A Multicenter Trial Assessing the Efficacy and Safety of tamOxifen Plus LY2228820 in Advanced or Metastatic Breast Cancer Progressing on aromatasE Inhibitors

NCT ID: NCT02322853

Last Updated: 2017-05-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2017-04-30

Brief 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).

Conditions

Postmenopausal; Metastatic Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

TAMOXIFEN

Tamoxifen will be administered daily orally

Patients will receive study medication until disease progression or unacceptable toxicity

Group Type: ACTIVE_COMPARATOR

Tamoxifen

Intervention Type: DRUG

hormonotherapy

TAMOXIFEN + LY2228820

Tamoxifen will be administered daily orally LY2228820 dimesylate (Ralimetinib) will be administered orally

Patients will receive study medication until disease progression or unacceptable toxicity

Group Type: EXPERIMENTAL

Tamoxifen

Intervention Type: DRUG

hormonotherapy

Ralimetinib (LY2228820 dimesylate)

Intervention Type: DRUG

Interventions

Tamoxifen

hormonotherapy

Intervention Type: DRUG

Ralimetinib (LY2228820 dimesylate)

Intervention Type: DRUG

Other Intervention Names

target therapy

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute, France

OTHER_GOV

Sponsor Role: collaborator

ARC Foundation for Cancer Research

OTHER

Sponsor Role: collaborator

Centre Francois Baclesse

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christelle LEVY, MD

Role: PRINCIPAL_INVESTIGATOR

c.levy@baclesse.unicancer.fr

Locations

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

Saint-Cloud, , France

Institut Claudius Regaud

Toulouse, , France

Institut Gustave Roussy

Villejuif, , France

Countries

France

Other Identifiers

OLYMPE / 2013-005084-29

Identifier Type: -

Identifier Source: org_study_id