Overcoming Endocrine Resistance in Metastatic Breast Cancer

Metastatic Breast Cancer Clinical Trial

— OVER  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02394496
• Other study ID #: GIM8-OVER
• Secondary ID: 2007-006031-30
• Status: Recruiting
• Phase: Phase 3
• First received: December 16, 2014
• Last updated: June 14, 2016
• Start date: November 2007
• Est. completion date: January 2017

Study information

• Verified date: June 2016
• Source: Consorzio Oncotech
• Contact: Clinical Research Technology
• Phone: 0039089301545
• Is FDA regulated: No
• Health authority: Italy: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 396
• Est. completion date: January 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

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.
• Lapatinib
1500mg (TBD) O.S. qd
• Aromatase Inhibitors
as indicated in the Summary Product Characteristic
• Placebo Lapatinib
1500mg (TBD) O.S. qd

Locations

Country	Name	City	State
Italy	Centro di Riferimento Oncologico S.O.C. di Oncologia Medica C	Aviano	Pordenone
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	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	Azienda Ospedaliera `Sant'Anna e San Sebastiano` U.O.C. di Oncologia	Caserta
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	Presidio Ospedaliero Garibaldi - Nesima S.C. di Oncologia Medica	Catania
Italy	Azienda Ospedaliera S. Anna U.O. di Oncologia Medica	Como
Italy	Ospedale San Sebastiano Day Hospital Oncologico - Divisione Medicina Acuti	Correggio	Reggio Emilia
Italy	A.S.U.R. Zona Territoriale 6 Fabriano U.O. Oncologia Medica	Fabriano	Ancona
Italy	Arcispedaliera S. Anna di Ferrara U.O. Oncologia Clinica	Ferrara
Italy	Ospedale `S. Antonio Abate` U.O. Oncologia	Gallarate	Varese
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	Ospedale Civile Renzetti U.O. Oncologia Medica	Lanciano	Chieti
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	Ospedale Unico Versilia U.O. Oncologia Medica	Lido Di Camaiore	Lucca
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	Ospedale Sacro Cuore - Don Calabria U.O.C. Oncologia Medica	Negrar	Verona
Italy	Azienda Ospedaliera - Ospedale Umberto I U.O. di Medicina e Oncoematologia	Nocera Inferiore	Salerno
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	Ospedale S. Francesco da Paola U.O. Oncologia Medica	Paola	Cosenza
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	Ospedale `Felice Lotti` - Azienda USL 5 di Pisa U.O. di Oncologia Medica	Pontedera	Pisa
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	Ospedale Oncologico Regionale - Centro di Riferimento Oncologico di Basilicata U.O. di Oncologia Medica	Rionero in vulture	Potenza
Italy	Azienda Ospedaliera S. Andrea - Università La Sapienza U.O.C. Oncologia	Roma
Italy	Azienda Ospedaliera San Camillo - Forlanini Day Hospital Oncologia Mammella	Roma
Italy	Istituto Regina Elena per lo studio e la cura dei tumori S.C. Oncologia Medica A	Roma
Italy	Ospedale Fatebenefratelli San Giovanni Calibita - Isola Tiberina U.O. Oncologia	Roma
Italy	Ospedale San Pietro Fatebenefratelli Dipartimento di Oncologia - Day Hospital Oncologico	Roma
Italy	Policlinico Universitario `Agostino Gemelli` U.O.C. Ginecologia Oncologica	Roma
Italy	Azienda Ospedaliera `San Giovanni di Dio e Ruggi D'Aragona` Struttura Complessa di Oncologia	Salerno
Italy	Ospedale G. Da Procida - ASL SA U.O. di Oncologia	Salerno
Italy	IRCCS - `Casa Sollievo della Sofferenza` U.O. Oncologia Medica	San Giovanni Rotondo	Foggia
Italy	Azienda Ospedaliera Busto Arsizio - Presidio Ospedaliero Saronno S.C. Oncologia Medica	Saronno	Varese
Italy	Azienda Ospedaliera n. 1 - Annunziata Oncologia Medica	Sassari
Italy	Università di Sassari U.O. di Oncologia Medica	Sassari
Italy	AOVV - Ospedale E. Morelli S.O.C. Medicina Interna - D.H. Oncologico-Ematologico-Internistico	Sondalo	Sondrio
Italy	Ospedale Civile di Sondrio - Azienda Ospedaliera Valtellina e Valchiavenna S.C. Oncologia Medica	Sondrio
Italy	Ospedale `SS. Trinità` U.O. Oncologia Medica	Sora	Frosinone
Italy	Ospedale Civico San Vincenzo U.O. Oncologia Medica	Taormina	Messina
Italy	Ospedale Evangelico Valdese - ASL TO1 U.O. di Oncologia Medica	Torino
Italy	Ospedale Mauriziano Umberto I S.C.D.U. Ginecologia e Ostetricia	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	Azienda Ospedaliera Treviglio-Caravaggio U.O. Oncologia Medica	Treviglio	Bergamo
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	Presidio Ospedaliero di Vallo della Lucania U.O. Oncologia Medica	Vallo Della Lucania	Salerno
Italy	Azienda Ospedaliera Circolo e Fondazione Macchi U.O. di Oncologia Medica	Varese
Italy	Presidio Ospedaliero `Belcolle` U.O.C. Oncologia Medica	Viterbo

Sponsors (1)

Lead Sponsor	Collaborator
Consorzio Oncotech

Country where clinical trial is conducted

Italy, 

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* Note: There are 61 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival	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.	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	No
Secondary	Time To Progression	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.	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	No
Secondary	Overall Survival	Overall survival. (OS): it is defined as the time between the first study dose administration and the date death from any cause.	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	No
Secondary	Response Rate:	Response Rate: It will be classified according to the RECIST criteria.	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	No
Secondary	Clinical Benefit Rate	Clinical Benefit Rate: it is defined as the sum of rates of PR, CR and SD lasting = 6 months.	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	No
Secondary	Safety as measured by expected and Non-expected toxicity events	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.	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	Yes
Secondary	Safety assessed by number of Participants with Adverse Events	Withdrawals from the treatment plan (causes of withdrawals will be compared per each study group).	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	Yes