Overcoming Endocrine Resistance in Metastatic Breast Cancer

Phase 3

• Conditions: Metastatic Breast Cancer
• Interventions: Drug: Fulvestrant; Drug: Placebo Lapatinib; Drug: Aromatase Inhibitors; Drug: Lapatinib

• Registration Number: NCT02394496
• Lead Sponsor: Consorzio Oncotech

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.

Study Timeline

• Study Start: 2007-11
• Study First Submitted: 2014-12-16
• Study First Submitted QC: 2015-03-19
• Study First Posted: 2015-03-20
• Status Verified: 2016-06
• Last Update Submitted: 2016-06-14
• Last Update Posted: 2016-06-15
• Primary Completion: 2016-12
• Study Completion: 2017-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Female
• Target Recruitment: 396

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

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
ARM 1	Placebo Lapatinib	Fulvestrant + Placebo Lapatinib
ARM 2	Fulvestrant	Fulvestrant + Aromatase Inhibitors + Placebo Lapatinib
ARM 2	Aromatase Inhibitors	Fulvestrant + Aromatase Inhibitors + Placebo Lapatinib
ARM 2	Placebo Lapatinib	Fulvestrant + Aromatase Inhibitors + Placebo Lapatinib
ARM 3	Fulvestrant	Fulvestrant + Lapatinib
ARM 3	Lapatinib	Fulvestrant + Lapatinib
ARM 4	Lapatinib	Fulvestrant + Lapatinib + Aromatase Inhibitors
ARM 4	Aromatase Inhibitors	Fulvestrant + Lapatinib + Aromatase Inhibitors
ARM 1	Fulvestrant	Fulvestrant + Placebo Lapatinib
ARM 4	Fulvestrant	Fulvestrant + Lapatinib + Aromatase Inhibitors

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.
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).

Trial Locations

Locations (69)

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

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