E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Refractory Indolent Non-Hodgkin Lymphoma |
Linfoma Non-Hodgkin Indolente Refrattario |
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E.1.1.1 | Medical condition in easily understood language |
Indolent Non-Hodgkin’s Lymphoma (iNHL) |
Linfoma Non-Hodgkin Indolente (iNHL) |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029627 |
E.1.2 | Term | Non-Hodgkin's lymphoma unspecified histology intermediate grade refractory |
E.1.2 | System Organ Class | 100000004864 |
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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 evaluate the antitumor activity of IPI-145 administered to subjects diagnosed with indolent non-Hodgkin lymphoma (iNHL) (defined as follicular lymphoma [FL], marginal zone lymphoma [MZL; splenic, nodal and extranodal], or small lymphocytic lymphoma [SLL]) whose disease is refractory to rituximab and to either chemotherapy or radioimmunotherapy (RIT). |
Valutare l'attività antitumorale di IPI-145, somministrato a soggetti con diagnosi di Linfoma Non-Hodgkin Indolente Refrattario (iNHL) (definito come linfoma follicolare [FL], linfoma della zona marginale [MZL, splenico, nodale ed extranodale], o piccolo linfoma linfocitico [SLL ]), la cui malattia è refrattaria al rituximab e a chemioterapia o radioimmunoterapia (RIT). |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives:
• To evaluate the safety of IPI-145 in all subjects
• To evaluate additional efficacy parameters in all subjects
• To evaluate the pharmacokinetics (PK) of IPI-145 and, if applicable, its metabolite(s)
Exploratory objectives:
• To evaluate whether baseline values or treatment-related changes in biomarkers correlate with IPI-145 clinical activity, safety and/or resistance in iNHL
• To evaluate whether tumor genomic or pharmacogenomic markers correlate with IPI-145 clinical activity, safety, PK and/or resistance in iNHL
• To evaluate the health-related quality of life (QoL) of subjects |
Obiettivi Secondari:
• Valutare la sicurezza di IPI-145 in tutti i soggetti
• Valutare parametri supplementari di efficacia in tutti i soggetti
• Valutare la farmacocinetica (PK) di IPI-145 e, se applicabile, del suo metabolita/i
Obiettivi Sperimentali:
• Valutare sia i valori basali che modifiche nei valori dei biomarcatori correlati al trattamento sperimentale , in relazione con l’attività clinica, la sicurezza e/o la resistenza di IPI-145 nel iNHL.
• Valutare i marcatori tumorali genomici o farmacogenomici, in relazione con l’attività clinica, la sicurezza, la PK e/o la resistenza di IPI-145 nel iNHL.
• Valutare la qualità della vita (QoL) in relazione alla salute dei soggetti
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Subjects who have been diagnosed with indolent NHL that has progressed.
•Subjects must have exhibited no response or progression within 6 months after the last dose of a chemotherapy induction regimen or RIT.
•Subjects must have rituximab-refractory disease.
•Measurable disease with a lymph node or tumor mass ≥1.5 cm in at least one dimension by CT.
•Adequate renal and hepatic function. |
• Soggetti con diagnosi di Linfoma Non-Hodgkin Indolente NHL che è progredito.
• I soggetti devono aver mostrato nessuna risposta o progressione entro 6 mesi dopo l'ultima dose di un regime chemioterapia di induzione o RIT.
• I soggetti devono avere la malattia refrattaria al rituximab.
• Malattia misurabile con linfonodo o tumore ≥ 1,5 cm in almeno una dimensione misurata con TAC.
• Adeguata funzione renale ed epatica. |
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E.4 | Principal exclusion criteria |
•Candidate for potentially curative therapies in the opinion of the investigator.
•Previous treatment with any PI3K inhibitor or BTK inhibitor.
•Prior history of allogeneic hematopoietic stem cell transplant (HSCT).
•Prior chemotherapy, cancer immunosuppressive therapy, or other investigational agents within 4 weeks before first dose of study drug.
•Grade 3B FL and/or clinical evidence of transformation to a more aggressive subtype of lymphoma.
•Symptomatic central nervous system (CNS) NHL.
•Ongoing systemic bacterial, fungal, or viral infections at the time of initiation of study treatment. |
• Candidato per terapie potenzialmente curative a giudizio dello sperimentatore.
• Precedente trattamento con qualsiasi inibitore di PI3K o inibitore della BTK.
• Precedente storia di trapianto allogenico di cellule staminali ematopoietiche (HSCT).
• Precedente chemioterapia, terapia tumorale immunosoppressiva, o altri farmaci sperimentali entro le 4 settimane precedenti la prima dose del farmaco in studio.
• Grado 3B FL e / o evidenza clinica di trasformazione in un sottotipo più aggressivo di linfoma.
• NHL del sistema nervoso centrale( CNS ) sintomatico.
• Infezioni sistemiche batteriche, fungine o virali in corso al momento dell'inizio del trattamento sperimentale.
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Rate (ORR), with overall response defined as best response of complete response/remission (CR) or partial response/remission (PR) according to the revised International Working Group (IWG) Criteria |
Tasso di risposta globale (ORR), con "risposta globale" intesa come migliore risposta in termini di risposta/remissione completa (CR) o risposta/remissione parziale (PR), secondo i Criteri rivisti dell'International Working Group (IWG). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
CT scans of chest, abdomen and pelvis & focused physical examination and assessment of B symptoms & response assessment: screening, Day -7 to Day 1 of Cycles 3, 5, 7, 10, 14, 18 and every 4th cycle thereafter, end of treatment
Bone marrow biopsy and bone marrow aspiration: screening, Day -7 to Day 1 of Cycles 3, 5, 7, 10, 14, 18 and every 4th cycle thereafter |
TAC del torace, dell'addome e della pelvi & esame obiettivo
e la valutazione dei sintomi B & valutazione della risposta: screening, Giorno -
7 al Giorno 1 dei Cicli 3, 5, 7, 10, 14, 18 e ogni 4° ciclo successivo,
fine del trattamento
Biopsia del midollo osseo e aspirazione del midollo osseo: screening, Giorno -7 al Giorno 1 dei Cicli 3, 5, 7, 10, 14, 18 e ogni 4° ciclo successivo
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E.5.2 | Secondary end point(s) |
Secondary endpoints:
• Treatment-emergent adverse events (TEAEs), ECG measures, and changes in safety laboratory values
• Duration of response (DOR), defined as the time from the first documentation of response to the first documentation of progressive disease (PD) or death due to any cause
• Progression-free survival (PFS), defined as the time from the first dose of study treatment to the first documentation of PD or death due to any cause
• Overall survival (OS) defined as the time from the first dose of study treatment to the date of death
• Time to response (TTR), defined as the time from the first dose of study treatment to the first documentation of response (complete or partial)
• PK parameters derived from plasma IPI-145 concentrations and, if applicable, its metabolite(s)
Exploratory endpoints:
• Serum, plasma and tissue biomarkers, and blood immunophenotype
• Germline DNA sequence variations
• Tumor genomic features (e.g. DNA sequence variation, DNA copy number variation, and/or RNA expression)
• Health-related QoL of subjects as assessed by the following subject-reported questionnaire:
o EuroQol-5D (EQ-5D), a standardized instrument for use as a measure of health-related QoL |
Endpoint Secondari
• Eventi avversi emergenti dovuti al trattamento sperimentale (TEAEs), valutazioni ECG, cambiamenti nei valori normali di laboratorio
• Durata della risposta (DOR), definita come il tempo dalla prima documentazione della risposta alla prima documentazione di progressione di malattia (PD) o di morte per qualsiasi causa
• Sopravvivenza libera da progressione (PFS), definito come il tempo dalla prima dose di trattamento sperimentale alla prima documentazione di progressione di malattia (PD) o di morte per qualsiasi causa
• Sopravvivenza globale (OS), definita come il tempo dalla prima dose di trattamento sperimentale in studio alla data del decesso
• Tempo di risposta (TTR), definito come il tempo dalla prima dose di trattamento sperimentale alla prima documentazione di risposta (completa o parziale)
• Parametri farmacocinetici derivati dalle concentrazioni plasmatiche di IPI-145 e, se applicabile, del suo metabolita/i
Endpoint Sperimentali:
• Biomarcatori sierici, plasmatici e tissutali e immunofenotipo sanguigno
• Variazioni di sequenza del DNA germinale
• Caratteristiche genomiche del tumore (es. variazione nella sequenza di DNA, variazione del numero di copie di DNA, e/o di espressione dell' RNA)
• Qualità della vita (QoL) in relazione alla salute dei soggetti, come valutato dal seguente questionario riportato ai soggetti:
o EuroQol-5D (EQ-5D), uno strumento standardizzato per la misura della QoL correlata alla salute
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
AE/SAE: screening, cycles 1 (Day 1 & 15) to 8 and beyond (every 2 cycles), end of treatment and 30 days post-treatment
PK blood sample collection: Day 15 of Cycle 1, Day 1 of Cycles 2 and 3
ECG: Day 1 and 15 of Cycle 1
Serum and plasma biomarkers: Day 1 and 15 of Cycle 1, Day 1 of Cycles 2, 3, 5, 7, 10 and 14, end of treatment
Immunoglobulin blood levels: Day 1 of Cycles 1, 3, 5, 7, 10 and 14, end of treatment
Immunophenotyping evaluations: Day 1 of Cycles 1, 2, 3, 5, 7, 10 and 14, end of treatment
Archival tumor tissue & optional pharmacogenomics blood sample: Day 1 of Cycle 1
Optional tumor tissue biopsy: Day 1 and 15 of Cycle 1, end of treatment
Quality of Life (EQ-5D): screening, cycles 1 (Day 1) to 8 and beyond (every 2 cycles), end of treatment |
AE/SAE: SCRN, dal ciclo 1 (Giorno 1 e 15) al Ciclo 8 e oltre (ogni 2 cicli), fine trattam.e 30 giorni post-trattamento.
Raccolta campioni sangue PK: Giorno 15 del Ciclo1, Giorno1 dei Cicli2 e 3
ECG: Giorno1 e 15 del Ciclo 1
Biomarc.Siero-plasma: Giorno 1 e 15 del Ciclo 1, Giorno 1, dei Cicli2, 3, 5, 7, 10 e 14, fine del trattam.
Livelli ematici mmunogl: Giorno 1 dei Cicli 1, 3, 5, 7, 10 e 14, fine del trattam.
Immunofenotipizzazione: Giorno1 dei Cicli 1, 2, 3, 5, 7, 10 e 14, fine del trattam.
Archivio storico tessuto tumorale e campione opzionale di sangue farmacogenomica: Giorno1 del Ciclo 1
Biopsia tessuto tumorale opzionale: Giorno1 e 15 ciclo 1, fine del trattam.
Qualità della vita (EQ-5D): SCRN, dal Ciclo1 (Giorno1) a Ciclo 8 e oltre (ogni 2 cicli), fine del trattam. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 | 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) | 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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 43 |
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 |
Belarus |
Belgium |
Bulgaria |
Canada |
Czech Republic |
France |
Georgia |
Hungary |
Italy |
Spain |
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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Last survival follow-up visit/communication for the last patient. As per the protocol, survival follow-up for all subjects will end after the last subject enrolled into the study has at least 1 year of survival follow-up. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
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 |