Overcoming Endocrine Resistance in Metastatic Breast Cancer

Study Overview
=================
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.

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

Conditions
-----------------
Metastatic Breast Cancer

Intervention / Treatment
-----------------
* Drug: Fulvestrant
* Drug: Lapatinib
* Drug: Aromatase Inhibitors
* Drug: Placebo Lapatinib


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM 1<br>Fulvestrant + Placebo Lapatinib | Drug: Fulvestrant<br>* 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.<br>* Other names: Faslodex;Drug: Placebo Lapatinib<br>* 1500mg (TBD) O.S. qd<br>* Other names: Placebo;|
| Experimental: ARM 2<br>Fulvestrant + Aromatase Inhibitors + Placebo Lapatinib | Drug: Fulvestrant<br>* 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.<br>* Other names: Faslodex;Drug: Aromatase Inhibitors<br>* as indicated in the Summary Product Characteristic<br>* Other names: Aromatase Inhibitor;Drug: Placebo Lapatinib<br>* 1500mg (TBD) O.S. qd<br>* Other names: Placebo;|
| Experimental: ARM 3<br>Fulvestrant + Lapatinib | Drug: Fulvestrant<br>* 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.<br>* Other names: Faslodex;Drug: Lapatinib<br>* 1500mg (TBD) O.S. qd<br>|
| Experimental: ARM 4<br>Fulvestrant + Lapatinib + Aromatase Inhibitors | Drug: Fulvestrant<br>* 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.<br>* Other names: Faslodex;Drug: Lapatinib<br>* 1500mg (TBD) O.S. qd<br>Drug: Aromatase Inhibitors<br>* as indicated in the Summary Product Characteristic<br>* Other names: Aromatase Inhibitor;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Lapatinib, Fulvestrant, Aromatase Inhibitor, metastatic breast cancer