E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Metastatic Breast Cancer in HER2- positive CTC with primary HER2-negative. |
Tumore mammario metastatico con CTC HER2-positive e tumore primario al seno HER2-negativo. |
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E.1.1.1 | Medical condition in easily understood language |
Metastatic Breast Cancer |
Tumore della Mammella Metastatico |
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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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027475 |
E.1.2 | Term | Metastatic breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 determine the overall Clinical Benefit (CB) of the two regimens (nab-paclitaxel plus trastuzumab (ARM A) versus nab-paclitaxel alone (ARM B)) among evaluable patients. |
Determinare il beneficio clinico complessivo (CB) dei due regimi nab-paclitaxel più trastuzumab (braccio A) rispetto al nab-paclitaxel (braccio B) da solo tra i pazienti valutabili. |
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E.2.2 | Secondary objectives of the trial |
To determine the prognostic and predictive significance of HER2-positive CTC.
To evaluate additional measures of tumor control to further characterize the efficacy of the nab-paclitaxel plus trastuzumab vs. nab-paclitaxel. |
Determinare il valore prognostico e predittivo dI CTC HER2-positive.
Valutare misure aggiuntive di controllo tumorale per caratterizzare ulteriormente l'efficacia del regime di combinazione vs. nab-paclitaxel. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Signed written informed consent.
2.Age ≥18 years.
3.ECOG 0-2
4.At least one clinically or radiologically measurable lesion and/or non-measurable disease evaluable according to Response Evaluation Criteria In Solid Tumors (RECIST version 1.1). Osteoblastic/osteolytic bone metastasis will be included.
5.HER2 negative on primary tumor (HER-2 score of 0 or 1+/2+ with FISH not amplified) as locally diagnosed.
6.Detection of at least 1 HER2+ve CTC.
7.Patients may have received chemotherapy/hormonotherapy as neo/adjuvant treatment.
8.Adequate bone marrow, renal and hepatic functions: ANC greater than 1.5x10^9/l, platelets greater than 100x10^9/l, serum creatinine < 1.5 x UNL, serum AST/ALT < 1.5 x UNL unless liver metastasis < 2.5 x UNL.
9.Adequate cardiac function: left ventricular ejection fraction (LVEF) at rest measured by echocardiography or MUGA scan must be no lower than the local normal limit.
10.Troponin level below the cut-off.
11.Absence of clinically significant cardiovascular disease (e.g. myocardial infarction, unstable angina), New York Hearth Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, or grade II or greater peripheral vascular disease within 12 months prior to day 1 on study.
12.Geographically accessible for follow-up.
13.Pregnancy test negative.
14.For women of childbearing potential who are sexually active, agreement to use a highly effective, non-hormonal form of contraception or two effective forms of non-hormonal contraception during and for at least 6 months post-study treatment.
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1.Firma del consenso informato.
2.Età ≥ 18 anni.
3.ECOG 0-2.
4.Almeno una lesione clinicamente o radiologicamente misurabile e/o malattia non misurabile valutabile in accordo al Response Evaluation Criteria in Solid Tumor (RECIST versione 1.1). Le metastasi ossee osteoblastiche/osteolitiche saranno incluse.
5.Tumore primitivo HER2 negativo (HER-2 punteggio di 0 o 1 + / 2 + con FISH non amplificato) come da diagnosi locale.
6.Rilevamento di almeno 1 CTC HER2 positiva.
7.I pazienti possono essere stati sottoposti a chemioterapia /ormonoterapia come trattamento neo / adiuvante.
8.Adeguata funzionalità midollare, renale ed epatica:
ANC superiore a 1.5x10^9 /l, piastrine superiori a 100x10^9 / l, creatinina
sierica <1,5 x UNL, siero AST / ALT <1,5 x UNL, in presenza di metastasi
epatiche <2,5 x UNL.
9.Adeguata funzionalità cardiaca: la frazione di eiezione ventricolare sinistra (LVEF) misurata a riposo mediante ecocardiografia o scansione con MUGA non deve essere inferiore ail limiti di normalità.
10.Livello di troponina al di sotto del cut-off
11.Assenza di malattia cardiovascolare clinicamente significativa (per esempio infarto del miocardio, angina instabile), insufficienza cardiaca congestizia di grado II o superiore secondo New York Hearth Association (NYHA), gravi aritmie cardiache che richiedono trattamento, malattia vascolare periferica di grado II o maggiore nei 12 mesi precedenti l’entrata dello studio.
12.Accessibilità geografica per il follow-up.
13.Test di gravidanza negativo.
14.Per donne potenzialmente fertili, consenso ad utilizzare metodi di contraccezione non ormonali altamente efficaci o due forme efficaci di contraccettivi non ormonali durante e per almeno 6 mesi dopo il trattamento di studio. |
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E.4 | Principal exclusion criteria |
1.Previous chemotherapy or hormonotherapy for metastatic disease
2.Any psychiatric disorder that would impair the understanding and giving of informed consent.
3.Male patients
4.Non evaluable lesions as ascitic, pleural and pericardial effusions, carcinomatous lymphangitis of the lung, meningeal involvement.
5.Pregnant or lactating patients.
6.History of atrial ventricular arrhythmia, congestive heart failure or angina pectoris, even if medically controlled; uncontrolled hypertension; history of 2nd or 3rd degree heart blocks.
7.Any history of a second neoplasm except for curatively treated non melanoma skin cancer or carcinoma in situ of the cervix.
8.Concomitant treatment with other anticancer drugs.
9.Concomitant treatment with any other experimental drug.
10.Patients with not adequate haematological, hepatic and renal function.
11.Current known infection with HIV, HBV or HCV.
12.Any other serious illness or medical condition.
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1.Precedente chemioterapia o ormonoterapia per la malattia metastatica.
2.Qualsiasi disturbo psichiatrico che comprometta la comprensione della terapia e del consenso informato
3.Pazienti di sesso maschile
4.Lesioni non valutabili come liquido ascitico, pleurico e pericardico, linfangite carcinomatosa del polmone, interessamento meningeo.
5.Pazienti in gravidanza o in allattamento.
6.Storia di aritmia atrio-ventricolare, insufficienza cardiaca congestizia
o angina pectoris, anche se clinicamente controllate; ipertensione non
controllata; anamnesi positiva per blocchi atrio-ventricolari di 2 ° o 3 °grado.
7.Qualsiasi storia di una seconda neoplasia ad eccezione del trattamento curativo del cancro della pelle non melanoma o carcinoma in situ della cervice.
8.Il trattamento concomitante con altri farmaci antitumorali.
9.Il trattamento concomitante con qualsiasi altro farmaco sperimentale.
10.I pazienti con non adeguata funzionalità ematologica, epatica e renale.
11.Infezione nota in corso per HIV, HBV e HCV.
12.Qualsiasi altra malattia grave o condizione medica.
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E.5 End points |
E.5.1 | Primary end point(s) |
The evaluation of the overall CB among evaluable patients. |
Valutazione del beneficio clinico complessivo CB tra i pazienti eleggibili.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
24 weeks after treatment initiation |
24 settimane dopo l’inizio del trattamento |
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E.5.2 | Secondary end point(s) |
•To evaluate the early response based on CTCs variations as a predictor of patients’ outcome;
•To validate the prognostic significance of HER2+ve CTCs in patients with primary HER2-ve MBC;
•To obtain RNA from EpCAM+ve CTC isolated from MBC patients using the Veridex® Profile kit for pharmacodynamic evaluation (HER2-neu, PI3K, PTEN, pAKT, mTOR).
•To determine HER2 expression, proliferation index in fine needle aspirate (FNA) biopsies (optional).
•To evaluate the prognostic and predictive role of circulating HER2 and EGFR.
•To evaluate the Progression Free Survival.
•To evaluate the Overall Survival.
•To determine patient’s tolerability and safety of the treatment.
•To evaluate the Quality of Life.
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•Valutare la risposta precoce sulla base delle variazioni CTC come un predittore di outcome dei pazienti;
•Convalidare il significato prognostico di CTC HER2 positive nel setting metastatico in pazienti con carcinoma mammario primitivo HER2 negativo;
•Ottenere RNA da CTC EpCAM positive isolate dai pazienti carcinoma mammario metastatico con il kit Profile-Veridex® per la valutazione farmacodinamica (HER2-neu, PI3K, PTEN, pAKT, mTOR).
•Determinare l'espressione di HER2, indice di proliferazione su aspirato eseguito con ago sottile (FNA) o biopsia (opzionale).
•Valutare il ruolo prognostico e predittivo di HER2 ed EGFR circolanti
•Valutare la PFS
•Valutare l’OS
•Determinare tollerabilità e sicurezza del trattamento
•Valutare la qualità della vita
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
24 months from the end of last treatment of LSI. |
24 mesi dalla fine dell'ultimo trattamento del LSI (Last Subject In). |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Quality of Life |
Qualità della vita |
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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 | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | No |
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 | No |
E.8.7 | Trial has a data monitoring committee | No |
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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2 years follw up after last subject last study treatment |
2 anni di Follow Up dalla fine dell'ultimo trattamento dell'ultimo paziente |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |