E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Febrile neutropenia in breast cancer patients undergoing TAC chemotherapy |
|
E.1.1.1 | Medical condition in easily understood language |
Low white blood cell counts in breast cancer patients undergoing chemotherapy |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10016288 |
E.1.2 | Term | Febrile neutropenia |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
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 demonstrate an equivalent efficacy of Pegylated Apo‐Filgrastim as
compared to each of the commercially available US and EU licensed
Neulasta® in patients suffering from early breast cancer and receiving TAC
(docetaxel, doxorubicin, cyclophosphamide) anticancer chemotherapy in
adjuvant setting. |
|
E.2.2 | Secondary objectives of the trial |
• To assess the safety of Pegylated Apo‐Filgrastim as compared to that
of commercially available US and EU licensed Neulasta® when administered through 6 cycles of TAC anticancer chemotherapy
• To assess the potential antigenicity of Pegylated Apo‐Filgrastim during the chemotherapy and 30 weeks after the completion of chemotherapy |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Female, ≥18 of age, suitable and intended to undergo adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide) chemotherapy.
2. Body weight within 40 and 120 kg
3. Subjects within 60 days of complete surgical resection of the primary breast tumor: either lumpectomy or mastectomy with sentinel lymph node biopsy or axillary dissection, with clear margins for both invasive and ductal carcinoma in situ (DCIS)
4. Stage IIA, IIB or IIIA breast cancer
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
6. Absolute neutrophil count (ANC) ≥1,5 x 109/L; platelet count ≥100 x 109/L
7. Adequate renal (serum creatinine <1,5 x upper limit of normal (ULN)) and hepatic function (bilirubin < ULN, transaminases and alkaline phosphatase (AP) <1,5 x ULN)
8. Normal cardiac function evidenced by a left ventricle ejection fraction (LVEF) ≥55%
9. No evidence of metastatic disease
10. Baseline bilateral mammography (or other scan to exclude cancer on the contralateral breast)
11. Subjects must not intend to conceive during or shortly after the study. They must be either post‐menopausal, surgically incapable of bearing children, or practicing an acceptable method of birth control (e.g., hormonal contraceptives, intrauterine device, or spermicide and barrier) and be willing to continue the same method of birth control during the entire course of the study
12. Females of child‐bearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test before the first dose of study medication
13. Willing and able to give written informed consent
14. Willing and able to undergo procedures required by this protocol. |
|
E.4 | Principal exclusion criteria |
1. Bilateral breast cancer (concomitant or prior) except in situ lesion, either ductal or lobular, of the contralateral breast
2. History of severe hypersensitivity reaction to medications intended to use in this protocol
3. Prior chemotherapy (either adjuvant or neoadjuvant) for this breast cancer
4. History of myocardial infarction, heart failure, uncontrolled angina, severe uncontrolled arrhythmias, pericardial disease, or electrocardiographic evidence of acute ischemic changes
5. Immunotherapy, hormonal therapy (e.g. tamoxifen or aromatase inhibitors), Herceptin (trastuzumab) concurrently or within 30 days of screening
6. Concurrent radiation therapy
7. Investigational therapy concurrently or within 30 days of screening
8. Peripheral neuropathy >Grade 1
9. Major organ allograft or condition requiring chronic immunosuppression (i.e. kidney, liver, lung, heart, bone marrow transplant, or autoimmune diseases). Patients who received corneal transplants or cadaver skin or bone transplants are eligible.
10. Serious uncontrolled intercurrent medical or psychiatric illness, including serious viral (including clinically defined acquired immunodeficiency syndrome ‐ AIDS), bacterial or fungal infection; or history of uncontrolled seizures, or diabetes, or central nervous system disorders deemed by the Investigator to be clinically
significant, precluding informed consent
11. Active hepatitis B or hepatitis C with abnormal liver function tests (LFTs) or is known to be HIV positive
12. History of other malignancy within the last 5 years (except cured basal cell carcinoma of skin, carcinoma in situ of uterine cervix or DCIS)
13. Pregnancy or breastfeeding. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Duration of severe neutropenia (DSN) in cycle 1. Severe neutropenia is
defined as occurrence of ANC below 0,5 x 109/L. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
D0,D1,D3,D5,D6,D8 and D10-15 |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
• The frequency of grade 3 and 4 severe neutropenia (ANC below 1,0 x
109/L and 0,5 x 109/L, respectively)
• The depth of ANC nadir in cycles 1
• The time to the post nadir ANC recovery (ANC ≥2,0 X 109) in cycle 1
• The rates of Febrile Neutropenia (FN) by cycle and across the cycles.
The definition of FN used for the purpose of this protocol will be,
single temperature: ≥38,3°C measured orally or ≥38,0°C for over 1
hour; neutropenia: ANC <0,5 X 109/L or <1 X 109/L and a predicted
decline to ≤0,5 X 109/L over the next 48 hours.
• The ANC‐time profile in cycle 1 (The time from the beginning of
chemotherapy to the occurrence of the ANC nadir)
• The frequency and type of (culture‐confirmed) infections
• The incidence of i.v. antibiotic therapy and hospitalization
• The mobilization of CD34+ cells (in selected centers only)
• Incidence, severity and distribution of bone pain
• Percentage of scheduled chemotherapy dose that was delivered
• Proportion with chemotherapy doses reduced, omitted, or delayed
• Number of days of delay of chemotherapy
• Occurrence and/or resolution of chemotherapy‐induced mucositis
Safety endpoints
• Incidence of adverse events (all severe and serious) classified by
system organ class, preferred term, severity, and relationship to
study medication
• Injection site reactions
• Vital signs
• Presence of antibodies and abnormal clinical laboratory results. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cycle1: D0,D1,D2,D3,D5,D6,D7,D9 and D8, D10-15
Cycle 2-6:D1,D2,D9±1, W20,W24,W36 and W48 |
|
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 | 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 | Yes |
E.8.1.4 | Double blind | No |
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 | 3 |
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 | 67 |
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 |
Belarus |
Bosnia and Herzegovina |
Bulgaria |
Czech Republic |
Egypt |
Georgia |
Hungary |
Morocco |
Poland |
Romania |
Russian Federation |
Serbia |
Slovakia |
Tunisia |
Turkey |
Ukraine |
|
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
|
|
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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |