| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2 POSITIVE METASTATIC BREAST CANCER |
| CARCINOMA MAMMARIO METASTATICO HER2 POSITIVO |
|
| E.1.1.1 | Medical condition in easily understood language |
| HER2 POSITIVE METASTATIC BREAST CANCER |
| CARCINOMA MAMMARIO METASTATICO HER2 POSITIVO |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025541 |
| E.1.2 | Term | Malignant breast neoplasm |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| Our trial will primarily aim at evaluating the clinical activity of T-DM1 vs lapatinib/capecitabine in HER2+ ABC pertuzumab- pretreated pts. PFS, defined as the time elapsed between randomization and objective cancer progression or death, will be our primary endpoint for treatment efficacy. We will also report on 1. OS, defined as the time elapsed between randomization and death from any cause, and 2. Adverse events (AE). |
| Valutare l'attività clinica di T-DM1 rispetto al trattamento con lapatinib/capecitabina in pazienti con carcinoma mammario HER2+ pretrattate con pertuzumab. La PFS, definita come il tempo trascorso tra la randomizzazione e la progressione di malattia oppure il decesso, sarà il nostro endpoint primario per valutare l'efficacia del trattamento in studio. Verranno valutate inoltre sia la OS, definita come il tempo intercorso tra la randomizzazione e il decesso avvenuto per qualsiasi causa, che il tasso di eventi avversi (AE), definiti secondo Common Terminology Criteria for Adverse Events (CTCAE, version 4.03). |
|
| E.2.2 | Secondary objectives of the trial |
Specific Aim 2:
The secondary objective is to evaluate the predictive role of circulating miRNA and ctDNA in HER2+ ABC pts treated in second-line. Circulating biomarkers will be assessed at baseline, after 3 cycles of therapy and at treatment discontinuation from any cause.
Specific Aim 3:
This task aims at exploring the potential mechanisms of resistance to pertuzumab in pertuzumab-resistant CL. The most promising candidate biomarkers will be validated in bioptic samples from pts whose disease progressed after pertuzumab treatment. |
Valutare il ruolo predittivo di miRNA e ctDNA circolanti nelle pazienti arruolate nello studio.
I biomarcatori circolanti saranno valutati al basale, dopo 3 cicli di terapia e alla sospensione del trattamento, avvenuta per qualsiasi causa.
- Esplorare i potenziali meccanismi di resistenza al pertuzumab in linee cellulari resistenti al pertuzumab.
I biomarcatori più promettenti saranno poi validati in campioni bioptici di pazienti la cui malattia è progredita dopo il trattamento con pertuzumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all the following inclusion criteria to be eligible for enrolment into the study:
1. Signed, written informed consent (approved by the institutional review board or independent ethics committee) obtained prior to any study specific procedure initiation or treatment as confirmation of the patient’s awareness and willingness to comply with the study requirements
2. Female aged >18 years at the time of the randomization
3. Histological or cytological confirmed and documented carcinoma of the breast with metastatic disease [confirmed by histology, cytology or other clinical means (e.g. CT, MRI)]. Subjects must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)
4. Documentation of HER2 overexpression or gene amplification, in the invasive component of either the primary tumor or metastatic disease site as defined as:
- 3+ by Immunohistochemistry (IHC Dako) and/or
- HER2/neu gene amplification by fluorescence, chromogenic or silver in situ hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH, CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of =2.0]
5. Patients must have been already treated with pertuzumab-trastuzumab and taxane in the metastatic setting
6. Allowed prior neoadjuvant/adjuvant treatment
7. Life expectancy of > 6 months as assessed by the treating investigator
8. Left ventricular ejection fraction (LVEF) =50% during a baseline period of 28 days, as determined by either echocardiography (ECHO) or multigated acquisition (MUGA) scan. ECHO is the preferred method; the same method of LVEF assessment, ECHO or MUGA, must be used throughout the study and, to the extent possible, be obtained at the same institution. Assessments made within 42 days prior to randomisation are not required to be repeated.
9. ECOG PS 0-2
10. Adequate haematological function as defined by: ANC ¿ 1.5 x 109/L, platelet count ¿100 x 109/L, haemoglobin ¿ 10 g/dL.
11. Adequate renal function, as defined by: creatinine¿ 1.5 x UNL
12. Adequate hepatobiliary function, as defined by the following baseline liver function tests: total serum bilirubin ¿1.5 upper normal limit (UNL); alanine aminotransferase (ALT), aspartate aminotransferase (AST) ¿ 2.5xUNL; alkaline phosphatase (AP) ¿ 2.5xUNL; if total alkaline phosphatase (AP) > 2.5xUNL, alkaline phosphatase liver fraction must be ¿ 2.5xUNL
13. All prior treatment related toxicities must be CTCAE (Version 4.03) = Grade 1 at the time of randomization
14. Adequate contraception for all fertile patients
15. Negative pregnancy test
16. Allowed previous and concomitant bisphosphonates/denosumab |
- Età >18 anni
- Diagnosi istologica di carcinoma mammario avanzato HER2-positivo;
- Precedente trattamento con pertuzumab per malattia metastatica;
- Performance status ECOG 0-2;
- Adeguata funzionalità d’organo, definita come: neutrofili =1,5x109/l; conta piastrinica = 100x109/l; emoglobina =10g/dL; creatinina =1,5x limite superiore normale (UNL), bilirubina sierica totale =1,5xUNL; alanina aminotransferasi (ALT), aspartato aminotransferasi (AST) =2.5xUNL; fosfatasi alcalina (AP) = 2.5xUNL; se la fosfatasi alcalina totale (AP)> 2.5xUNL, la frazione epatica di fosfatasi alcalina deve essere =2.5xUNL; frazione di eiezione ventricolare sinistra (LVEF) =50% misurata nei 28 giorni precedenti la prima somministrazione del trattamento in studio, determinata dall'ecocardiografia (ECHO) o dalla scintigrafia miocardica (MUGA);
- Malattia misurabile;
- Risoluzione delle eventuali tossicità correlate al trattamento precedente, che devono essere = Grado 1 al momento della randomizzazione;
- Contraccezione adeguata per tutti i pazienti fertili
- Test di gravidanza negativo;
- Sono ammessi trattamenti precedenti e/o concomitanti con bifosfonati/denosumab;
- Consenso informato scritto. |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. History of persistent Grade = 2 hematologic toxicity resulting from previous systemic therapy
2. Current peripheral neuropathy of NCI-CTCAE, Version 4.03, Grade = 3 at randomization
3. History of other malignancy within the last 5 years, except for a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma
4. Patients not pretreated with pertuzumab as first-line regimen for metastatic disease
5. Patient treated with more than one regimens for metastatic disease
6. Serious cardiac illness or medical conditions including but not confined to: history of documented congestive heart failure (CHF) or systolic dysfunction (LVEF <50%); high-risk uncontrolled arrhythmias (ventricular tachycardia, high-grade AV-block, supraventricular arrhythmias which are not adequately rate-controlled); congenital long QT syndrome; angina pectoris requiring antianginal medication; clinically significant valvular heart disease; evidence of transmural infarction on ECG; poorly controlled hypertension (e.g. systolic >180mm Hg or diastolic >100mm Hg)
7. Inadequate organ function, evidenced by the following laboratory results within 28 days prior to randomization:
• Inadequate bone marrow function: Absolute neutrophil count <1,500 cells/mm3;Platelet count <100,000 cells/mm3;Haemoglobin <9 g/dL
• Inadequate liver function: Total bilirubin > upper limit of normal (ULN) (unless the patient has documented Gilbert’s syndrome);AST (SGOT) or ALT (SGPT) >1.5 times ULN with concurrent serum alkaline phosphatase >2.5 times ULN (unless bone metastases are present);
• Inadequate renal function: Serum creatinine>2.0 mg/dL or >177 µmol/L;
• International normalised ratio and activated partial thromboplastin time or partial thromboplastin time >1.5 times ULN (unless on therapeutic coagulation).
8. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures)
9. Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment
10. History of receiving any investigational treatment within 30 days of randomization or 5 half-lives, whichever is longer, preceding the first dose of study treatment
11. Known immediate or delayed hypersensitivity to any of the study drugs or idiosyncrasy to drugs chemically related to any of the study agents or their excipients that, in the opinion of the Investigator, contraindicates their participation
12. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol, or have a concurrent disease or condition that may interfere with study participation, or any serious medical disorder that would interfere with the subject's safety (for example, active or uncontrolled infection or any psychiatric condition prohibiting understanding or rendering of informed consent)
13. Lack of physical integrity of the upper gastrointestinal tract, clinically significant malabsorption syndrome, or inability to take oral medications
14. Concurrent interventional or non-interventional studies
15. History of current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
16. Known symptomatic central nervous system (CNS) metastases or leptomeningeal carcinomatosis
17. Patients who are pregnant or breastfeeding
18. Radiotherapy within four weeks prior to enrollment except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to enrollment. Patients must have recovered from radiotherapy toxicities prior to enrollment. |
- Pazienti con storia di altre neoplasie maligne ad eccezione di tumori cutanei del tipo non melanoma e/o della cervice uterina eradicati chirurgicamente;
- Pazienti che non abbiano ricevuto trattamento con pertuzumab;
- Pazienti che abbiano ricevuto più di un trattamento per carcinoma della mammella in fase metastatica;
- Comorbidità severe non controllate con adeguata terapia medica (ad esempio, patologia cardiovascolare, polmonare o metabolica clinicamente significativa, disturbi della cicatrizzazione delle ferite, ulcere o fratture ossee);
- Procedura chirurgica maggiore o lesione traumatica significativa nei 28 giorni precedenti la randomizzazione;
- Anamnesi positiva per partecipazione a studi clinici nei 30 giorni precedenti la randomizzazione o 5 emivite, a seconda di quale periodo è più lungo, prima della prima dose del trattamento in studio;
- Metastasi sintomatiche e/o non controllate a carico del sistema nervoso centrale o carcinomatosi leptomeningea;
- Mancanza di integrità fisica del tratto gastrointestinale superiore, sindrome da malassorbimento clinicamente significativa o incapacità di assumere farmaci orali;
- Gravidanza o allattamento in corso;
- Pazienti potenzialmente fertili che si rifiutino di utilizzare una contraccezione efficace durante lo studio e fino a 90 giorni dall’ultima dose di trattamento in studio
- Ipersensibilità presunta o accertata ad uno dei farmaci in studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PROGRESSION FREE SURVIVAL |
| PROGRESSION FREE SURVIVAL |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| SAFETY (CTCAE V4); OVERALL SURVIVAL |
| TOSSICITA' (CTCAE V4); OVERALL SURVIVAL |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| EACH CYCLE; 12 MONTHS |
| OGNI CICLO; 12 MESI |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| 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) | 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 | Yes |
| E.8.1.3 | Single blind | No |
| 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 | 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 | Information not present in EudraCT |
| 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
|
|
| 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 | 36 |
| E.8.9.1 | In the Member State concerned days | 10 |
| 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 | 36 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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