| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Her-2 Positive Early Breast Cancer |
| HER2 pozitivni rani karcinom dojke |
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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 | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
| 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 |
| The primary objective of this study is to demonstrate equivalence of CT-P6 and Herceptin, both given in combination with docetaxel (75 mg/m2, Cycles 1 to 4) followed by FEC (5-fluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2,, Cycles 5 to 8), in terms of efficacy as determined by pathological complete response (pCR), in patients with HER2-positive operable early breast cancer. |
| Primarni cilj ovog ispitivanja je dokazivanje ekvivalencije lijeka CT-P6 i lijeka Herceptin kada se daju u kombinaciji s docetakselom (75 mg/m2, od 1. do 4. ciklusa) i kombinacijom FEC (5-fluorouracil 500 mg/m2, epirubicin 75 mg/m2 i ciklofosfamid 500 mg/m2 od 5. do 8. ciklusa) prema kriteriju učinkovitosti utvrđenom prema potpunom odgovoru tumora u ispitanica s HER2-pozitivnim ranim karcinomom dojke koji se može operirati. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of this study are to evaluate additional efficacy parameters (overall response rate, disease-free survival, progression-free survival, overall survival, breast conservation rate, and other pCRs) and to obtain additional PK, pharmacodynamic, safety, and biomarker data. |
| Sekundarni ciljevi ovog ispitivanja su procjena dodatnih parametara učinkovitosti (ukupna stopa odgovora, preživljavanje bez bolesti, preživljavanje bez pogoršanja bolesti, ukupno preživljavanje, stopa očuvanja dojke i ostali potpuni odgovori tumora) i prikupljanje dodatnih podataka o farmakokinetici, farmakodinamici, sigurnosti i biomarkerima. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following criteria to be enrolled in this study:
1.Patient is a female 18 years of age or older.
2.Patient who has Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
3.Patient who has histologically confirmed and newly diagnosed breast cancer.
4.Patient who has clinical stage I, II, or IIIa operable breast cancer according to the AJCC Breast Cancer Staging 7th edition.
5.At least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1
a.Tumor lesions: ≥10 mm in long axis by computerized tomography (CT) scan
b.Malignant lymph nodes: ≥15 mm in short axis when assessed by CT scan
6.Patient who has HER2 positive status confirmed locally, defined as 3 + score by immunohistochemistry (IHC). When the IHC result is equivocal (defined as 2 + score), patient who has a positive fluorescence in situ hybridization (FISH) or a chromogenic in situ hybridization (CISH) result.
7.Patient who has a normal LVEF (≥55%) at Baseline, as determined by either two-dimensional echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan. If the patient is randomized, the same method of LVEF assessment, ECHO or MUGA, must be used throughout the study.
8.Patient who has known estrogen receptor and progesterone receptor status tested at Screening.
9.Patient who has adequate bone marrow function, defined as:
a.Absolute neutrophil count ≥1,500/µL
b.Hemoglobin ≥10.0 g/dL
c.Platelets ≥100,000/µL
10.Patient who has adequate hepatic and renal function, defined as:
a.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN)
b.Total bilirubin ≤1.5 × ULN
c.Alkaline phosphatase ≤2.5 × ULN
d.Serum creatinine ≤1.5 mg/dL
11.Patient who has the ability to comprehend the full nature and purpose of the study, including possible risks and side effects, to cooperate with the investigator, to understand verbal and/or written instructions, and to comply with the requirements of the entire study.
12.Patient must voluntarily sign an Institutional Review Board/Independent Ethics Committee (IRB/IEC)-approved informed consent form (ICF) before any study specific procedures. |
1. Bolesnice u dobi od 18 ili više godina.
2. Bolesnice s indeksom općeg stanja zdravlja prema ECOG-ljestvici od 0 ili 1.
3. Bolesnice s histološki potvrđenim novodijagnosticiranim karcinomom dojke.
4. Bolesnice s karcinomom dojke koji se može operirati stadija I, II ili IIIa prema 7. izdanju stupnjevanja karcinoma dojke Američkog odbora za karcinom (AJCC).
5. Barem jedna mjerljiva lezija prema Kriterijima procjene odgovora čvrstih tumora
(RECIST) inačice 1.1:
a. tumorske lezije ≥ 10 mm po dužoj osi utvrđeno snimanjem kompjutorskom tomografijom;
b. maligne limfne žlijezde ≥ 15 mm po kraćoj osi utvrđeno snimanjem kompjutorskom tomografijom.
6. Bolesnice koje imaju u lokalnom laboratoriju potvrđen pozitivan status receptora ljudskog epidermalnog faktora rasta (HER) 2 definiran kao rezultat 3 + utvrđen imunohistokemijskom analizom, a ako je imunohistokemijski rezultat nepouzdan (definiran kao rezultat 2 +), bolesnice koje imaju pozitivan rezultat utvrđen fluorescentnom in situ hibridizacijom (FISH) ili hromogenom in situ hibridizacijom (CISH).
7. Bolesnice s normalnom početnom vrijednošću ejekcijske frakcije lijeve klijetke (≥ 55 %) utvrđenom dvodimenzionalnim ehokardiogramom ili radionuklidnom ventrikulografijom (MUGA). Ako se bolesnica randomizira, tijekom cijelog ispitivanja mora se koristiti ista metoda procjene ejekcijske frakcije lijeve klijetke ehokardiogramom ili radionuklidnom ventrikulografijom.
8. Bolesnice koje imaju poznat status receptora estrogena i progesterona testiran na probiru.
9. Bolesnice koje imaju odgovarajuću funkciju koštane srži definiranu kao:
a. apsolutni broj neutrofila ≥ 1500/µ l;
b. hemoglobin ≥ 10,0 g/dl;
c. trombociti ≥ 100,000µ/ l.
10. Bolesnice koje imaju odgovarajuću funkciju jetre i bubrega definiranu kao:
a. aspartat aminotransferaza i alanin aminotransferaza ≤ 2,5 × gornja granica normale;
b. ukupni bilirubin ≤ 1,5 × gornja granica normale;
c. alkalna fosfataza ≤2,5 × gornja granica normale;
d. serumski kreatinin ≤1,5 mg/dl.
11. Bolesnice koje mogu u potpunosti razumjeti prirodu i svrhu ovog ispitivanja, uključujući i moguće rizike i nuspojave, koje mogu surađivati s ispitivačem i razumjeti usmene i pisane upute te ispunjavati zahtjeve cjelokupnog ispitivanja.
12. Prije provođenja postupaka iz ispitivanja bolesnice moraju dobrovoljno potpisati informirani pristanak koji je odobrilo Središnje etičko povjerenstvo.
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| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will be excluded from the study:
1.Patient who has bilateral breast cancer.
2.Patient who is pregnant or lactating.
3.Patient who has received prior treatment for breast cancer, including chemotherapy, biologic therapy, hormone therapy, immunotherapy, radiation, or surgery, with the exception of diagnostic biopsy for primary breast cancer.
4.Patient who has received any prior therapy with anthracyclines.
5.Patient who has other concomitant active malignancy or history of malignancy in the past 5 years except treated basal cell carcinoma of the skin or carcinoma in situ of the cervix.
6.Serious cardiac illness or medical conditions that could preclude the use of trastuzumab, specifically: New York Heart Association (NYHA) class ≥2, history of documented congestive heart failure (CHF), high-risk uncontrolled arrhythmias, angina pectoris requiring medication, clinically significant valvular disease, evidence of transmural infarction on electrocardiogram (ECG), poorly controlled hypertension.
7.Patient who has a current history of infection with hepatitis B, hepatitis C, or infection with human immunodeficiency virus, or who has a positive result to the screening test for those infections.
8.Patient who has had any recent infection requiring a course of systemic anti infectives that were completed ≤14 days before randomization (with the exception of uncomplicated urinary tract infection).
9.Patient who is a woman of childbearing potential who is not consenting to use highly effective methods of birth control (e.g., intra-uterine device, barrier methods including condom and diaphragm, also in conjunction with spermicidal jelly, or total abstinence; Oral, injectable, or implant hormonal contraceptives are not acceptable) during treatment and for an additional 6 months after the last administration of the protocol specified treatment.
10.Patient who is currently receiving treatment with another investigational device or medical product, or less than 30 days or 5 half-lives, whichever is longer, have spanned since ending treatment with another investigational device or medical product.
11.Patient who has known sensitivity to any of the products to be administered during the study, including mammalian cell derived drug products, trastuzumab, and murine proteins, or to any of the excipients.
12.Patient who has previously participated in this study.
13.Patient who will likely not be available to complete all protocol required study visits or procedures.
14.Patient who has history or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the investigator, would pose a risk to patient safety or interfere with the study evaluation, procedures, or completion. |
1. Bolesnice koje imaju bilateralni karcinom dojke.
2. Bolesnice koje su trudne ili doje.
3. Bolesnice koje su primale prethodno liječenje karcinoma dojke, uključujući kemoterapiju, biološku terapiju, hormonsku terapiju, imunoterapiju, zračenje ili operaciju, uz iznimku dijagnostičke biopsije za primarni karcinom dojke.
4. Bolesnice koje su primale bilo koje prethodno liječenje antraciklinima.
5. Bolesnice koje imaju drugu popratnu malignu bolest ili povijest malignih bolesti u zadnjih 5 godina, osim liječenoga karcinoma bazalnih stanica kože ili karcinoma in situ vrata maternice.
6. Ozbiljna srčana bolest ili zdravstveno stanje koje bi moglo spriječiti korištenje trastuzumaba, a posebno klase ≥ 2 prema ljestvici NYHA, povijest dokazanog kongestivnog zatajenja srca, visokorizična nekontrolirana aritmija, angina pektoris koja zahtijeva primjenu lijekova, klinički značajna bolest srčanih zalistaka, dokaz transmuralnog infarkta na EKG-u i slabo kontrolirana hipertenzija.
7.Bolesnice s postojećom infekcijom hepatitisom B ili C ili HIV-om ili bolesnice s pozitivnim rezultatom na te infekcije na probiru.
8.Bolesnice koje su imale nedavne infekcije zbog kojih su morale primati liječenje sistemskim protuinfekcijskim lijekovima koje je završeno ≤ 14 dana prije randomizacije (uz iznimku nekomplicirane infekcije urinarnog trakta).
9.Bolesnice koje mogu zatrudnjeti, a tijekom ispitivanja i u 6 mjeseci nakon primanja zadnje doze lijeka navedenog u planu ispitivanja ne pristanu koristiti visokoučinkovitu metodu kontracepcije (primjerice, unutarmaternični usadak, barijerne metode uključujući kondom i dijafragmu u kombinaciji sa spermicidnim gelom) ili na potpunu apstinenciju. Hormonska kontracepcija u obliku tableta, injekcija ili implantata nije prihvatljiva.
10. Bolesnice koje trenutno primaju liječenje ispitivanim sredstvom ili medicinskim proizvodom ili je od završetka liječenja drugim ispitivanim sredstvom ili medicinskim proizvodom prošlo manje od 30 dana ili 5 poluvremena eliminacije iz organizma.
11. Bolesnice koje imaju poznatu osjetljivost na bilo koji lijek koji se primjenjuje tijekom ispitivanja, uključujući lijekove izvedene iz stanica sisavaca, trastuzumab i mišje proteine, ili na bilo koje od pomoćnih sredstava.
12. Bolesnice koje su prethodno sudjelovale u ovom ispitivanju.
13. Bolesnice za koje je vjerojatno da neće biti dostupne za obavljanje svih posjeta ili postupaka iz ispitivanja u skladu s planom ispitivanja.
14. Bolesnice koje imaju povijest ili dokaz bilo kojeg klinički značajnog poremećaja, stanja ili bolesti (uz gore navedene iznimke) koji bi prema mišljenju ispitivača predstavljali rizik za njihovu sigurnost ili bi utjecali na procjene, postupke ili završetak ispitivanja
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the pCR, defined as the absence of invasive tumor cells in the breast and in axillary lymph nodes, regardless of DCIS. |
| Primarna krajnja točka učinkovitosti bit će potpuni odgovor tumora koji se definira kao nepostojanje invazivnih tumorskih stanica u dojci i limfnim čvorovima u pazuhu, bez obzira na duktalni karcinom in situ. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The pCR will be determined at the time of surgery, using hematoxylin and eosin evaluation of the resected breast specimen. |
| Potpuni odgovor tumora utvrdit će se u trenutku operacije koristeći postupak bojanja reseciranog uzorka dojke hematoksilinom i eozinom. |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints will be the following:
•ORR (clinical response rate and radiological response rate), defined as CR or PR as assessed by RECIST Version 1.1 (Appendix 12.2) (Eisenhauer et al 2009)
•DFS, measured from the time of occurrence of attained CR to disease recurrence or death as a result of any cause
•PFS, measured from the randomization to disease recurrence, progression or death from any cause
•OS, defined as time from randomization to death from any cause
•Breast conservation rate, measured as the proportion of patients who undergo breast conservation surgery
•Other pCRs
•pCRB
•pCR of breast and axillary nodes with absence of DCIS
The secondary PK endpoints during the Neoadjuvant Period will be the following:
•Observed maximum serum concentration after administration (Cmax), at each dose
•Observed trough serum concentration (Ctrough), prior to next dose for Cycle 1 to Cycle 7, and at EOT1 for dose 8.
The secondary pharmacodynamic endpoint is serum HER2 shed antigen during the Neoadjuvant Period
The secondary safety endpoints will be the following:
•Incidence and severity of AEs, including SAEs graded according to the NCI CTCAE Version 4.03.
•Cardiotoxicity, as assessed by mean change from Baseline to endpoint assessment in LVEF.
•Immunogenicity, as assessed by the incidence of antidrug antibody.
Biomarker Endpoints (Optional):
The FcγR genotype (FcγRIIa, IIIa, and/or any necessary genotypes) will be evaluated as secondary endpoints.
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Sekundarne krajnje točke učinkovitosti:
•ukupna stopa odgovora (stopa kliničkog odgovora i stopa radiološkog odgovora), definirana kao potpuni ili parcijalni odgovor prema kriterijima RECIST inačice 1.1;
•ukupno preživljavanje definirano kao vrijeme od randomizacije do smrti od bilo kojeg uzroka;
•preživljavanje bez bolesti, mjereno od trenutka pojave ostvarenog potpunog odgovora do povrata bolesti ili smrti zbog bilo kojeg razloga;
•preživljavanje bez napretka bolesti, mjereno od trenutka randomizacije do povrata ili pogoršanja bolesti ili smrti zbog bilo kojeg razloga;
•stopa očuvanja dojke, mjereno kao omjer ispitanica podvrgnutih operaciji za poštedu dojke;
•ostali potpuni odgovori tumora:
o potpuni odgovor tumora samo dojke;
o potpuni odgovor tumora dojke i limfnih čvorova u pazuhu uz odsustvo duktalnog karcinoma in situ.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| see protocol table 12.1 |
| Pogledati tablicu plana ispitivanja 12.1 |
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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 | Yes |
| E.6.8 | Bioequivalence | Yes |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | 2 |
| 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 | 90 |
| 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 |
| Argentina |
| Belarus |
| Brazil |
| Chile |
| France |
| Georgia |
| Greece |
| Hungary |
| India |
| Italy |
| Korea, Republic of |
| Latvia |
| Mexico |
| Netherlands |
| Peru |
| Philippines |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Serbia |
| South Africa |
| Spain |
| Ukraine |
| United States |
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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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| The date of study termination will be defined as the date on which the last patient completes the last visit (including the Follow-Up Visit). |
| Datum završetka ispitivanja definirat će se kao datum na koji je posljednji ispitanik završio posljednji posjet (uključujući i posjet za praćenje). |
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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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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