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

Sponsor

Centre Francois Baclesse (Other)

Overall Status

Terminated

CT.gov ID

NCT02322853

Collaborator

National Cancer Institute, France (Other), ARC Foundation for Cancer Research (Other)

Enrollment

Locations

Arms

Actual Duration (Months)

0.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Postmenopausal Metastatic Breast Cancer	Drug: Tamoxifen Drug: Ralimetinib (LY2228820 dimesylate)	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

8 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jan 1, 2015

Actual Primary Completion Date :

Apr 1, 2017

Actual Study Completion Date :

Apr 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: TAMOXIFEN Tamoxifen will be administered daily orally Patients will receive study medication until disease progression or unacceptable toxicity	Drug: Tamoxifen hormonotherapy
Experimental: 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	Drug: Tamoxifen hormonotherapy Drug: Ralimetinib (LY2228820 dimesylate) Other Names: target therapy

Arm

Intervention/Treatment

Active Comparator: TAMOXIFEN

Tamoxifen will be administered daily orally Patients will receive study medication until disease progression or unacceptable toxicity

Drug: Tamoxifen

hormonotherapy

Experimental: 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

Drug: Tamoxifen

hormonotherapy

Drug: Ralimetinib (LY2228820 dimesylate)

Other Names:

target therapy

Outcome Measures

Primary Outcome Measures

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. [at 6 months after treatment start.]

Secondary Outcome Measures

- To evaluate the toxicity profile (Safety and Tolerability) of the LY2228820 in combination with tamoxifen [From date of randomization until study participation (during average 12 months)]
Adverse events description and grade in all participants
- To estimate the Progression-Free Survival of the LY2228820 in combination with tamoxifen [evaluated every 8-12 weeks (during average 12 months)]
- To assess the overall survival of the LY2228820 in combination with tamoxifen [From date of randomization until the date of first documented date of death from any cause, whichever came first, assessed up to 60 months]
- To assess response duration of the LY2228820 in combination with tamoxifen [evaluated every 8-12 weeks during treatment to progression or death for any cause.(during average 12 months)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country
1	Institut Bergonié	Bordeaux	France
2	Centre François Baclesse	Caen	France
3	Centre Jean Perrin	Clermont -Ferrand	France
4	Centre Georges-François Leclerc	Dijon	France
5	Centre Léon Bérard	Lyon	France
6	Institut Paoli Calmettes	Marseille	France
7	Institut de Cancérologie de l'Ouest	Nantes	France
8	Hegp, Ap-Hp	Paris	France
9	Hôpital St Louis, AP-HP	Paris	France
10	Centre Eugène Marquis	Rennes	France
11	Centre Henri Becquerel	Rouen	France
12	Institut Curie	St Cloud	France
13	Institut Claudius Regaud	Toulouse	France
14	Institut Gustave Roussy	Villejuif	France