E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006203 |
E.1.2 | Term | Breast cancer stage unspecified |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
To assess the efficacy of EP2006 compared to Neupogen® (US-licensed) with respect to the mean duration of severe neutropenia (DSN), defined as the number of consecutive days with Grade 4 neutropenia (absolute neutrophil count [ANC] less than 0.5 x 10 9/L), during Cycle 1 of the neoadjuvant or adjuvant TAC regimen (Taxotere® [docetaxel 75 mg/m2] in combination with Adriamycin® [doxorubicin 50 mg/m2] and Cytoxan® [cyclophosphamide 500 mg/m2]) in breast cancer patients. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to further assess the efficacy, safety, and immunogenicity of EP2006 and Neupogen® and to compare the effects of repeated switching between EP2006 and Neupogen®. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
As part of protocol EP06-302, pharmacokinetics (development of
filgrastim serum concentrations within 24 hours after the first
administration of study drug in Cycle 1 of chemotherapy) will be
evaluated in a subset of 50 patients.
Additionally, trough concentrations during Cycle 1 and on Day 1 of Cycle 2 will be evaluated for this subset of patients. |
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E.3 | Principal inclusion criteria |
1. Written informed consent before any assessment is performed
2. Patients with histologically proven breast cancer, eligible for neoadjuvant or adjuvant TAC chemotherapy
3. Women ≥ 18 years of age
4. Estimated life expectancy of more than six months
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
6. Adequate bone marrow function on Cycle 1 Day 1, prior to chemotherapy administration:
• ANC ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Hemoglobin ≥ 10 g/dL
7. Total bilirubin within normal limits, unless the patient has Gilbert’s syndrome
8. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) level ≤ 2 x upper limit of normal (ULN)
9. Liver-derived alkaline phosphatase level ≤ 3 x ULN
10. Creatinine ≤ 1.5 x ULN
11. For all women of childbearing potential: negative serum pregnancy test within seven days prior to randomization, and using a highly effective method of birth control.
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E.4 | Principal exclusion criteria |
1. History of myelogenous leukemia or myelodysplastic syndrome
2. History or presence of sickle cell disease
3. Previous or concurrent malignancy except non-invasive non-melanoma skin cancer, in situ carcinoma of the cervix, or other solid tumor treated curatively, and without evidence of recurrence for at least ten years prior to study entry
4. Any serious illness or medical condition, that may interfere with safety, compliance, response to the products under investigation or chemotherapy and their evaluation, such as:
• Active uncontrolled infection
• Clinically significant impairment of left ventricular ejection fraction (LVEF) (measured within three month before study entry by echocardiography or Multiple Gated Acquisition scan (MUGA) must be above the lower limit of normal for the respective center)
• Severe valvular heart disease, myocardial infarction, unstable angina pectoris, uncontrolled hypertension or uncontrolled arrhythmias within six months from study entry
• Significant neurologic or psychiatric disorders including psychotic disorders, dementia, or seizures that would prohibit the understanding and giving of informed consent
5. Concurrent or prior radiotherapy within four weeks of randomization
6. Concurrent or prior chemotherapy for breast cancer
7. Concurrent or prior anti-cancer treatment for breast cancer such as endocrine therapy, immunotherapy, monoclonal antibodies, and/or biological therapy
8. Concurrent prophylactic antibiotics
9. Prior bone marrow or stem cell transplant
10. Previous therapy with any rhG-CSF product
11. Known hypersensitivity to E. coli proteins or any of the excipients used in the IMPs
12. Patient known to have HIV, Hepatitis B, Hepatitis C or who have a positive serology for HIV, Hepatitis B or Hepatitis C at screening
13. Known control drug addiction, including alcoholism
14. Participation in any other clinical study using an IMP or device within three months before the screening visit
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint the mean duration of severe (Grade 4)
neutropenia in Cycle 1, defined as the number of consecutive days in
which a patient has an ANC < 0.5 × 10 9/L |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Depth of ANC nadir, defined as the patient's lowest ANC
2. Time to ANC recovery, defined as the time from the chemotherapy administration until the ANC increases to ≥ 2 × 10 9/L after the nadir
3. Incidence of febrile neutropenia (defined as orally temperature of ≥38.3°C concurrent with an ANC < 0.5 × 10 9/L) by treatment group, by cycle and across all cycles; and the number of days of fever, defined as orally temperature ≥ 38.3°C, for each cycle. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1/2: Depth of ANC nadir and time to ANC recovery will be evaluated:
• Cycle 1 daily prior to the IMP administration until the ANC recovers to 10 x 109/L after the nadir or until Day 15, whichever occurs first.
• Cycle 2 to Cycle 6 daily from Day 7 prior to IMP administration until the ANC recovers to 10 x 10 9/L after the nadir or until Day 15, whichever occurs first. Additional CBC samples will be collected on each day a patient reports a fever episode (orally temperature ≥ 38.3 °C), the next day, and every other day thereafter until the ANC reaches a value > 0.5 x 10 9/L.
3. Incidence of febrile neutropenia will be evaluated across all cycles. |
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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 | Yes |
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 | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 46 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Czech Republic |
Hungary |
India |
Latvia |
Lithuania |
Russian Federation |
Serbia |
Slovakia |
Ukraine |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |