A Multicenter Trial Assessing the Efficacy and Safety of tamOxifen Plus LY2228820 in Advanced or Metastatic Breast Cancer Progressing on aromatasE Inhibitors
Information source: Centre Francois Baclesse
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Postmenopausal; Metastatic Breast Cancer
Intervention: Tamoxifen (Drug); Ralimetinib (LY2228820 dimesylate) (Drug)
Phase: Phase 2
Status: Suspended
Sponsored by: Centre Francois Baclesse Official(s) and/or principal investigator(s): Christelle LEVY, MD, Principal Investigator, Affiliation: c.levy@baclesse.unicancer.fr
Summary
Metastatic breast cancer (MBC) remains an incurable disease and despite an improvement of
the effect of systemic treatments. After relapse on first-line non-steroidal aromatase
inhibitor, current clinical practice and treatment guidelines include tamoxifen, fulvestrant
(an ER antagonist) and exemestane as available options (NCCN treatment guidelines 2012), but
in this context of resistance, their efficacy are poor.
Some results confirm the possibility to improve the efficacy of tamoxifen in metastatic
setting by a combination with therapy targeting signal transduction pathways. Other
transduction pathways seem to be involved in endocrine sensitivity/resistance, such as
RAS/RAF/MEK/MAK pathway.
LY2228820 inhibits the activity of p38 MAPK (selective inhibitor of the α and β isoforms of
p38 MAPK in vitro) and reduces phosphorylation of its cellular target, MAPK-activated
protein kinase 2 (MAPKAP-K2).
Clinical Details
Official title: A Randomized Open-label Phase II Multicenter Trial Assessing the Efficacy and Safety of tamOxifen Plus LY2228820 in Advanced or Metastatic Breast Cancer Progressing on aromatasE Inhibitors
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: To define the efficacy (progression-free survival rate at 6 months) of LY2228820 in combination with tamoxifen for postmenopausal women with an ER positive and HER2 negative advanced or metastatic breast cancer who progressed on aromatase inhibitors.
Secondary outcome: - To evaluate the toxicity profile (Safety and Tolerability) of the LY2228820 in combination with tamoxifen- To estimate the Progression-Free Survival of the LY2228820 in combination with tamoxifen - To assess the overall survival of the LY2228820 in combination with tamoxifen - To assess response duration of the LY2228820 in combination with tamoxifen
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Female.
Criteria:
Inclusion Criteria:
- Women with histologically confirmed breast cancer
- 18 < age < 80 years old
- Menopausal status Women are considered post-menopausal and not of child bearing
potential if they have had
- 12 months of spontaneous amenorrhea with an appropriate clinical profile (e. g.,
age appropriate, history of vasomotor symptoms) or
- 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and
estradiol < 20 pg/mL or
- surgical bilateral oophorectomy (with or without hysterectomy) at least six
weeks ago. In the case of oophorectomy alone, only when the reproductive status
of the woman has been confirmed by follow up hormone level assessment is she
considered not of child bearing potential
- ER-positive status by local laboratory testing (>10% by IHC) and HER2-negative status
(IHC 0 or 1+ or 2+ and FISH negative) on the last biopsy or surgical specimen
available.
- Disease progression defined as inoperable locally advanced or metastatic breast
cancer (MBC) excluding aggressive visceral disease requiring other approaches, such
as chemotherapy
- Disease refractory to aromatase inhibitors (AI) defined as:
- recurrence while on, or within 12 months of end of adjuvant treatment with
aromatase inhibitor, or
- progression while on, or within 3 months of end of AI for locally advanced or
MBC
- Patients who have received fulvestrant are eligible
- Maximum 2 previous lines of chemotherapy for MBC
- Performance Status (PS) ≤ 2
- Patient able to swallow and retain oral medication
- Measurable or evaluable lesions as per RECIST 1. 1
- Measurable disease (≥ 20 mm by conventional techniques or ≥ 10 mm by spiral
computed tomography scan) or
- Non-measurable lytic or mixed (lytic + blastic) bone lesions in the absence of
measurable disease.
- Patients with only pleural effusion and/or ascites are not eligible.
- Adequate bone marrow and organ function as defined by the following laboratory
values:
- Absolute Neutrophil Count (ANC) ≥ 1. 0 x 109/L
- Platelets (plt) ≥ 100 x 109/L
- Hemoglobin (Hgb) ≥ 9 g/dl
- INR ≤ 1. 5 without any anticoagulation treatment
- Serum creatinine ≤ 1. 5 x ULN
- Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) within
normal range (or < 3. 0 x ULN if liver metastases are present)
- Total serum bilirubin within normal range (or ≤ 1. 5 x ULN if liver metastases
are present; or total bilirubin ≤ 3. 0 x ULN with direct bilirubin within normal
range in patients with well documented Gilbert's Syndrome, which is defined as
presence of several episodes of unconjugated hyperbilirubinemia with normal
results from CBC count (including normal reticulocyte count and blood smear),
normal liver function test results, and absence of other contributing disease
processes at the time of diagnosis
- Patient has signed informed consents obtained before any trial related activities and
according to local guidelines
Exclusion Criteria:
- • Previous treatment with p38 MAPK inhibitors or Tamoxifen in metastatic setting
(adjuvant treatment by tamoxifen is allowed)
- More than 2 lines of chemotherapy for locally advanced and/or metastatic breast
cancer
- Brain metastasis
- Other malignancy (with the exception of adequately treated, basal or squamous
cell carcinoma, non-melanomatous skin cancer or curatively resected cervical
cancer).
- Clinically significant (i. e. active) cardiovascular disease: cerebro-vascular
accident/stroke or myocardial infarction within 6 months prior to first study
medication; unstable angina; CHF of New York Heart Association (NYHA) Grade II
or higher; or serious cardiac arrhythmia requiring medication.
- Have had a major bowel resection that would alter oral drug absorption.
- Have a diagnosis of inflammatory bowel disease (Crohn's disease or ulcerative
colitis).
- Are receiving concurrent administration of immunosuppressive therapy
- Concurrent participation in any therapeutic clinical trial
- Assessed by the investigator to be unable or unwilling to comply with the
requirements of the protocol
Locations and Contacts
Institut Bergonié, Bordeaux, France
Centre François Baclesse, Caen, France
Centre Jean Perrin, Clermont -Ferrand, France
Centre Georges-François Leclerc, Dijon, France
Centre Léon Bérard, Lyon, France
Institut Paoli Calmettes, Marseille, France
Institut de Cancérologie de l'Ouest, Nantes, France
Hegp, Ap-Hp, Paris, France
Hôpital St Louis, AP-HP, Paris, France
Centre Eugène Marquis, Rennes, France
Centre Henri Becquerel, Rouen, France
Institut Curie, St Cloud, France
Institut Claudius Regaud, Toulouse, France
Institut Gustave Roussy, Villejuif, France
Additional Information
Starting date: January 2015
Last updated: April 28, 2015
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