STRIDE - STimulating Immune Response In aDvanced brEast Cancer

Study Overview
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Brief Summary
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EMD Serono has decided to permanently terminate the trial EMR 200038-010 (STRIDE) in the indication of breast cancer following the clinical hold on the investigational new drug application for tecemotide (L-BLP25).

Detailed Description
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The purpose of the study is to determine whether the addition of the experimental mucinous glycoprotein 1 (MUC1) antigen-specific cancer immunotherapy tecemotide (L-BLP25) to hormonal treatment is effective in prolonging progression-free survival in postmenopausal women with endocrine-sensitive inoperable locally advanced, recurrent or metastatic breast cancer.

Official Title
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A Randomized, Double-blind, Controlled Phase III Study of Stimuvax® (L-BLP25 or BLP25 Liposome Vaccine) in Combination With Hormonal Treatment Versus Hormonal Treatment Alone for First-line Therapy of Post-menopausal Women With Estrogen Receptor (ER)-Positive and/or Progesterone Receptor (PgR)-Positive, Inoperable Locally Advanced, Recurrent, or Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Biological: Tecemotide (L-BLP25) and Hormonal Treatment
* Biological: Placebo of tecemotide (L-BLP25) and Hormonal Treatment
* Drug: cyclophosphamide
* Drug: sodium chloride (NaCl)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal women as defined in the protocol Estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive, histologically or cytologically confirmed primary carcinoma of the breast Expressing at least one of the following five human leukocyte antigen (HLA) haplotypes, as centrally assessed by HLA genotyping from whole blood: HLA-A2, -A3, -A11, -B7, or -B35 Locally advanced, recurrent, or metastatic breast cancer (Subject must have at least one lesion not located in bone) Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), and inoperable Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate hematologic, hepatic, and renal function within two weeks prior to initiation of therapy, as defined by the protocol Other protocol-defined inclusion criteria may apply Exclusion Criteria: Disease Status PD either during hormonal therapy for early breast cancer (adjuvant therapy) or within 48 months from the initiation of such therapy Human epidermal growth factor receptor 2-positive (HER2+) breast cancer as defined in the protocol Autoimmune disease that in the opinion of the investigator could compromise the safety of the subject in this study (Exception will be granted for well-controlled Type I diabetes mellitus) Recognized immunodeficiency disease, including cellular immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; hereditary or congenital immunodeficiencies Past or current history of malignant neoplasm other than breast cancer (BRCA), except for curatively treated non-melanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively treated and with no evidence of disease for at least five years Known active Hepatitis B infection or carrier state and/or Hepatitis C infection, known Human Immunodeficiency Virus infection, or any other infectious process that in the opinion of the investigator could compromise the subject's ability to mount an immune response or could expose her to the likelihood of more and/or severe side effects Pre-therapies Receipt of immunotherapy (for example [e.g.], interferons; tumor necrosis factor; interleukins; growth factors granulocyte macrophage-colony stimulating factor [GM-CSF], granulocyte-colony stimulating factor [G-CSF], macrophage-colony stimulating factor [M-CSF], or monoclonal antibodies), or chemotherapy, within four weeks (28 days) prior to randomization. Note: Subjects who have received monoclonal antibodies for imaging are eligible Prior receipt of investigational systemic drugs (including off-label use of approved products) or any kind of systemic treatment (chemotherapy, or immunotherapy), with the exception of hormonal therapy (HT) when given for a period not exceeding 4 weeks (28 days) prior to randomization, for treatment of inoperable, locally advanced, recurrent, or metastatic breast cancer Prior radiotherapy to the site of cancer, if only one site will be used for evaluation of tumor response Prior use of bisphosphonates or concurrent use while on study treatment is allowed Physiological Function Central nervous system disease or brain metastases, as documented by computed tomography (CT) or magnetic resonance imaging (MRI) Medical or psychiatric conditions that would interfere with the ability to provide informed consent, communicate side effects, or comply with protocol requirements Clinically significant cardiac disease, e.g., cardiac failure of New York Heart Association (NYHA) classes III-IV; uncontrolled angina pectoris, uncontrolled arrhythmia, uncontrolled hypertension, or myocardial infarction in the previous six months, as confirmed by an electrocardiogram (ECG) Splenectomy Standard Criteria Need for concurrent treatment with a non-permitted therapy (e.g., concurrent chemotherapy, radiotherapy, systemic immunosuppressive drugs, use of herbal medicines or botanical formulations intended to treat cancer) while on protocol therapy. Palliative radiation to painful bone lesions is allowed Participation in another clinical study within 30 days prior to randomization Known hypersensitivity to the study drugs Known alcohol or drug abuse Legal incapacity or limited legal capacity Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such. Subject who could be regarded as vulnerable according to International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines (e.g., the subject's willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate, plus persons kept in detention; persons in nursing homes; subjects in emergency situations; homeless persons; and nomads) Any other reason that, in the opinion of the investigator, precludes the subject from participating in this study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational Arm<br>Investigational Arm: Pretreatment (Single Dose): 300 milligrams per square meter (mg/m^2) up to a maximum dose of 600 mg of intravenous cyclophosphamide tecemotide (L-BLP25) plus Hormonal Therapy (Standard Dose) | Biological: Tecemotide (L-BLP25) and Hormonal Treatment<br>* Investigational Arm: Pretreatment (Single Dose) 300 mg/m^2 of intravenous cyclophosphamide in investigational arm to a maximum of 600 milligrams (mg). Primary treatment phase: Hormonal treatment plus 8 consecutive weekly subcutaneous vaccinations with tecemotide (L-BLP25) 1000 micrograms (actual delivered dose was 930 micrograms)* (Week 1 to 8). Maintenance treatment phase: Hormonal treatment plus vaccinations with tecemotide (L-BLP25) 1000 micrograms (actual delivered dose was 930 micrograms)* at six-week intervals beginning at Week 14 and continued until Progressive Disease (PD). *calculated as mass of lipopeptide (antigen)<br>Drug: cyclophosphamide<br>* 300 mg/m^2 (to a maximum of 600 mg) of intravenous cyclophosphamide.<br>|
| Active Comparator: Control Arm<br>Control Arm: Pretreatment (Single Dose): sodium chloride (NaCl) 9 grams per liter (g/L) infusion Placebo plus Hormonal Therapy (Standard Dose) | Biological: Placebo of tecemotide (L-BLP25) and Hormonal Treatment<br>* Control Arm: Pretreatment (Single Dose) NaCl 9 g/L infusion as a substitute for cyclophosphamide. Primary treatment phase: Hormonal therapy plus 8 consecutive weekly subcutaneous placebo doses (Week 1 to 8). Maintenance treatment phase: Hormonal therapy plus placebo doses at six-week intervals beginning at Week 14 and continued until Progressive Disease (PD).<br>Drug: sodium chloride (NaCl)<br>* NaCl 9 g/L infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS was defined as the duration from randomization to first observation of progressive disease (PD) as confirmed by the independent radiological review or death. | Time from randomization to disease progression, death or last tumor assessment, reported between day of first participant randomized i.e. 30 Sep 2009, until end of trial i.e. 27 Aug 2010 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Time | OS time was defined as the time from randomization to death. Participants without event were to be censored at the last date known to be alive or at the clinical cut-off date, whichever was earlier. | Time from randomization to death or last day known to be alive reported between day of first participant randomized i.e. 30 Sep 2009, until end of trial i.e. 27 Aug 2010 | 
| Percentage of Participants With Objective Tumor Response | Percentage of participants with objective tumor response was to be reported. An objective response (OR) was defined as a participant having a best overall response of either confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST 1.0) as assessed by independent radiological review. | Randomization until the date of first documented progression, until end of trial i.e. 27 Aug 2010 | 
| Duration of Response | Duration of response is defined as the time from the first assessment of CR or PR until the date of the first occurrence of PD, or until the date of death. | Time from first assessment of CR or PR until PD, death or last tumor assessment, reported between day of first participant randomized i.e. 30 Sep 2009, until end of trial i.e. 27 Aug 2010 | 
| Percentage of Participants With Clinical Benefit | Clinical Benefit is defined as having achieved at least disease stabilization; that is participants with confirmed CR, PR, or stable disease (SD,) lasting for at least 22 weeks. | Randomization until the date of first documented progression assessed up to end of trial i.e. 27 Aug 2010 | 
| Time to Progression (TTP) | TTP is defined as the time from date of randomization to the date of radiological diagnosis of PD (censoring for death without progression). | Time from randomization to PD, reported between day of first participant randomized i.e. 30 Sep 2009, until end of trial i.e. 27 Aug 2010 | 
| Time to Chemotherapy | Time to chemotherapy is defined as the time from date of randomization to the start date of chemotherapy. | Time from randomization to start of chemotherapy, reported between day of first participant randomized i.e. 30 Sep 2009, until end of trial i.e. 27 Aug 2010 | 
| Functional Assessment of Cancer Therapy-Breast (FACT-B) Questionnaire | FACT-B questionnaire consists of 36 questions; 7 in physical well-being (PWB); 7 in social well-being (SWB); 6 in emotional well-being (EWB); 7 in functional well-being (FWB); 9 in breast cancer subscale (BCS). Trial outcome Index (TOI) was calculated by the sum of the physical well-being (PWB), functional well-being (FWB), and breast cancer scale (BCS) subscales of FACT-B. Total score of subscores or TOI is calculated from each score of question. Higher score means better and lower score means worthier. Score range; 0-28 in PWB; 0-28 in SWB; 0-24 in EWB; 0-28 in FWB; 0-36 in BCS; 0-92 in TOI. | Baseline, Week 9, 20, 32, 44 and end of trial visit | 
| European Questionnaire-5 Dimensions (EQ-5D) Questionnaire | EQ-5D questionnaire is a measure of health status that provides a simple descriptive profile and a single index value. The optional part of the questionnaire was not applied. EQ-5D defines health in terms of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 5 items are combined to generate health profiles. These profiles were to be converted to a continuous single index score using a one to one matching. The lowest possible score is -0.59 and the highest is 1.00. Higher scores on the EQ-5D represent a better quality of life (QoL) and lower scores on the EQ-5D represent a worst QoL. | Baseline, Week 9, 20, 32, 44 and end of trial visit | 
| Number of Participant Utilizing Healthcare Resources | Healthcare Resource Utilization (HRU) parameters included direct medical resources (e.g., nonscheduled procedures, unplanned hospitalization, outpatient visits), nonmedical resources (e.g., travel, paid and unpaid assistance), and occupational resources (e.g., occupational changes and concerns). | Randomization up to end of trial visit | 
| Serum Carcinoma Antigen (CA) 15-3 Levels | CA 15-3 is a serum marker for breast cancer which is a possible measure for immune response. | Baseline, Week 5, 9, 20, 32, 44 and end of trial visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MUC1, Phase III trial, randomized, cancer vaccine, BLP25, advanced breast cancer, postmenopausal breast cancer, immunotherapy of breast cancer, Inoperable locally advanced, recurrent, or metastatic endocrine-sensitive Breast Cancer