| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Study to investigate the safety and efficacy of GB1211 (a galectin-3 inhibitor) in combination with atezolizumab in patients with Non-Small Cell Lung Cancer (NSCLC). |
| pazienti affetti da carcinoma polmonale non a piccole cellule (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell Lung Cancer (NSCLC) |
| pazienti affetti da tumore al polmone non a piccole cellule |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
Part A: To assess the safety and tolerability of GB1211 200 mg and 400 mg administrated BID in combination with atezolizumab.
Part B: To assess the safety and tolerability of GB1211 in combination with atezolizumab compared to atezolizumab and placebo in patients with NSCLC. To assess the efficacy of GB1211 compared to placebo by measuring the change of the longest diameters of target lesions at week 12 in NSCLC patients who are receiving atezolizumab.
Part C: To assess the long-term safety and tolerability of GB1211 in combination with atezolizumab compared to atezolizumab alone. |
Parte A: Per valutare la sicurezza e la tollerabilità di GB1211 200 mg e 400 mg BID somministrati in combinazione con atezolizumab.
Parte B: per valutare la sicurezza e la tollerabilità di GB1211 in combinazione con atezolizumab rispetto ad atezolizumab e placebo nei pazienti con NSCLC. Valutare l'efficacia di GB1211 rispetto al placebo misurando la variazione dei diametri più lunghi delle lesioni target alla settimana 12 nei pazienti con NSCLC che stanno ricevendo atezolizumab.
Parte C: Per valutare la sicurezza e la tollerabilità a lungo termine di GB1211 in combinazione con atezolizumab rispetto ad atezolizumab da solo. |
|
| E.2.2 | Secondary objectives of the trial |
Part A: To determine the recommended dose (200 mg BID or 400 mg BID) of GB1211 in combination with atezolizumab.
Part A and B: To assess overall response rate ORR (complete response [CR] and partial response [PR]), clinical benefit rate (stable disease [SD], PR and CR), time to response (TTR), duration of response (DoR) according to RECIST v1.1 of GB1211 versus placebo in combination with atezolizumab. For part A of the study, the same parameters will be assessed for the two GB1211 dose groups. To assess the pharmacokinetics of GB1211 in combination with atezolizumab.
Part C: To assess ORR (CR and PR), clinical benefit (CR, PR and SD), DoR and progression-free survival (PFS). Time to PR or CR for those patients who enter the study with SD as best response. |
Parte A: Per determinare la dose raccomandata (200 mg BID o 400 mg BID) di GB1211 in associazione con atezolizumab.
Parte A e B: Per valutare il tasso di risposta globale ORR (risposta completa [CR] e risposta parziale [PR]), tasso di beneficio clinico (malattia stabile [SD], PR e CR), tempo alla risposta (TTR), durata della risposta (DoR) secondo RECIST v1.1 di GB1211 rispetto al placebo in combinazione con atezolizumab. Per la parte A dello studio, verranno valutati gli stessi parametri per i due gruppi di dosaggio GB1211. Per valutare la farmacocinetica di GB1211 in combinazione con atezolizumab.
Parte C: Per valutare ORR (CR e PR), beneficio clinico (CR, PR e SD), DoR e sopravvivenza libera da progressione (PFS). Tempo per PR o CR per quei pazienti che entrano nello studio con SD come migliore risposta. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must be = 18 years of age at the time of signing the Informed Consent Form (ICF).
2. Must provide signed ICF.
3. Must have the ability to comply with the study protocol, in the investigator’s judgment.
4. Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agree to refrain from donating eggs.
5. Men must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agree to refrain from donating sperm.
6. Diagnosed NSCLC with adenocarcinoma and its variants according to the 2015 WHO classification.
7. Measurable disease, as defined by RECIST v1.1.
8. Have histologically or cytologically confirmed advanced or metastatic NSCLC defined as: Stage IIIB that either progressed after curative therapy or is not candidate to curative therapy, or Stage IV metastatic disease.
9. Expressing PD-L1 on at least 50% of tumour cells.
10. Agree to have a tumour biopsy that is eligible for Gal-3 expression evaluation before the first study drug dose.
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
12. Have not received prior systemic chemotherapy for the treatment of recurrent, advanced or metastatic disease, treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as completed at least 4 weeks prior to diagnosis of recurrent advanced or metastatic disease.
13. Patients must not have received immune checkpoint inhibitors previously.
14. Must be eligible for atezolizumab at 1200 mg every 3 weeks as defined in the atezolizumab product label.
15. Patients receiving therapeutic anticoagulation must be on stable regimen.
16. Adequate haematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
• Absolute neutrophil count (ANC) = 1.5 × 109/L (1500/µL) without granulocyte colony-stimulating factor support.
• Lymphocyte count = 0.5 × 109/L (500/µL).
• Platelet count = 100 × 109/L (100,000/µL) without transfusion.
• Haemoglobin = 90 g/L (9 g/dL). Patients may be transfused to meet this criterion.
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) = 2.5 × upper limit of normal (ULN), with the following exceptions:
o Patients with documented liver metastases: AST and ALT = 5 × ULN.
o Patients with documented liver or bone metastases: ALP = 5 × ULN.
• Total bilirubin = 1.5 × ULN with the following exception:
Patients with known Gilbert disease: total bilirubin = 3 × ULN.
• Creatinine clearance = 50 mL/min (calculated using the Cockcroft-Gault formula).
• Albumin = 25 g/L (2.5 g/dL).
• For patients not receiving therapeutic anticoagulation: INR and a PTT = 1.5 × ULN. |
1. Deve avere = 18 anni di età al momento della firma del Modulo di Consenso Informato (ICF).
2. Deve fornire ICF firmato.
3. Deve avere la capacità di rispettare il protocollo dello studio, a giudizio dello sperimentatore.
4. Le donne in età fertile devono accettare di rimanere astinenti (astenersi da rapporti eterosessuali) o utilizzare misure contraccettive e accettare di astenersi dal donare ovuli.
5. Gli uomini devono accettare di rimanere astinenti (astenersi da rapporti eterosessuali) o utilizzare misure contraccettive e accettare di astenersi dal donare sperma.
6. NSCLC diagnosticato con adenocarcinoma e sue varianti secondo la classificazione dell'OMS del 2015.
7. Malattia misurabile, come definita da RECIST v1.1.
8. Avere un NSCLC avanzato o metastatico confermato istologicamente o citologicamente definito come: Stadio IIIB che è progredito dopo la terapia curativa o non è candidato alla terapia curativa, o malattia metastatica di Stadio IV.
9. Esprimere PD-L1 su almeno il 50% delle cellule tumorali.
10. Accettare di avere una biopsia del tumore che sia idonea per la valutazione dell'espressione di Gal-3 prima della prima dose del farmaco in studio.
11. Performance status ECOG (Eastern Cooperative Oncology Group) da 0 a 1.
12. Non hanno ricevuto una precedente chemioterapia sistemica per il trattamento della malattia ricorrente, avanzata o metastatica, il trattamento con chemioterapia e/o radioterapia come parte della terapia neoadiuvante/adiuvante è consentito purché completato almeno 4 settimane prima della diagnosi di recidiva avanzata o malattia metastatica.
13. I pazienti non devono aver ricevuto in precedenza inibitori del checkpoint immunitario.
14. Deve essere idoneo per atezolizumab a 1200 mg ogni 3 settimane come definito nell'etichetta del prodotto atezolizumab.
15. I pazienti che ricevono anticoagulanti terapeutici devono essere in regime stabile.
16. Adeguata funzione ematologica e degli organi terminali, definita dai seguenti risultati dei test di laboratorio, ottenuti entro 14 giorni prima dell'inizio del trattamento in studio:
• Conta assoluta dei neutrofili (ANC) = 1,5 × 109/L (1500/µL) senza supporto del fattore stimolante le colonie di granulociti.
• Conta linfocitaria = 0,5 × 109/L (500/µL).
• Conta piastrinica = 100 × 109/L (100.000/µL) senza trasfusione.
• Emoglobina = 90 g/L (9 g/dL). I pazienti possono essere trasfusi per soddisfare questo criterio.
• Aspartato aminotransferasi (AST), alanina aminotransferasi (ALT) e fosfatasi alcalina (ALP) = 2,5 × limite superiore della norma (ULN), con le seguenti eccezioni:
o Pazienti con metastasi epatiche documentate: AST e ALT = 5 × ULN.
o Pazienti con metastasi epatiche o ossee documentate: ALP = 5 × ULN.
• Bilirubina totale = 1,5 × ULN con la seguente eccezione:
Pazienti con malattia di Gilbert nota: bilirubina totale = 3 × ULN.
• Clearance della creatinina = 50 ml/min (calcolato utilizzando la formula di Cockcroft-Gault).
• Albumina = 25 g/L (2,5 g/dL).
• Per i pazienti che non ricevono anticoagulanti terapeutici: INR e PTT = 1,5 × ULN. |
|
| E.4 | Principal exclusion criteria |
2. Patients with known hypersensitivity to GB1211 or any of the excipients.
6. Life expectancy = 12 weeks.
9. Diagnosed NSCLC with squamous cell carcinoma.
16. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, anti-phospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis.
18. Patients with acute neurological events (e.g., intracranial or subarachnoid haemorrhage, stroke, intracranial trauma) within 6 months of inclusion.
19. Patients with symptomatic, untreated, or actively progressing central nervous system (CNS) metastases confirmed by a CT or MRI scan.
21. History of malignancy other than NSCLC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate = 90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
22. Patients with past medical history or any evidence of clinically active interstitial lung disease, including drug-induced interstitial lung disease.
23. Uncontrolled significant pleural effusion.
24. History of non-infectious pneumonitis that required steroids or current pneumonitis.
26. Patients with a history of arrhythmia, especially ventricular arrhythmias, atrial fibrillation or recent recovery of rhythm after atrial fibrillation.
27. Patients with bradycardia (<50 beats per minute).
28. Patients with left ventricular ejection fraction (LVEF) of =40%.
29. Patients with a family history of sudden cardiac death before the age of 50.
30. Patients with a QT/QTc interval > 470 ms (for women) and > 450 ms (for men) at screening or congenital long QT syndrome.
31. Patients with electrolyte imbalances: hypokalaemia, hypomagnesemia, or hypocalcaemia.
32. Patients with history of organ transplant or hematopoietic stem cell transplantation.
36. Patients who have received GB1211 prior to this study.
38. Surgery within 3 weeks before the study.
42. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment.
43. Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumour necrosis factor-a [TNF-a] agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment.
|
2. Pazienti con nota ipersensibilità a GB1211 o ad uno qualsiasi degli eccipienti.
6. Aspettativa di vita = 12 settimane.
9. Diagnosi di NSCLC con carcinoma a cellule squamose.
16. Malattia autoimmune o immunodeficienza attiva o pregressa, inclusi, a titolo esemplificativo ma non esaustivo, miastenia grave, miosite, epatite autoimmune, lupus eritematoso sistemico, artrite reumatoide, malattia infiammatoria intestinale, sindrome da anticorpi anti-fosfolipidi, granulomatosi di Wegener, sindrome di Sjögren, Sindrome di Guillain-Barré, o sclerosi multipla.
18. Pazienti con eventi neurologici acuti (ad es. emorragia intracranica o subaracnoidea, ictus, trauma intracranico) entro 6 mesi dall'inclusione.
19. Pazienti con metastasi del sistema nervoso centrale (SNC) sintomatiche, non trattate o in fase di progressione attiva confermate da una TC o una risonanza magnetica.
21. Storia di tumori maligni diversi dal NSCLC nei 2 anni precedenti lo screening, ad eccezione dei tumori con un rischio trascurabile di metastasi o morte (es. tasso di OS a 5 anni = 90%), come il carcinoma in situ adeguatamente trattato cervice, carcinoma cutaneo non melanoma, carcinoma prostatico localizzato, carcinoma duttale in situ o carcinoma uterino di stadio I.
22. Pazienti con storia medica pregressa o qualsiasi evidenza di malattia polmonare interstiziale clinicamente attiva, inclusa malattia polmonare interstiziale indotta da farmaci.
23. Versamento pleurico significativo incontrollato.
24. Storia di polmonite non infettiva che ha richiesto steroidi o polmonite in corso.
26. Pazienti con una storia di aritmia, in particolare aritmie ventricolari, fibrillazione atriale o recente recupero del ritmo dopo fibrillazione atriale.
27. Pazienti con bradicardia (<50 battiti al minuto).
28. Pazienti con frazione di eiezione ventricolare sinistra (LVEF) = 40%.
29. Pazienti con una storia familiare di morte cardiaca improvvisa prima dei 50 anni.
30. Pazienti con un intervallo QT/QTc > 470 ms (per le donne) e > 450 ms (per gli uomini) allo screening o sindrome congenita del QT lungo.
31. Pazienti con squilibri elettrolitici: ipokaliemia, ipomagnesiemia o ipocalcemia.
32. Pazienti con storia di trapianto d'organo o trapianto di cellule staminali ematopoietiche.
36. Pazienti che hanno ricevuto GB1211 prima di questo studio.
38. Intervento chirurgico entro 3 settimane prima dello studio.
42. Trattamento con agenti immunostimolatori sistemici (inclusi, a titolo esemplificativo, interferone e interleuchina 2 [IL-2]) entro 4 settimane o 5 emivite di eliminazione del farmaco (a seconda di quale sia il periodo più lungo) prima dell'inizio del trattamento in studio.
43. Trattamento con farmaci immunosoppressori sistemici (inclusi, a titolo esemplificativo, corticosteroidi, ciclofosfamide, azatioprina, metotrexato, talidomide e agenti anti-fattore di necrosi tumorale-a [TNF-a]) entro 2 settimane prima dell'inizio del trattamento in studio, o anticipazione della necessità di farmaci immunosoppressori sistemici durante il trattamento in studio. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Part A: number of AEs in the 200 mg group compared to number of AEs in the 400 mg group.
• Part B: number of AEs with GB1211 and atezolizumab compared to placebo and atezolizumab. The incidence, frequency and severity of AEs, SAEs, treatment related AEs, immune-related AEs, Grade 3 and above AEs and AEs leading to GB1211 discontinuation or study withdrawal. The incidence and frequency of laboratory parameter abnormalities.
• Part B: The percentage change from baseline in the sum of longest diameters of target lesions at Week 12, %¿TSWk12, based on ICR according to RECIST 1.1.
• Part C: The number of AEs with GB1211 and atezolizumab compared to placebo and atezolizumab. The incidence, frequency and severity of AEs, SAEs, treatment related AEs, immune-related AEs, Grade 3 and above AEs and AEs leading to GB1211 discontinuation or study withdrawal. |
Parte A: numero di eventi avversi nel gruppo 200 mg rispetto al numero di eventi avversi nel gruppo 400 mg.
• Parte B: numero di eventi avversi con GB1211 e atezolizumab rispetto a placebo e atezolizumab. L'incidenza, la frequenza e la gravità di eventi avversi, SAE, eventi avversi correlati al trattamento, eventi avversi immuno-correlati, eventi avversi di grado 3 e superiore e eventi avversi che hanno portato all'interruzione di GB1211 o alla sospensione dello studio. L'incidenza e la frequenza delle anomalie dei parametri di laboratorio.
• Parte B: la variazione percentuale rispetto al basale nella somma dei diametri più lunghi delle lesioni target alla settimana 12, %¿TSWk12, sulla base dell'ICR secondo RECIST 1.1.
• Parte C: il numero di eventi avversi con GB1211 e atezolizumab rispetto a placebo e atezolizumab. L'incidenza, la frequenza e la gravità di eventi avversi, SAE, eventi avversi correlati al trattamento, eventi avversi immuno-correlati, eventi avversi di grado 3 e superiore e eventi avversi che hanno portato all'interruzione di GB1211 o alla sospensione dello studio. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Part A and B: Week 12, Part C: At disease progression or unacceptable toxicity |
| Parte A e B: Settimana 12, Parte C: Alla progressione della malattia o alla tossicità inaccettabile |
|
| E.5.2 | Secondary end point(s) |
• Part A: The recommended tolerable dose (200 mg BID or 400 mg BID) of GB1211 in combination with atezolizumab determined by assessment of SAEs, treatment related AEs, immune-related AEs, Grade 3 and above AEs and AEs leading to GB1211 discontinuation or study withdrawal in the sentinel groups of 200 mg GB1211 BID and 400 mg GB1211 BID.
• Part A and B: Clinical effects in accordance with RECIST v1.1:
o ORR based on ICR.
o DoR and TTR.
o TTP is defined as the time from randomisation until objective tumour progression. TTP does not include deaths.
o Disease Control defined as patients with a response or stable disease, assessed at each imaging assessment from randomisation to progression or death due to any cause, whichever occurs first.
• Part A and B: Plasma concentrations of GB1211 and derived pharmacokinetic parameters including Cmax, Tmax, AUC and others, as appropriate.
• Part C: ORR (CR and PR), clinical benefit (CR, PR and SD), DoR and PFS. Time to PR or CR for those patients who enter the study with SD as best response. PFS is defined as the time from the first dose until the first documentation of disease progression or death due to any cause, whichever occurs first. |
• Part A: The recommended tolerable dose (200 mg BID or 400 mg BID) of GB1211 in combination with atezolizumab determined by assessment of SAEs, treatment related AEs, immune-related AEs, Grade 3 and above AEs and AEs leading to GB1211 discontinuation or study withdrawal in the sentinel groups of 200 mg GB1211 BID and 400 mg GB1211 BID.
• Part A and B: Clinical effects in accordance with RECIST v1.1:
o ORR based on ICR.
o DoR and TTR.
o TTP is defined as the time from randomisation until objective tumour progression. TTP does not include deaths.
o Disease Control defined as patients with a response or stable disease, assessed at each imaging assessment from randomisation to progression or death due to any cause, whichever occurs first.
• Part A and B: Plasma concentrations of GB1211 and derived pharmacokinetic parameters including Cmax, Tmax, AUC and others, as appropriate.
• Part C: ORR (CR and PR), clinical benefit (CR, PR and SD), DoR and PFS. Time to PR or CR for those patients who enter the study with SD as best response. PFS is defined as the time from the first dose until the first documentation of disease progression or death due to any cause, whichever occurs first. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Part A and B: Week 12, Part C: At disease progression or unacceptable toxicity |
| Part A and B: Week 12, Part C: At disease progression or unacceptable toxicity |
|
| 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 | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase Ib/IIa study design |
| Phase Ib/IIa study design |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Part A is OL followed by a DB randomised part B. Part C will be OL upon completion of part B . |
| Part A is OL followed by a DB randomised part B. Part C will be OL upon completion of part B . |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 20 |
| 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 | Information not present in EudraCT |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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