E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
relapsed and primary refractory Hodgkin Lymphoma |
pazienti affetti da Linfoma di Hodgkin recidivo e refrattario |
|
E.1.1.1 | Medical condition in easily understood language |
relapsed and primary refractory Hodgkin Lymphoma |
pazienti affetti da Linfoma di Hodgkin recidivo e refrattario |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020328 |
E.1.2 | Term | Hodgkin's lymphoma |
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 determine the best tolerated and effective dose (dose finding) for oral Lenalidomide among 10, 15, 20 e 25 mg dose levels in a 28-day cycle, as associated to a fixed dose of weekly bendamustine (60 mg/m2 on days 1, 8 and 15), based on the best trade-off between toxicity and efficacy according to the Bayesian phase I/II dose finding method of Thall and Cook in subjects with Recurrent Hodgkin Lymphoma |
Determinare la dose orale meglio tollerata ed efficace (dose finding) di Lenalidomide scegliendo tra quattro livelli di dosaggio (10, 15, 20 e 25 mg/die) in un ciclo di 28 giorni associata ad una dose prestabilita di Bendamustina (60 mg/m2 nei giorni 1, 8 e 15), basata sulla strategia del trade-off tra tossicità ed efficacia in accordo al metodo Bayesiano del dose finding di Thall and Cook per gli studi di Fase 1/2 in pazienti con Linfoma di Hodgkin ricorrente |
|
E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety profile of lenalidomide in combination with bendamustine in terms of AE/SAE rate
2. To evaluate the antitumor activity of lenalidomide in combination with bendamustine in terms of ORR, TTP, PFS and response duration |
1. Valutare il profilo di sicurezza di Lenalidomide in associazione con Bendamustina in termini di rapporto AE/SAE
2. Valutare l’attività antitumorale della Lenalidomide in combinazione con Bendamustina in termini di ORR, TTP, PFS e durata della risposta. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients must have histologically confirmed classical Hodgkin lymphoma (HL).
- Patients must have failed an autologous stem cell transplant or be ineligible for high-dose therapy due to chemorefractory disease (as defined as <50% response to standard salvage chemotherapy), age or comorbidity.
- Patients must have at least one target PET-avid bidimensionally measurable lesion,
- Age >18 years
- Life expectancy of greater than 3 months
- ECOG performance status <2
- Patients must have adequate organ and marrow function as defined below:
- absolute neutrophil count >1,000/L
- platelets >75,000/L
- total bilirubin < 2.0 mg/dl in the absence of a history of Gilbert's disease (or pattern consistent with Gilbert's); however dose reduction is recommended for Bendamustine. in patients with 30 – 70 % tumour involvement of the liver and moderately diminished liver function (serum bilirubin 1.2 – 3.0 mg/dl).
- AST(SGOT)/ALT(SGPT) <3 X institutional upper limit of normal
- creatinine within normal institutional limits OR creatinine clearance >50 mL/min/1.73 m2
- Patients must have echocardiogram or gated blood pool scan (MUGA) with an ejection fraction > or = to 50%
- If patients have a history of malignancy other than cutaneous basal cell or squamous cell carcinoma, they must be disease-free for ~ 5 years at the time of enrolment
- Patients must accept contraception measures until 4 weeks after the completion of chemotherapy, and up to 6 months for male patients.
- Women of child-bearing must have a medically supervised negative pregnancy test even if had been using effective contraception.
- Patients agree not to share study medication with another person and to return all unused study drug to the investigator
- Patients or their guardians must be capable to understand and must be willing to sign a written informed consent document |
-Pazienti con conferma istologica di Linfoma di Hodgkin (HL).
-Pazienti con fallimento di ASCT o non eleggibili a terapie ad alte dosi per malattia chemorefrattaria (definite come <50% della risposta alla tarapia standard di salvataggio), età o comorbidità.
-Pazienti con almeno una lesione misurabile tramite PET,
-Età >18 anni
-Aspettativa di vita > di 3 mesi
-ECOG performance status <2
-Pazienti con adeguate funzionalità d’organo e midollari definite come:
-Conta neutrofilica assoluta >1,000/L
-Piastrine >75,000/L
-Bilirubina tot < 2.0 mg/dl in assenza di malattia di Gilbert's (o modello coerentecon Gilbert); la riduzione della dose di Bendamustina è raccomandata in pazienti con 30 – 70 % di convolgimento di tumore del fegato o moderata ridotta funzionalità del fegato (bilirubina sierica 1.2 – 3.0 mg/dl).
- AST(SGOT)/ALT(SGPT) <3 X limite superiore di normalità
-Creatinina nei range di normalità O clearance creatinica>50 mL/min/1.73 m2
-Pazienti con ecocardiogramma o MUGA con una frazione di eiezione cardiaca > o = a 50%
-Pazienti con almeno 5 anni di sopravvivenza libera malattia al momento dell’arruolamento in caso di storia di pregresso tumore ad esclusione del tumore cutaneo delle cellule basali o carcinoma delle cellule squamose
-Pazienti che acconsentono all’utilizzo di metodi contraccettivi fino a 4 settimane dopo il completamento della chemioterapia e fino a sei mesi per i pazienti di sesso maschile.
-Donne fertile con test di gravidanza negativo, anche se utilizzano metodi contraccettivi.
-Pazienti che acconsentono di non condividere il farmaco in studio con altre persone e che acconsentono di restituire il farmaco inutilizzato agli investigatori.
-Pazienti in grado di intendere e di volere e che abbiano firmato il consenso informato per partecipare allo studio |
|
E.4 | Principal exclusion criteria |
Treatment with chemotherapy or external radiotherapy within 6 weeks, or monoclonal antibodies within 8 weeks or radio-immunoconiugates in the previous 12 weeks prior to entering the study
Treatment with any other investigational agent
Parenchymal brain or leptomeningeal HL involvement
History of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used in the study
Known HIV positivity or active infectious hepatitis, type A, B, or C
Clinically significant cardiac disease (NYHA Class III or IV)
Abnormal QTcF interval prolonged (> 459 msec)
- Known pregnancy or breastfeeding.
- Jaundice
Yellow fever vaccination
Medical illness unrelated to HL, which in the opinion of the attending physician and principal investigator will preclude safe administration of lenalidomide and bendamustine
Corticoid treatment different from low dose prednisone or methylprednisone (up to 16 mg), used for B symptoms control.
Controindications for receiving prophylaxis against deep vein thrombosis
Thromboembolic disease grade 3-4 in the last 6 months
More than one month between staging procedures and the start of the treatment
Major surgical procedures less than 30 days before the start of treatment |
Pazienti trattati con chemioterapia o radioterapia nelle 6 settimane, o anticorpi monoclonali nelle 8 settimane o radio-immunoconiugati nelle 12 settimane prima di entrare nello studio.
Pazienti trattati con altri farmaci sperimentali.
Pazienti con coinvolgimento del parenchima cerebrale o HL leptomeningeo
Pazienti ipersensibili ad agenti con struttura chimica o composizione biologica simile ai farmaci usati nello studio.
Nota positività al virus HIV o infezione attiva da epatite tipo A, B, o C.
Pazienti con compromissione cardiaca clinicamente significativa (NYHA Classe III o IV)
Pazienti con intervallo QTcF allungato (> 459 msec)
Pazienti gravide o in allattamento.
Pazienti con Ittero
Pazienti con vaccino per la febbre gialla
Condizioni generali scadenti non correlabili al Linfoma che possono precludere la sicurezza del paziente nella somministrazione di Lenalidomide e Bendamustina.
Trattamento con corticosteroidi diversi da prednisone o metilprednisone a basse dosi (fino a 16 mg) usati per i sintomi B. .
Pazienti con controindicazioni per la profilassi della trombosi venosa profonda.
Patologia tromboembolica di grado 3-4 negli ultimo 6 mesi.
Più di un mese dalla procedura di staging e le procedure di inizio trattamento.
Procedure chirurgiche di entità maggiore nei 30 giorni prima del trattamento |
|
E.5 End points |
E.5.1 | Primary end point(s) |
NA |
migliore dose tollerata in grado di dare risposta terapeutica |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
• Overall Response rate (CR+PR)
• Time to Progression
• Event free Survival
• Response duration (see section 11.0) |
ORR, TTP, PFS e durata della risposta |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | 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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
- Stesso farmaco ad altro dosaggio |
- same IMP used at different dosage |
|
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 9 |
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
|
|
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 | 18 |
E.8.9.1 | In the Member State concerned days | 0 |