E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hairy Cell Leukemia |
Leucemia a cellule capellute |
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E.1.1.1 | Medical condition in easily understood language |
A specific type of cancer of the blood |
Un tipo specifico di tumore del sangue |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019056 |
E.1.2 | Term | Hairy cell leukemia variant |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10019055 |
E.1.2 | Term | Hairy cell leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the rate of durable complete response (CR) in multiply relapsed HCL with moxetumomab pasudotox. |
determinare il tasso di risposta completa (CR) duratura in pazienti con HCL multi-recidivante trattati con moxetumomab pasudotox. |
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E.2.2 | Secondary objectives of the trial |
Determine the overall response rate (ORR), progression-free survival (PFS), time to treatment failure (TTF), and duration of responses (CR and partial response [PR]). -Confirm the tolerability and safety of moxetumomab pasudotox in patients with HCL. -Evaluate immunogenicity and pharmacokinetics (PK) of moxetumomab pasudotox. |
determinazione del tasso di risposta complessivo (ORR, Overall Response Rate), la sopravvivenza libera da progressione (PFS, Progression-free Survival), il tempo all'insuccesso del trattamento (TTF, Time to Treatment Failure), la durata della risposta (CR e risposta parziale [PR, Partial Response]), la conferma di sicurezza e tollerabilit¿ e la valutazione dell'immunogenicit¿ e della farmacocinetica di moxetumomab pasudotox. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must have histologically confirmed hairy cell leukemia or hairy cell leukemia variant .with a need for therapy based on at least one of the following criteria: neutrophils less than 1000/mm(3) platelets less than 100,000/mm(3) hemoglobin less than 10 g/dL) symptomatic splenomegaly. Patients must be Pseudomonas-immunotoxin naive Patients must have had at least 2 prior purine analogs, or at least 1 course of purine analog and 1 of either rituximub or BRAF inhibitor. Men or women age greater than or equal to 18 years. Because this disease does not generally occur in children, children are excluded from this study, but will be eligible for future pediatric trials in other indications. ECOG performance status less than or equal to 2. The effects of moxetumomab pasudotox on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and 4 months after completion of moxetumomab pasudotox administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Patients must have adequate organ function as defined below: total bilirubin less than or equal to 1.5 mg/dL, unless consistent with Gilbert s (ratio between total and direct bilirubin greater than 5) AST and ALT less than or equal to 3 times upper limit of normal (ULN) alkaline phosphatase less than or equal to 2.5 ULN serum creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater than or equal to 60 mL/min as estimated by the Cockcroft-Gault equation Prothrombin time/INR or partial thromboplastin time less 2.5 ULN, fibrinogen greater than or equal to 0.5 LLN; if on warfarin, INR less than 3.5, if on any other anticoagulation, PT less than 2.5 times baseline Ability to understand and the willingness to sign a written informed consent document. Life expectancy greater than or equal to 6 months |
1. I pazienti devono presentare leucemia a cellule capellute o una variante della leucemia a cellule capellute, con conferma istologica, e necessitare di una terapia sulla base di almeno uno fra i seguenti criteri: a. neutrofili < 1,0 x 109/l b. piastrine < 100 x 109/l c. emoglobina < 10 g/dl d. splenomegalia sintomatica 2. I pazienti devono essere naïve all'immunotossina di Pseudomonas 3. I pazienti devono aver ricevuto almeno 2 terapie sistemiche precedenti, compresi 2 cicli di un PNA, oppure 1 ciclo di rituximab o inibitore BRAF dopo un singolo ciclo di PNA. 4. Uomini o donne di età > 18 anni. Poiché solitamente questa malattia non si manifesta nei bambini, questi sono esclusi dallo studio. 5. Stato di prestazione Eastern Cooperative Oncology Group (ECOG) = 2 (vedere Appendice 2). 6. I pazienti devono presentare una funzionalità adeguata degli organi, come definito di seguito: a. bilirubina totale = 1,5 mg/dl, a meno che non sia coerente con un quadro di sindrome di Gilbert (rapporto fra bilirubina totale e diretta > 5) b. AST e ALT = 3 volte il limite superiore dell'intervallo di normalità (ULN) c. fosfatasi alcalina < 2,5 ULN d. creatinina nel siero = 1,5 mg/dl o clearance della creatinina = 60 ml/min come stimato in base all'equazione di Cockcroft-Gault (Appendice 3) 7. Tempo di protrombina (PT)/rapporto internazionale normalizzato (INR) o tempo di tromboplastina parziale (PTT) < 2,5 ULN, fibrinogeno = 0,5 del limite inferiore dell'intervallo di normalità; se il paziente assume warfarin, INR < 3,5, se utilizza qualsiasi altro anticoagulante, PT < 2,5 volte il valore basale 8. Capacità di comprendere e volontà di firmare un documento scritto di consenso informato. 9. Aspettativa di vita = 6 mesi.
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E.4 | Principal exclusion criteria |
Patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks prior to initiation of treatment. Patients who are receiving any other investigational agents. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with clinically significant ophthalmologic findings during screening Pregnant or breastfeeding females. The effects of moxetumomab pasudotox on the developing fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with moxetumomab pasudotox breastfeeding should be discontinued if the mother is treated with moxetumomab pasudotox Positive for Hepatitis B surface antigen unless the patient is on Lamivudine or Entecavir and Hepatitis B Viral DNA load is less than 2000 IU/mL.
Active second malignancy requiring treatment other than minor resection of indolent cancers like basal cell and squamous skin cancers Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, malaria infection or psychiatric illness/social situations that would limit compliance with study requirements. HIV-positive patients unless taking appropriate anti-HIV medications with a CD4 count of greater than 200. Otherwise, there may be increased risk of lethal infections when temporarily suppressing normal B-cells. History of allogeneic bone marrow transplant. Patients with history of both thromboembolism and known congenital hypercoagulable conditions. Uncontrolled pulmonary infection, pulmonary edema. Oxygen saturation at rest less than 88% measured by pulse oximetry or PaO (2) less than or equal to 55 mm Hg. Serum albumin less than 2 g/dL. Radioimmunotherapy within 2 years prior to enrollment in study. ANC less than 1000/mm(3), or platelet count less than 50,000/mm(3), if these cytopenias are not judged by the investigator to be due to underlying disease (ie, potentially reversible with antineoplastic therapy). A patient will not be excluded because of pancytopenia greater than or equal to Grade 3, or erythropoietin dependence, if it is due to disease, based on the results of bone marrow studies. Patients with less than 50% of predicted forced expiratory volume (FEV1) or less than 50% of predicted diffusing capacity for carbon monoxide (DLCO), corrected for hemoglobin concentration and alveolar volume. Note: Patients with no prior history of pulmonary illness are not required to have PFTs. FEV1 will be assessed after bronchodilator therapy. Patients with history of thrombotic microangiopathy or TTP-HUS. Patients with QTc elevation > grade 1 Patient on high dose estrogen (defined as > 0.625 mg/day of an estrogen compound. Patients with clinical evidence of disseminated intravascular coagulation (grade 3-4) |
1. Pazienti che sono stati sottoposti a chemioterapia, immunoterapia o radioterapia nelle 4 settimane precedenti l'inizio del trattamento. 2. Pazienti che assumono qualsiasi altro farmaco sperimentale. 3. I pazienti con metastasi cerebrali note devono essere esclusi da questa sperimentazione clinica a causa della loro prognosi negativa e poiché spesso sviluppano una disfunzione neurologica progressiva, che può confondere la valutazione degli eventi avversi (AE, Adverse Event) neurologici e di altro tipo. 4. Pazienti con distacco retinico o coroidale identificato durante la valutazione oftalmologica nella fase di screening. 5. Donne in gravidanza o in allattamento (al seno). Non sono noti gli effetti di moxetumomab pasudotox sullo sviluppo del feto. Poiché esiste un rischio non noto ma potenziale di AE per i bambini in allattamento, associato al trattamento della madre con moxetumomab pasudotox, interrompere l'allattamento al seno se la madre viene trattata con moxetumomab pasudotox. 6. Pazienti positivi all'anticorpo contro il core o l'antigene di superficie dell'epatite B, a meno che il paziente non assuma lamivudina o entecavir e la carica virale per il DNA del virus dell'epatite B non sia < 2000 UI/ml.
8. Secondo tumore maligno attivo che richiede un trattamento diverso da una resezione di piccola entità di tumori indolenti, come i tumori cutanei a cellule basali e squamosi. 9. Patologia intercorrente non controllata, comprese, a titolo esemplificativo, infezioni in corso o attive, insufficienza cardiaca congestizia sintomatica, angina pectoris instabile, ipertensione non controllata, aritmia cardiaca, infezione malarica o disturbo psichiatrico/condizioni sociali che limiterebbero la conformità ai requisiti dello studio. 10. Pazienti con positività nota al virus dell'immunodeficienza umana (HIV), a meno che non assumano i farmaci anti-HIV appropriati e con un conteggio CD4 > 200. In caso contrario, esiste un maggiore rischio di contrarre infezioni letali se vengono temporaneamente soppresse le cellule B normali. 11. Anamnesi di trapianto allogenico di midollo osseo. 12. Pazienti con anamnesi di tromboembolia e condizioni congenite note di ipercoagulazione. 13. Infezione polmonare non controllata, edema polmonare. 14. Saturazione dell'ossigeno a riposo < 88% misurata con pulsossimetria o PaO2 = 55 mmHg 15. Albumina nel siero < 2 g/dl 16. Radioimmunoterapia nei 2 anni precedenti all'arruolamento nello studio. 17. Conta assoluta dei neutrofili (ANC, Absolute Neutrophil Count) < 1,0 x 109/l o conta delle piastrine < 50 x 109/l, a meno che lo sperimentatore non la giudichi come associata a una malattia sottostante (ovvero potenzialmente reversibile con una terapia antineoplastica). Un paziente non verrà escluso in presenza di una pancitopenia di grado = 3 o di dipendenza da eritropoietina, se dovuta alla malattia, sulla base di risultati degli studi sul midollo osseo. 18. Pazienti con < 50% del volume espiratorio forzato previsto (FEV1) o < 50% della capacità di diffusione prevista per il monossido di carbonio, corretta in base alla concentrazione di emoglobina a al volume alveolare (DLCO). Nota: per i pazienti senza anamnesi precedente di malattie polmonari non è necessario procedere al test della funzione polmonare (PFT). Il volume espiratorio forzato verrà valutato dopo la terapia broncodilatatoria. 19. Pazienti con anamnesi di microangiopatia trombotica o microangiopatia trombotica/sindrome emolitica-uremica 20. Pazienti con elevazione dell'intervallo QT corretta (Frederica) > 500 ms (sovralettura manuale da parte di personale medico qualificato) in base ad almeno due ECG a 12 derivazioni distinti. 21. Pazienti che assumono estrogeni ad alte dosi (definite come > 0,625 mg/die di un composto estrogeno). 22. Pazienti con evidenza clinica di coagulazione intravascolare disseminata (Grado 3-4). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Durable Complete response |
tasso di risposta completa |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Approximately 12 months from the start of treatment |
Circa 12 mesi da inizio trattamento |
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E.5.2 | Secondary end point(s) |
Overall Response Rate (ORR), progression free survival (PFS), time to treatment failute, duration fo response (CR and PR), Safety,Immunogenicty, and Pharmokokinetics |
tasso di risposta complessivo (ORR, Overall Response Rate), la sopravvivenza libera da progressione (PFS, Progression-free Survival), il tempo all'insuccesso del trattamento (TTF, Time to Treatment Failure), la durata della risposta (CR e risposta parziale [PR, Partial Response]), la sicurezza,immunogenicit¿ e farmacocinetica |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Duration of study |
Durata dello studio |
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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 | Yes |
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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 | Information not present in EudraCT |
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 |
Argentina |
Belgium |
Brazil |
Canada |
Czechia |
Denmark |
Finland |
France |
Germany |
Greece |
Ireland |
Israel |
Italy |
Mexico |
Netherlands |
Norway |
Poland |
Portugal |
Spain |
Sweden |
United Kingdom |
United States |
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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
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |