Clinical Trials /

Overcoming Endocrine Resistance in Metastatic Breast Cancer

NCT02394496

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Unknown status

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: GIM8-OVER
  • SECONDARY ID: 2007-006031-30
  • NCT ID: NCT02394496

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
FulvestrantFaslodexARM 1
LapatinibARM 3
Aromatase InhibitorsAromatase InhibitorARM 2
Placebo LapatinibPlaceboARM 1

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
ARM 1ExperimentalFulvestrant + Placebo Lapatinib
  • Fulvestrant
  • Placebo Lapatinib
ARM 2ExperimentalFulvestrant + Aromatase Inhibitors + Placebo Lapatinib
  • Fulvestrant
  • Aromatase Inhibitors
  • Placebo Lapatinib
ARM 3ExperimentalFulvestrant + Lapatinib
  • Fulvestrant
  • Lapatinib
ARM 4ExperimentalFulvestrant + Lapatinib + Aromatase Inhibitors
  • Fulvestrant
  • Lapatinib
  • Aromatase Inhibitors

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival
Time Frame: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 Issue:
Description: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

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

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Consorzio Oncotech

Trial Keywords

  • Fulvestrant
  • Lapatinib
  • Aromatase Inhibitor
  • metastatic breast cancer

Last Updated

June 14, 2016