E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
metastatic breast cancer, resistant to aromatase inhibitors |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Main objective : To compare the clinical benefit rate between fulvestrant plus enzastaurin and fulvestrant plus placebo in Aromatase Inhibitor resistant MBC. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives: o response rates (RR) according to the Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines o duration of clinical benefit o progression-free survival (PFS) o safety and adverse event profile using Common Terminology Criteria for Adverse Events (CTCAE; version 3.0; NCI 2006) o assess biomarkers relevant to enzastaurin and the disease state, as well as their correlation to clinical outcome.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients will be included from the study if they meet all of the following criteria: [1] Female patients with a histological-documented diagnosis of locally advanced or metastatic breast cancer. The primary or metastatic tumor must be ER and/or PR receptor positive. [2] Patients are resistant to AI therapy In the case of adjuvant therapy: patient should have been on treatment for at least 1 year and have had an objective recurrence during this treatment or in the first year after finishing it In the case of treatment in advanced disease: patients must have achieved a tumor response or stabilization lasting at least 6 months and have had an objective progression after treatment [3] Females with postmenopausal status defined as: • Age ≥ 60 years or age ≥ 45 years and 24 months from the last menstrual period with intact uterus • Follicle-stimulating hormone level within postmenopausal range • Prior radiation, medical or surgical castration (such as bilateral salpingo-oophorectomy) [4] Previous radiation therapy is allowed, but should have been limited and must not have included whole pelvis radiation. Patients must have recovered from the toxic effects of the treatment prior to study enrollment (except for alopecia). Lesions that have been irradiated cannot be included as sites of measurable disease unless clear tumor progression, according to RECIST criteria, has been documented in these lesions since the end of radiation therapy [5] Measurable or nonmeasurable disease defined by: • At least 1 unidimensionally measurable lesion meeting RECIST (Protocol Attachment S023.5; Therasse et al. 2000) Guidelines (at least 10 mm in longest diameter by spiral computerized tomography [CT] scan, or at least 20 mm by standard techniques). Positron emission tomography (PET) scans and ultrasounds may not be used • At least 1 nonmeasurable lesion whose presence is assessable using standard techniques or a spiral CT scan even though the lesion is smaller than the minimum size required for measurability (PET scans and ultrasounds may not be used). Patients with bone lesion(s) in the absence of measurable disease can be recruited provided they can be evaluated by X-ray, CT or MRI (patients with lesions assessed only by bone scan cannot be included). (Note: The number of patients with evaluable-only (nonmeasurable, for example bone metastases) disease to be enrolled in the trial will be limited to a maximum of 40 patients) [6] Prior bisphosphonate therapy is allowed if begun 4 weeks before study enrollment [7] Have a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) scale (Oken et al. 1982) [8] Have adequate organ function including the following: Adequate bone marrow reserve: white blood cell (WBC) count > or = 3.0 x 109/L, absolute neutrophil count (ANC) > or = 1.5 x 109/L, platelet count > or = 75.0 x 109/L, and hemoglobin > or = 10.0 g/dL (> or = 6.2 mmol/L). Hepatic: bilirubin < or = 1.5 times the upper limit of normal (x ULN); alkaline phosphatase (ALP), aspartate transaminase (AST), and alanine transaminase (ALT) < or = 2.5 x ULN or < or = 5 x ULN with liver metastases. Renal: serum creatinine < 1.5 x ULN. [9] Are at least 18 years of age [10] Have an estimated life expectancy of at least 24 weeks [11] Exhibit patient compliance and geographic proximity that allow for adequate follow-up [12] Must sign an informed consent document (or legal representative has given informed consent)
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E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria: [13] Have received treatment with more than 1 line of hormonal therapy in the metastatic setting [14] Have had prior treatment with fulvestrant or enzastaurin [15] Have received chemotherapy for metastatic disease [16] Are receiving concurrent administration of any other antitumor therapy, with the exception of gonadotropin-releasing hormone (GnRH) antagonists. [17] Have received treatment within the last 4 weeks with a drug that has not received regulatory approval for any indication at the time of study entry [18] Have received supplemental estrogen or progesterone within 4 weeks prior to study entry [19] Are HER2-positive [20] Are unable to discontinue use of anticoagulants [21] Have hypercalcemia: corrected calcium >10% over ULN [22] Have a second primary malignancy that is clinically detectable at the time of consideration for study enrollment [23] Have documented central nervous system (CNS) metastases, symptomatic pulmonary lymphangitis, or involvement of more than 1/3 of the liver (that is, patients with rapidly progressive disease, or those whose assessment dictates that chemotherapy would be more appropriate) [24] Have a serious concomitant systemic disorder (for example, active infection including HIV) incompatible with the study (at the discretion of investigator), previous history of bleeding diathesis, or coagulation treatment [25] Have a serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease, as defined by the New York Heart Association Class III or IV (Bruce RA 1956) [26] Are unwilling or unable to discontinue use of carbamazepine, phenobarbital, or phenytoin at least 14 days prior to study therapy [27] Are unable to swallow tablets.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy measure is the clinical benefit rate. Clinical benefit (CB) is defined as the best response of CR, PR, and SD for > or = 24 weeks duration. The CB rate is defined, for each treatment arm, as the number of patients with the best response of CR, PR, and SD for > or = 24 weeks duration divided by the number of randomized and treated patients. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |