| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with relapsed, indolent or aggressive Non Hodgkin’s lymphomas |
| Linfoma Non-Hodgkin (LNH) recidivato, indolente o aggressivo. |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients with relapsed, indolent or aggressive Non Hodgkin’s lymphomas |
| Linfoma Non-Hodgkin recidivato, indolente o aggressivo. |
|
| 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 | HLT |
| E.1.2 | Classification code | 10029608 |
| E.1.2 | Term | Non-Hodgkin's lymphomas unspecified histology aggressive |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 | 10065856 |
| E.1.2 | Term | Non-Hodgkin's lymphoma unspecified histology indolent |
| 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 |
| The objective of this study is to evaluate the efficacy and safety of BAY 80 6946 in patients with indolent or aggressive Non-Hodgkin’s Lymphoma (NHL) who have progressed after standard therapy. |
| Lo scopo di questo studio è valutare l’efficacia e la sicurezza di BAY 80-6946 in pazienti affetti da LNH indolente o aggressivo, in progressione dopo terapia standard. |
|
| E.2.2 | Secondary objectives of the trial |
| Further objectives are to evaluate the pharmacokinetics of BAY 80-6946 and biomarkers. |
| Obiettivi secondari sono la valutazione della farmacocinetica di BAY 80-6946 e di marcatori biologici. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Indolent NHL: • Histologically confirmed diagnosis of follicular lymphoma (FL), marginal zone lymphoma (including nodal or splenic marginal zone B-cell lymphoma and mucosa-associated lymphoid tissue [MALT] lymphoma), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL). • Relapsed after ≥ 2 prior chemotherapy- or immunotherapy-based regimens for indolent NHL, or refractory to 2 prior chemotherapy- and/or immunotherapy-based regimens. Aggressive NHL: • Histologically confirmed diagnosis of Grade 3 follicular lymphoma (FL), transformed indolent lymphoma, diffuse large B-cell lymphoma, mediastinal large B-cell lymphoma(DLBCL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma, or anaplastic large cell lymphoma. • Relapsed after ≥ 2 prior chemotherapy regimens, including the following: first-line treatment with standard anthracycline-containing regimen (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone or equivalent). At least 1 additional combination chemotherapy regimen. Patients refractory to first prior chemotherapy- and/or immunotherapy-based regimen for aggressive NHL or not eligible for high-dose regimen followed by transplant. High-dose chemotherapy, or chemoradiotherapy with autologous stem cell transplantation is considered 1 regimen. Patients with CD20 expressing neoplastic cells must have received prior rituximab, if available. Applicable to all patients: • Ability to understand and willingness to sign written informed consent (IC). Signed informed consent must be obtained before any study specific procedure. • Male or female patients > 18 years of age. • Patients with NHL must have at least one measurable lesion according to the recommendations of the Report of an International Workshop to Standardize Response Criteria for NHL. • ECOG performance status ≤ 2. • Life expectancy of at least 3 months. • Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last test drug administration. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care. An adequate contraception includes a hormonal contraception with implants or combined oral, transdermal or injectable contraceptives, certain intrauterine devices, bilateral tubal ligation, hysterectomy, or vasectomy of the partner. In addition the use of condoms for patients or their partners is required unless the woman has had a hysterectomy. • Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days before starting study treatment: - Total bilirubin < 1.5 x the upper limit of normal (ULN) (< 3 x ULN for patients with Gilbert-Meulengracht syndrome). - ALT and AST < 2.5 x ULN (< 5 x ULN for patients with lymphomatous liver involvement of their cancer). - Amylase and lipase < 1.5 x the ULN - Serum creatinine < 1.5 x the ULN. - GFR ≥ 30 ml/min/1.73 m2 according to the MDRD abbreviated formula. - INR or PTT < 1.5 x ULN. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care. - Platelet count ≥ 75,000 /mm3, hemoglobin (Hb) ≥ 9 g/dL, ANC ≥ 1,500/mm3 - Alkaline phosphatase limit ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of their cancer). • LVEF ≥ LLN for the Institution |
| Diagnosi confermata istologicamente di linfoma follicolare (LF), linfoma della zona marginale (incluso il linfoma a cellule B della zona marginale nodale o splenico ed il linfoma del tessuto linfoide associato alle mucose [MALT]), linfoma linfoplasmocitico /macroglobulinernia di Waldenström, leucemia linfatica cronica (CLL). • Pazienti recidivati dopo almeno 2 precedenti regimi di chemioterapia od immunoterapia per LNH indolente, o refrattari a 2 precedenti regimi di chemioterapia o immunoterapia. Diagnosi confermata istologicamente di linfoma follicolare (LF) di grado 3, linfoma indolente trasformato, linfoma diffuso a grandi cellule B (DLBCL), linfoma a grandi cellule B mediastinico, linfoma mantellare (MCL), linfoma a cellule T periferiche o linfoma anaplastico a grandi cellule.-Pazienti recidivati dopo almeno 2 precedenti regimi chemioterapici comprendenti un trattamento di prima linea con un regime standard contenente antracicline (ad es. ciclofosfamide, doxorubicina, vincristina e prednisone od uno equivalente).Almeno un ulteriore regime chemioterapico combinato. Pazienti refrattari al primo regime di chemioterapia e/o immunoterapia per LNH aggressivi o che non siano elegibili per un regime ad alte dosi seguito da trapianto. La chemioterapia ad alte dosi o la chemioradioterapia seguita da trapianto autologo di cellule staminali sono considerate 1 regime. Pazienti le cui cellule neoplastiche esprimano il CD20 devono aver precedentemente ricevuto il rituximab, se disponibile.-Pazienti maschi o femmine di età > 18 anni • ECOG Performance status ≤ 2 (ECOG: Eastern Cooperative Oncology Group) • Aspettativa di vita di almeno 3 mesi • Adeguata funzione midollare, epatica e renale valutata entro i 7 giorni precedenti all’inizio del trattamento • Frazione di eiezione ventricolare sinistra (LVEF) ≥ al limite inferiore del normale intervallo di riferimento (LLN) del centro |
|
| E.4 | Principal exclusion criteria |
| • Previous or concurrent cancer that is distinct in primary site or histology from cancer of the lymphatic system within 5 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)]. • Symptomatic lymphomatous involvement of the brain. • Congestive heart failure > NYHA class 2. • Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction less than 6 months before start of test drug. • Uncontrolled hypertension. (Blood pressure ≥ 150/90 mmHg despite optimal medical management). • Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication. • Non-healing wound, ulcer, or bone fracture. • Active clinically serious infections (> CTCAE grade 2). • Known history of human immunodeficiency virus (HIV) infection. • Known history of chronic hepatitis B or C. • Patients with seizure disorder requiring medication. • Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks of start of study medication. • Renal failure requiring hemo-or peritoneal dialysis. • Dehydration of CTCAE grade ≥ 1 (NCI-CTC version 4.0). • Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results. • Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation. • History or concurrent condition of interstitial lung disease. • Persistent proteinuria of CTCAE grade 3 or higher (> 3.5 g/24 h, measured by urine protein: creatinine ratio on a random urine sample). • Unresolved toxicity higher than CTCAE grade 1 (NCI-CTC version 4.0) attributed to any prior therapy/procedure excluding alopecia. • Current diagnosis of Type 1 or 2 diabetes mellitus, fasting blood glucose > 125 mg/dL (> 6.9 mmol/L) or HbA1c ≥ 7.0 % • Patients with phaeochromocytoma. • Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment. • Close affiliation with the investigational site; e.g., a close relative of the investigator, dependent person (e.g. employee or student of the investigational site). • Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study (see also Section 6.9 and Appendix 14.2). • Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study. Excluded previous therapies and medications: • Prior treatment with PI3K inhibitors. • Treatment with investigational drugs other than PI3K inhibitors within the last 28 days. • Ongoing immunosuppressive therapy. • Radiotherapy within 4 weeks prior to treatment start. • Systemic corticosteroid therapy (ongoing). Patients may be using topical or inhaled corticosteroids. • History of having received an allogeneic bone marrow or organ transplant • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of study medication. • Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted). • Use of strong inhibitors of CYP3A4 is prohibited from Day -14 and for the duration of the study • Use of strong inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 and for the duration of the study. |
| • Ipertensione non controllata (pressione arteriosa ≥ 150/90 mmHg nonostante una terapia medica ottimale) • Diagnosi attuale di diabete mellito di tipo 1 o 2, glicemia a digiuno > 125 mg/dL (> 6,9 mmol/L) o HbAlc ≥ 7,0 % (HbA1c = emoglobina glicata) • Pazienti con evidenza o anamnesi postiva per diatesi emorragica. Qualunque emorragiao sanguinamento di grado CTCAE ≥ 3 nelle 4 settimane precedenti la prima assunzione del farmaco sperimentale (CTCAE: Common Terminology Criteria for Adverse Events) • Storia o presenza concomitante di pneumopatia interstiziale • Qualunque tossicità non risolta di grado CTCAE superiore a 1 (NCI-CTC versione 4.0) attribuita a qualsiasi precedente terapia/procedura ad esclusione dell’alopecia. (NCI: National Cancer Institute) • Precedente trattamento con inibitori di PI3K • Terapia sistemica con corticosteroidi (in corso) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable will be the objective tumor response (OR). OR will be assessed in all patients up to 16 weeks after the last patient fully evaluable for the primary endpoint will have started treatment. |
| La variabile primaria di efficacia sarà la risposta globale oggettiva del tumore. La risposta globale verrà valutata in tutti i pazienti 16 settimane dopo che l’ultimo paziente pienamente valutabile per l’obiettivo primario abbia cominciato il trattamento. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary analysis of the primary efficacy variable will be performed 16 weeks after the last patient fully evaluable for the primary endpoint will have started treatment. At that timepoint, an exploratory analysis of all other variables will be performed, if possible |
| La primaanalisi della variabile primaria di efficacia verrà eseguita 16 settimane dopo che l’ultimo paziente pienamente valutabile per l’obiettivo primario avrà iniziato il trattamento. In questo momento, se possibile, verrà eseguita un’analisi esplorativa di tutte le altre variabili. |
|
| E.5.2 | Secondary end point(s) |
| Secondary efficacy variables in this study will be: • Duration of response (DOR), defined as the time (in days) from first observed tumor response (CR, CRu [applicable only in patients with NHL] or PR) until PD or until death caused by PD. • Progression free survival (PFS), defined as the time (in days) from treatment assignment to disease progression or death (if death occurs before a documented progression). • Overall survival (OS), defined as the time (in days) from treatment assignment until death from any cause or until the last date the patient is known to be alive |
| Le variabili secondarie di efficacia sono: • Durata della risposta (DOR), definita come i giorni dalla prima risposta al tumore osservata (CR, CRu [solo per Pazienti con NHL] o PR) fino a progressione di malattia o morte. • Sopravvivenza libera da progressione (PFS), definita come il tempo(in giorni) dall'assegnazione del trattamento alla progressione di malattia o morte (se la morte avviene prima di una progressione documentata). Sopravvivenza globale (OS), definita come tempo (in giorni) dall'assegnazione del trattamento fino a morte per qualsiasi causa fino all'uiltimo giorno di vita del Paziente. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final analyses of all secondary efficacy and safety variables and an additional exploratory analysis of the primary efficacy variable will be performed 3 years after the last patient’s first treatment or when all patients got PD, whatever comes first |
| L’analisi finale di tutte le variabili secondarie di efficacia e di sicurezza ed un’ulteriore analisi esplorativa della variabile primaria di efficacia verranno eseguite 3 anni dopo il primo trattamentodell’ultimo pazientearruolato o quando tutti i pazienti saranno andati incontro a progressione di malattia, quale delle due condizioni si osservi per prima. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tumor response |
| Risposta tumore |
|
| 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 | No |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 35 |
| 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 |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 42 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 42 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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