OVER: Overcoming Endocrine Resistance in Metastatic Breast Cancer

Sponsor

Consorzio Oncotech (Other)

Overall Status

Unknown status

CT.gov ID

NCT02394496

Collaborator

(none)

396

Enrollment

Locations

Arms

110

Duration (Months)

5.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Fulvestrant Drug: Lapatinib Drug: Aromatase Inhibitors Drug: Placebo Lapatinib	Phase 3

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:

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

Study Design

Study Type:

Interventional

Anticipated Enrollment :

396 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Nov 1, 2007

Anticipated Primary Completion Date :

Dec 1, 2016

Anticipated Study Completion Date :

Jan 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ARM 1 Fulvestrant + Placebo Lapatinib	Drug: Fulvestrant 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. Other Names: Faslodex Drug: Placebo Lapatinib 1500mg (TBD) O.S. qd Other Names: Placebo
Experimental: ARM 2 Fulvestrant + Aromatase Inhibitors + Placebo Lapatinib	Drug: Fulvestrant 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. Other Names: Faslodex Drug: Aromatase Inhibitors as indicated in the Summary Product Characteristic Other Names: Aromatase Inhibitor Drug: Placebo Lapatinib 1500mg (TBD) O.S. qd Other Names: Placebo
Experimental: ARM 3 Fulvestrant + Lapatinib	Drug: Fulvestrant 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. Other Names: Faslodex Drug: Lapatinib 1500mg (TBD) O.S. qd
Experimental: ARM 4 Fulvestrant + Lapatinib + Aromatase Inhibitors	Drug: Fulvestrant 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. Other Names: Faslodex Drug: Lapatinib 1500mg (TBD) O.S. qd Drug: Aromatase Inhibitors as indicated in the Summary Product Characteristic Other Names: Aromatase Inhibitor

Outcome Measures

Primary Outcome Measures

Progression Free Survival [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]
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.

Secondary Outcome Measures

Time To Progression [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]
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 [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]
Overall survival. (OS): it is defined as the time between the first study dose administration and the date death from any cause.
Response Rate: [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]
Response Rate: It will be classified according to the RECIST criteria.
Clinical Benefit Rate [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]
Clinical Benefit Rate: it is defined as the sum of rates of PR, CR and SD lasting ≥ 6 months.
Safety as measured by expected and Non-expected toxicity events [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]
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.
Safety assessed by number of Participants with Adverse Events [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]
Withdrawals from the treatment plan (causes of withdrawals will be compared per each study group).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Provision of written informed consent
Histological/cytological confirmation of breast cancer
Documented positive hormone receptor status (ER+ve and/or PgR+ve) of primary or metastaic tumor issue, according to the local laboratory parameters
Postmenopausal women
Confirmed progression of disease after an adjuvant therapy or a therapy for metastatic disease with an aromatase inhibitors
Patients demonstrating prior response to AI therapy
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.
May have received prior radiotherapy as treatment for primary or metastatic tumour; however, is not required for study entry;
Life expectancy of at least 8 months
WHO performance status 0, 1 or 2
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.
Are able to swallow and retain oral medication;
Are able to complete all screening assessments as outlined in the protocol;
Patients must have normal organ and marrow function
Left ventricular ejection fraction (LVEF) within the institutional normal range

Exclusion Criteria:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	A.S.U.R. Zona Territoriale 6 Fabriano U.O. Oncologia Medica	Fabriano	Ancona	Italy	60044
2	Azienda Ospedaliera Treviglio-Caravaggio U.O. Oncologia Medica	Treviglio	Bergamo	Italy	24047
3	Ospedale Civile Renzetti U.O. Oncologia Medica	Lanciano	Chieti	Italy	66034
4	Ospedale S. Francesco da Paola U.O. Oncologia Medica	Paola	Cosenza	Italy	87027
5	IRCCS - 'Casa Sollievo della Sofferenza' U.O. Oncologia Medica	San Giovanni Rotondo	Foggia	Italy	71013
6	Ospedale 'SS. Trinità' U.O. Oncologia Medica	Sora	Frosinone	Italy	03039
7	Ospedale Unico Versilia U.O. Oncologia Medica	Lido Di Camaiore	Lucca	Italy	55041
8	Ospedale Civico San Vincenzo U.O. Oncologia Medica	Taormina	Messina	Italy	98039
9	Ospedale 'Felice Lotti' - Azienda USL 5 di Pisa U.O. di Oncologia Medica	Pontedera	Pisa	Italy	56025
10	Centro di Riferimento Oncologico S.O.C. di Oncologia Medica C	Aviano	Pordenone	Italy	33081
11	Ospedale Oncologico Regionale - Centro di Riferimento Oncologico di Basilicata U.O. di Oncologia Medica	Rionero in vulture	Potenza	Italy	85028
12	Ospedale San Sebastiano Day Hospital Oncologico - Divisione Medicina Acuti	Correggio	Reggio Emilia	Italy	42015
13	Azienda Ospedaliera - Ospedale Umberto I U.O. di Medicina e Oncoematologia	Nocera Inferiore	Salerno	Italy	84014
14	Presidio Ospedaliero di Vallo della Lucania U.O. Oncologia Medica	Vallo Della Lucania	Salerno	Italy	84078
15	AOVV - Ospedale E. Morelli S.O.C. Medicina Interna - D.H. Oncologico-Ematologico-Internistico	Sondalo	Sondrio	Italy	23035
16	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	10060
17	Ospedale 'S. Antonio Abate' U.O. Oncologia	Gallarate	Varese	Italy	21013
18	Azienda Ospedaliera Busto Arsizio - Presidio Ospedaliero Saronno S.C. Oncologia Medica	Saronno	Varese	Italy	21047
19	Ospedale Sacro Cuore - Don Calabria U.O.C. Oncologia Medica	Negrar	Verona	Italy	37024
20	Istituto Tumori 'Giovanni Paolo II' - IRCCS Ospedale Oncologico U.O. Oncologia Medica e Sperimentale	Bari		Italy	70124
21	Azienda Ospedaliera G. Rummo U.O. di Oncologia Medica	Benevento		Italy	82100
22	Ospedale Fatebenefratelli 'Sacro Cuore di Gesù' U.O. Oncologia	Benevento		Italy	82100
23	Presidio Ospedaliero 'Antonio Perrino' U.O.C. di Oncologia	Brindisi		Italy	72100
24	dazione di Ricerca e Cura 'Giovanni Paolo II' U.O. di Ginecologia Oncologia	Campobasso		Italy	86100
25	Ospedale Civile di Campobasso - A. Cardarelli U.O.C. Oncologia Medica	Campobasso		Italy	86100
26	Azienda Ospedaliera 'Sant'Anna e San Sebastiano' U.O.C. di Oncologia	Caserta		Italy	81100
27	Presidio Ospedaliero Garibaldi - Nesima S.C. di Oncologia Medica	Catania		Italy	95122
28	A.O.U. Ospedale Vittorio Emanuele e Ferrarotto U.O. di Oncologia Medica	Catania		Italy	95124
29	Humanitas Centro Catanese di Oncologia U.O. Oncologia Medica	Catania		Italy	95126
30	Azienda Ospedaliera S. Anna U.O. di Oncologia Medica	Como		Italy	22100
31	Arcispedaliera S. Anna di Ferrara U.O. Oncologia Clinica	Ferrara		Italy	44121
32	I.R.C.C.S. A.O.U. San Martino - I.S.T. S.C. Oncologia Medica A	Genova		Italy	16132
33	ASRM - Ospedale F. Veneziale - Zona di Isernia U.O. Oncologia	Isernia		Italy	86170
34	A.S.L. LT - Ospedale Santa Maria Goretti U.O.C. di Oncologia Medica	Latina		Italy	04100
35	Ospedale Vito Fazzi U.O. di Oncologia	Lecce		Italy	73100
36	Istituto Europeo di Oncologia (IRCCS) Dipartimento di Medicina - Unità Cure Mediche	Milano		Italy	20141
37	Azienda Ospedaliera Cardarelli Divisione Di Oncologia	Napoli		Italy	80131
38	Istituto Nazionale dei Tumori - Fondazione G. Pascale U.O. Oncologia Medica Senologica	Napoli		Italy	80131
39	Università di Napoli Federico II - Facoltà di Medicina Dipartimento di Medicina Clinica e Chirurgia - Oncologia	Napoli		Italy	80131
40	A.O.U. 'Maggiore della Carità' S.C. Oncologia	Novara		Italy	28100
41	Istituto Oncologico Veneto - I.R.C.C.S. U.O. di Oncologia Medica II	Padova		Italy	35128
42	A.O.U.P. 'Paolo Giaccone' U.O.C. di Oncologia Medica	Palermo		Italy	90127
43	A.R.N.A.S - Ospedale Civico e Benfratelli G. Di Cristina e M. Ascoli Divisione di Oncologia Medica	Palermo		Italy	90127
44	Fondazione S. Maugeri IRCCS U.O. Oncologia Medica II	Pavia		Italy	27100
45	IRCCS Policlinico S. Matteo S.C. di Oncologia Medica	Pavia		Italy	27100
46	Ospedale S. Maria della Misericordia S.C. Oncologia Medica	Perugia		Italy	06122
47	AUSL di Piacenza - Ospedale U.O. Oncologia Medica	Piacenza		Italy	29121
48	Azienda Ospedaliera Santa Maria degli Angeli U.O. Oncolgia Medica	Pordenone		Italy	33170
49	Azienda Ospedaliera Bianchi - Melacrino - Morelli U.O. di Oncologia Medica	Reggio Calabria		Italy	89125
50	Arcispedale S.Maria Nuova Servizio di Oncologia	Reggio Emilia		Italy	42123
51	Istituto Regina Elena per lo studio e la cura dei tumori S.C. Oncologia Medica A	Roma		Italy	00144
52	Azienda Ospedaliera San Camillo - Forlanini Day Hospital Oncologia Mammella	Roma		Italy	00149
53	Policlinico Universitario 'Agostino Gemelli' U.O.C. Ginecologia Oncologica	Roma		Italy	00168
54	Ospedale Fatebenefratelli San Giovanni Calibita - Isola Tiberina U.O. Oncologia	Roma		Italy	00186
55	Azienda Ospedaliera S. Andrea - Università La Sapienza U.O.C. Oncologia	Roma		Italy	00189
56	Ospedale San Pietro Fatebenefratelli Dipartimento di Oncologia - Day Hospital Oncologico	Roma		Italy	00189
57	Ospedale G. Da Procida - ASL SA U.O. di Oncologia	Salerno		Italy	84126
58	Azienda Ospedaliera 'San Giovanni di Dio e Ruggi D'Aragona' Struttura Complessa di Oncologia	Salerno		Italy	84131
59	Azienda Ospedaliera n. 1 - Annunziata Oncologia Medica	Sassari		Italy	07100
60	Università di Sassari U.O. di Oncologia Medica	Sassari		Italy	07100
61	Ospedale Civile di Sondrio - Azienda Ospedaliera Valtellina e Valchiavenna S.C. Oncologia Medica	Sondrio		Italy	23100
62	Ospedale Evangelico Valdese - ASL TO1 U.O. di Oncologia Medica	Torino		Italy	10125
63	Presidio San Lazzaro - A.O.U. San Giovanni Battista di Torino (Molinette) S.C. Oncologia Medica II	Torino		Italy	10126
64	Università degli Studi di Torino - Ospedale S. Anna U.O. di Oncologia Medica	Torino		Italy	10126
65	Ospedale Mauriziano Umberto I S.C.D.U. Ginecologia e Ostetricia	Torino		Italy	10128
66	Centro Oncologico A.S.S. N°1 Triestina Centro Sociale Oncologico	Trieste		Italy	34147
67	A.O.U. ´S. Maria della Misericordia´ Dipartimento di Oncologia	Udine		Italy	33100
68	Azienda Ospedaliera Circolo e Fondazione Macchi U.O. di Oncologia Medica	Varese		Italy	21100
69	Presidio Ospedaliero 'Belcolle' U.O.C. Oncologia Medica	Viterbo		Italy	01100

Sponsors and Collaborators

Consorzio Oncotech

Investigators

Principal Investigator: Sabino De Placido, MD, Dipartimento di Medicina Clinica e Chirurgia Oncologia Università degli Studi di Napoli "Federico II"
Study Chair: Michelino De Laurentiis, MD, Istituto Nazionale dei Tumori - Fondazione G. Pascale