sclerotic), in the absence of measurable disease as defined by RECIST criteria.
8. May have received prior radiotherapy as treatment for primary or metastatic tumour; however, is not required for study entry;
9. Life expectancy of at least 8 months
10. WHO performance status 0, 1 or 2
11. Patients with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence.
12. Are able to swallow and retain oral medication;
13. Are able to complete all screening assessments as outlined in the protocol;
14. Patients must have normal organ and marrow function
15. Left ventricular ejection fraction (LVEF) within the institutional normal range

Exclusion Criteria:

1. Previous therapy with Fulvestrant and/or Lapatinib;
2. Patients with HER 2 overexpressing, either IHC 3+ or FISH +;
3. Concurrent non study anti-cancer therapy (
4. Have unresolved or unstable, serious toxicity from prior administration
5. Have malabsorption syndrome,
6. Have a concurrent disease or condition that would make the patient inappropriate for study participation,
7. Have an active or uncontrolled infection;
8. Have dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent;
9. Have a known history of uncontrolled or symptomatic angina, arrhythmias, or CHF;
10. Receive concurrent treatment with an investigational agent or participate in another clinical trial;
11. Receive concurrent treatment with prohibited medications
12. Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication;
13. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to fulvestrant, aromatase inhibitors or lapatinib or excipients.

Primary outcomes:
measure: Progression Free Survival
timeFrame: 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 assessed up to 12 months
Secondary outcomes:
measure: Time To Progression
timeFrame: 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 assessed up to 12 months
measure: Overall Survival
timeFrame: 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 assessed up to 12 months
measure: Response Rate:
timeFrame: 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 assessed up to 12 months
measure: Clinical Benefit Rate
timeFrame: 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 assessed up to 6 months
measure: Safety as measured by expected and Non-expected toxicity events
timeFrame: 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 assessed up to 12 months
measure: Safety assessed by number of Participants with Adverse Events
timeFrame: time between the first study dose administration and the date of progression of the disease or death from any cause, whichever occurs first assessed up to 12 months
Other outcomes:
Locations:
city: Fabriano
country: Italy
facility: A.S.U.R. Zona Territoriale 6 Fabriano U.O. Oncologia Medica
state: Ancona
city: Treviglio
country: Italy
facility: Azienda Ospedaliera Treviglio-Caravaggio U.O. Oncologia Medica
state: Bergamo
city: Lanciano
country: Italy
facility: Ospedale Civile Renzetti U.O. Oncologia Medica
state: Chieti
city: Paola
country: Italy
facility: Ospedale S. Francesco da Paola U.O. Oncologia Medica
state: Cosenza
city: San Giovanni Rotondo
country: Italy
facility: IRCCS - 'Casa Sollievo della Sofferenza' U.O. Oncologia Medica
state: Foggia
city: Sora
country: Italy
facility: Ospedale 'SS. Trinità' U.O. Oncologia Medica
state: Frosinone
city: Lido Di Camaiore
country: Italy
facility: Ospedale Unico Versilia U.O. Oncologia Medica
state: Lucca
city: Taormina
country: Italy
facility: Ospedale Civico San Vincenzo U.O. Oncologia Medica
state: Messina
city: Pontedera
country: Italy
facility: Ospedale 'Felice Lotti' - Azienda USL 5 di Pisa U.O. di Oncologia Medica
state: Pisa
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico S.O.C. di Oncologia Medica C
state: Pordenone
city: Rionero in vulture
country: Italy
facility: Ospedale Oncologico Regionale - Centro di Riferimento Oncologico di Basilicata U.O. di Oncologia Medica
state: Potenza
city: Correggio
country: Italy
facility: Ospedale San Sebastiano Day Hospital Oncologico - Divisione Medicina Acuti
state: Reggio Emilia
city: Nocera Inferiore
country: Italy
facility: Azienda Ospedaliera - Ospedale Umberto I U.O. di Medicina e Oncoematologia
state: Salerno
city: Vallo Della Lucania
country: Italy
facility: Presidio Ospedaliero di Vallo della Lucania U.O. Oncologia Medica
state: Salerno
city: Sondalo
country: Italy
facility: AOVV - Ospedale E. Morelli S.O.C. Medicina Interna - D.H. Oncologico-Ematologico-Internistico
state: Sondrio
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l'Oncologia - Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.) Direzione di Oncologia Medica
state: Torino
city: Gallarate
country: Italy
facility: Ospedale 'S. Antonio Abate' U.O. Oncologia
state: Varese
city: Saronno
country: Italy
facility: Azienda Ospedaliera Busto Arsizio - Presidio Ospedaliero Saronno S.C. Oncologia Medica
state: Varese
city: Negrar
country: Italy
facility: Ospedale Sacro Cuore - Don Calabria U.O.C. Oncologia Medica
state: Verona
city: Bari
country: Italy
facility: Istituto Tumori 'Giovanni Paolo II' - IRCCS Ospedale Oncologico U.O. Oncologia Medica e Sperimentale
city: Benevento
country: Italy
facility: Azienda Ospedaliera G. Rummo U.O. di Oncologia Medica
city: Benevento
country: Italy
facility: Ospedale Fatebenefratelli 'Sacro Cuore di Gesù' U.O. Oncologia
city: Brindisi
country: Italy
facility: Presidio Ospedaliero 'Antonio Perrino' U.O.C. di Oncologia
city: Campobasso
country: Italy
facility: dazione di Ricerca e Cura 'Giovanni Paolo II' U.O. di Ginecologia Oncologia
city: Campobasso
country: Italy
facility: Ospedale Civile di Campobasso - A. Cardarelli U.O.C. Oncologia Medica
city: Caserta
country: Italy
facility: Azienda Ospedaliera 'Sant'Anna e San Sebastiano' U.O.C. di Oncologia
city: Catania
country: Italy
facility: Presidio Ospedaliero Garibaldi - Nesima S.C. di Oncologia Medica
city: Catania
country: Italy
facility: A.O.U. Ospedale Vittorio Emanuele e Ferrarotto U.O. di Oncologia Medica
city: Catania
country: Italy
facility: Humanitas Centro Catanese di Oncologia U.O. Oncologia Medica
city: Como
country: Italy
facility: Azienda Ospedaliera S. Anna U.O. di Oncologia Medica
city: Ferrara
country: Italy
facility: Arcispedaliera S. Anna di Ferrara U.O. Oncologia Clinica
city: Genova
country: Italy
facility: I.R.C.C.S. A.O.U. San Martino - I.S.T. S.C. Oncologia Medica A
city: Isernia
country: Italy
facility: ASRM - Ospedale F. Veneziale - Zona di Isernia U.O. Oncologia
city: Latina
country: Italy
facility: A.S.L. LT - Ospedale Santa Maria Goretti U.O.C. di Oncologia Medica
city: Lecce
country: Italy
facility: Ospedale Vito Fazzi U.O. di Oncologia
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia (IRCCS) Dipartimento di Medicina - Unità Cure Mediche
city: Napoli
country: Italy
facility: Azienda Ospedaliera Cardarelli Divisione Di Oncologia
city: Napoli
country: Italy
facility: Istituto Nazionale dei Tumori - Fondazione G. Pascale U.O. Oncologia Medica Senologica
city: Napoli
country: Italy
facility: Università di Napoli Federico II - Facoltà di Medicina Dipartimento di Medicina Clinica e Chirurgia - Oncologia
city: Novara
country: Italy
facility: A.O.U. 'Maggiore della Carità' S.C. Oncologia
city: Padova
country: Italy
facility: Istituto Oncologico Veneto - I.R.C.C.S. U.O. di Oncologia Medica II
city: Palermo
country: Italy
facility: A.O.U.P. 'Paolo Giaccone' U.O.C. di Oncologia Medica
city: Palermo
country: Italy
facility: A.R.N.A.S - Ospedale Civico e Benfratelli G. Di Cristina e M. Ascoli Divisione di Oncologia Medica
city: Pavia
country: Italy
facility: Fondazione S. Maugeri IRCCS U.O. Oncologia Medica II
city: Pavia
country: Italy
facility: IRCCS Policlinico S. Matteo S.C. di Oncologia Medica
city: Perugia
country: Italy
facility: Ospedale S. Maria della Misericordia S.C. Oncologia Medica
city: Piacenza
country: Italy
facility: AUSL di Piacenza - Ospedale U.O. Oncologia Medica
city: Pordenone
country: Italy
facility: Azienda Ospedaliera Santa Maria degli Angeli U.O. Oncolgia Medica
city: Reggio Calabria
country: Italy
facility: Azienda Ospedaliera Bianchi - Melacrino - Morelli U.O. di Oncologia Medica
city: Reggio Emilia
country: Italy
facility: Arcispedale S.Maria Nuova Servizio di Oncologia
city: Roma
country: Italy
facility: Istituto Regina Elena per lo studio e la cura dei tumori S.C. Oncologia Medica A
city: Roma
country: Italy
facility: Azienda Ospedaliera San Camillo - Forlanini Day Hospital Oncologia Mammella
city: Roma
country: Italy
facility: Policlinico Universitario 'Agostino Gemelli' U.O.C. Ginecologia Oncologica
city: Roma
country: Italy
facility: Ospedale Fatebenefratelli San Giovanni Calibita - Isola Tiberina U.O. Oncologia
city: Roma
country: Italy
facility: Azienda Ospedaliera S. Andrea - Università La Sapienza U.O.C. Oncologia
city: Roma
country: Italy
facility: Ospedale San Pietro Fatebenefratelli Dipartimento di Oncologia - Day Hospital Oncologico
city: Salerno
country: Italy
facility: Ospedale G. Da Procida - ASL SA U.O. di Oncologia
city: Salerno
country: Italy
facility: Azienda Ospedaliera 'San Giovanni di Dio e Ruggi D'Aragona' Struttura Complessa di Oncologia
city: Sassari
country: Italy
facility: Azienda Ospedaliera n. 1 - Annunziata Oncologia Medica
city: Sassari
country: Italy
facility: Università di Sassari U.O. di Oncologia Medica
city: Sondrio
country: Italy
facility: Ospedale Civile di Sondrio - Azienda Ospedaliera Valtellina e Valchiavenna S.C. Oncologia Medica
city: Torino
country: Italy
facility: Ospedale Evangelico Valdese - ASL TO1 U.O. di Oncologia Medica
city: Torino
country: Italy
facility: Presidio San Lazzaro - A.O.U. San Giovanni Battista di Torino (Molinette) S.C. Oncologia Medica II
city: Torino
country: Italy
facility: Università degli Studi di Torino - Ospedale S. Anna U.O. di Oncologia Medica
city: Torino
country: Italy
facility: Ospedale Mauriziano Umberto I S.C.D.U. Ginecologia e Ostetricia
city: Trieste
country: Italy
facility: Centro Oncologico A.S.S. N°1 Triestina Centro Sociale Oncologico
city: Udine
country: Italy
facility: A.O.U. ´S. Maria della Misericordia´ Dipartimento di Oncologia
city: Varese
country: Italy
facility: Azienda Ospedaliera Circolo e Fondazione Macchi U.O. di Oncologia Medica
city: Viterbo
country: Italy
facility: Presidio Ospedaliero 'Belcolle' U.O.C. Oncologia Medica
Study officials:
affiliation: Dipartimento di Medicina Clinica e Chirurgia Oncologia Università degli Studi di Napoli "Federico II"
name: Sabino De Placido, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Istituto Nazionale dei Tumori - Fondazione G. Pascale
name: Michelino De Laurentiis, MD
role: STUDY_CHAIR
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