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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

Page last updated: August 23, 2015

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