| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ADVANCED BREAST CANCER |
| tumore della mammella metastatico |
|
| E.1.1.1 | Medical condition in easily understood language |
| ADVANCED BREAST CANCER |
| tumore della mammella metastatico |
|
| 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 | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 activity of PD 0332991 monotherapy and of PD 0332991 in combination with the endocrine therapy (anastrozole, letrozole, exemestane or fulvestrant) on which the patient has progressed in the previous line (1st or 2nd) for ER+, HER2 negative ABC in post-menopausal women |
| Valutare l’attività di PD 0332991 da solo o la capacità di PD 0332991 di revertire la resistenza alla terapia ormonale per donne con tumore della mammella metastatico ormonoresistente ER+ e HER2 negativo |
|
| E.2.2 | Secondary objectives of the trial |
| To assess the tolerability of PD 0332991 in combination with anastrozole, letrozole, exemestane or fulvestrant in postmenopausal women with ER+, HER2 negative ABC. To assess secondary measures of activity for PD 0332991 monotherapy and PD in combination with an endocrine therapy. To explore the relationship between copy number and expression of baseline genes of interest and protein levels including Rb, p16/INK4A, CCND1, CDK4, CDK6, and Ki67 markers with tumor response. To explore the relationship between germline polymorphism in CYP19A1 and CCND1 genes and tumor response |
| Valutare la tollerabilità di PD 0332991 ed anastrozolo, letrozolo, exemestano o fulvestrant in combinazione Valutare indicatori secondari di attività di PD 0332991 ed anastrozolo, letrozolo, exemestano o fulvestrant in combinazione Valutare il rapporto tra marcatori molacolari quali espressione di Ciclina D1 e di altre proteine ad essa correlate, con la risposta al trattamento per la determinazione di potenziali biomarkers |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Histologically proven diagnosis of adenocarcinoma of the breast with evidence of metastatic disease. 2. ER positive tumor ≥ 10% 3. HER2 negative breast cancer by FISH or IHC (IHC 0,1+, 2+ and/or FISH HER2: CEP17 ratio < 2.0,) 4. Progression of advanced breast cancer on first or second line endocrine therapy for advanced breast cancer 4. Paraffin-embedded tumor available for centralized assessment of biomarkers (either archived primary tumor tissue or biopsy of a metastatic site) 5. Measurable disease according to RECIST 1.1 or bone only disease (bone only disease is allowed if measurable or evaluable). Previously irradiated lesions are deemed measurable only if progression is documented at the site after completion of radiation. 6. Females, 18 years of age or older. 7. Postmenopausal status defined as: • Prior bilateral surgical oophorectomy; • Amenorrhea and age > 60 years; • Age <60 years and amenorrhea for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and FSH and estradiol in the postmenopausal ranges. 8. Eastern Cooperative Oncology Group (ECOG) Performance status 0 -2 9. Resolution of all acute toxic effects of prior therapy or surgical procedures to CTCAE grade >1 (except alopecia or other toxicities not considered a safety risk for the patient). 10. Adequate organ function |
| 1. Tumore della mammella con conferma istologica ed evidenza di malattia metastatica 2. Positività del recettore degli estrogeni (ER) in ≥ 10% delle cellule tumorali 3. Tumore HER2 negativo per FISH o IHC 4. Progressione ad un precedente trattamento con inibitore del’aromatasi in prima od in seconda linea di trattamento per malattia metastatica 4. Tumore incluso in paraffina disponibile per valutazione centralizzata di biomarcatori (tumore primitivo o biopsia di tumore metastatico) 5. Malattia misurabile secondo RECIST 1.1 6. Donne di età superiore a 18 anni 7. Stato post-menopausale definito come: • Precedente ovariectomia bilaterale; • Amenorrea ed età superiore a 60 anni; • Età inferiore a 60 anni e amenorrea da almeno 12 mesi 8. Eastern Cooperative Oncology Group (ECOG) Performance status 0 -2 9. Funzioni d’organo adeguate. |
|
| E.4 | Principal exclusion criteria |
| 1. Unstable brain metastases (stable brain metastases not requiring steroids are allowed); presence of spinal cord compression, carcinomatous meningitis, or leptomeningeal disease. 2. Major surgery within 3 weeks of first study treatment. 3. Prior treatment with: • More than one line of chemotherapy for advanced breast cancer • More than two lines of endocrine treatment for advanced breast cancer • Any CDK inhibitor. 4. Current treatment with: • Any experimental treatment on another clinical trial; • Therapeutic doses of anticoagulant (Low dose anticoagulants for deep vein thrombosis prophylaxis are allowed. Aspirin is permitted.) 5. Current use or anticipated need for: • food or drugs that are known strong CYP3A4 inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, posaconazole, erythromycin, clarithromycin, tilithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone, diltiazem, and delavirdine • drugs that are known strong CYP3A4 inducers (i.e., carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin, and St. John’s Wort) 6. Diagnosis of any secondary malignancy within the last 3 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix. 7. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism. 8. Active inflammatory bowel disease or chronic diarrhea. Short bowel syndrome. Upper gastrointestinal surgery including gastric resection. 9. Known hypersensitivity to letrozole, anastrazole, exemestane or fulvestrant, or to any of their excipients. 10. Known human immunodeficiency virus infection; active Hepatitis C, active hepatitis B 11. Severe medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with interpretation of study results and, in the investigator opinion, would make the subject inappropriate for this study. |
| 1. Metastasi cerebrali clinicamente instabili 2. Chirurgia maggiore nelle 3 settimane precedenti alla valutazione per lo studio 3. Trattamento precedente con: • Più di una linea di chemioterapia per la malattia metastatica • Più di due linee di terapia ormonale per la malattia metastatica • Qualsiasi inibitore di CDK. 4. Trattamento in corso con: • Altri farmaci sperimentali • Dosi terapeutiche di anticoagulanti 5. Precedente diagnosi di tumore negli ultimi 3 anni ad esclusione di: basalioma o carcinoma in situ dela cervice uterina 6. Qualsiasi delle seguenti condizioni negli ultimi sei mesi: IMA, angina istabile o severa, aritmie cardiache, scompenso cardiaco congestizio, TIA o ictus cerebrale, embolia polmonare |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Clinical benefit (CB) defined as complete response, partial response, and stable disease for at least 24 weeks, according to RECIST criteria 1.1 from randomization to termination of PD 0332991 ± endocrine therapy |
| Beneficio Clinico definito come somma di Risposte Complete, Risposte Parziali e Stabilità di malattia della durata di almeno 24 settimane, secondo i criteri RECIST 1.1, dalla randomizzazione al termine del trattamento |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Activity assessments will be every 12 weeks |
| Le pazienti verranno valutate per la risposta ogni 12 settimane |
|
| E.5.2 | Secondary end point(s) |
| •Adverse events according to CTCAE v4.0 •Objective response (OR) according to RECIST 1.1 •Progression Free Survival. •Time to tumor progression (TTP) •Duration of response (DR). •Overall survival (OS). •Tumor tissue levels including but not limited to Rb, p16/INK4A, CCND1, CDK4, CDK6 and Ki67 and copy number of CCND1 and p16. •Germline polymorphism in CYP19A1 and CCND1 genes |
| •Eventi avversi secondo CTCAE v4.0 •Risposte obiettive secondo RECIST 1.1 •Intervallo libero da malattia •Tempo alla progressione •Durata della risposta •Sopravvivenza globale •Livelli tumorali di Rb, p16/INK4A, CCND1, CDK4, CDK6, Ki67 e il numero di copie di CCND1 e p16. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Adverse events will be collected every cycle and activity assessments will be performed every 12 weeks. |
| Gli eventi avversi saranno raccolti ad ogni ciclo.Le valutazioni per la risposta saranno effettuate ogni 12 settimane. |
|
| 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 | 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) | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| farmaco in combinazione |
| different combination drug |
|
| 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 | 2 |
| 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
|
| Two-stage optimal phase II design:stop trial if are observed less then 5 responses in the first 25 valuable pts or continue until LVLS |
| Disegno in due stadi:stop se dopo arruolamento delle prime 25 pazienti non si osservano almeno 5 risposte altrimenti si prosegue fino a LVLS |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 42 |
| E.8.9.1 | In the Member State concerned days | 0 |
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