| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with with locally advanced or metastatic solid tumors. |
| Pazienti con tumori solidi localmente avanzati o metastatici. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with a solid tumor cancer that has grown or spread |
| Pazienti con tumore solido che è cresciuto o diffuso. |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 ORR by RECIST 1.1 of NKTR-214 plus pembrolizumab in patients with untreated metastatic NSCLC. |
| Determinare l’ORR secondo RECIST 1.1 di NKTR-214 più pembrolizumab in pazienti con NSCLC metastatico non trattato |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate safety and tolerability of NKTR-214 plus pembrolizumab in
patients with untreated NSCLC (Dose Expansion only).
• To assess the preliminary efficacy of NKTR-214 in combination with
pembrolizumab:
- objective response rate (ORR) by RECIST 1.1
- duration of response (DOR) by RECIST 1.1
- clinical benefit rate (CBR) by RECIST 1.1
- time to response (TTR) by RECIST 1.1
- progression-free survival (PFS) by RECIST 1.1
- overall survival (OS)
• To assess the association between efficacy measures and PD-L1
expression in tumors. |
• Valutare la sicurezza e la tollerabilità di NKTR-214 più pembrolizumab nei pazienti con NSCLC non trattato (solo per l’espansione della dose).
• Valutare l’efficacia preliminare di NKTR-214 in combinazione con pembrolizumab:
- tasso di risposta obiettiva (Objective Response Rate, ORR) secondo i criteri RECIST 1.1
- durata della risposta (Duration Of Response, DOR) secondo i criteri RECIST
1.1.
- tasso di beneficio clinico (Clinical Benefit Rate, CBR) secondo i criteri
RECIST 1.1
- tempo alla risposta (Time To Response, TTR) secondo i criteri RECIST 1.1.
- sopravvivenza libera da progressione (Progression-Free Survival, PFS)
secondo i criteri RECIST 1.1
- sopravvivenza globale (Overall Survival, OS)
• Valutare l’associazione tra le misure di efficacia e l’espressione di PD-L1 nei
tumori. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Provide written, informed consent to participate in the study and
follow the study procedures.
• Age 18 years or older at the time of signing the informed consent form
(ICF).
• Life expectancy > 12 weeks as determined by the Investigator.
• Patients may have received no more than one prior line of systemic
therapy for locally advanced or metastatic cancer.
• Prior IL-2 therapy is allowed for patients in the dose optimization
cohorts, but not in the dose expansion cohort.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1.
• Oxygen saturation = 92% on room air for all indications; oxygen
saturation = 90% on room air for lung cancer considered to be due to
lung metastasis.
• Measurable disease per RECIST 1.1.
• Patients with hypertension must be on = 2 antihypertensive
medications and without change for the 14 days prior to randomization.
Screening blood pressure must be systolic < 150 mm Hg and < 90 mm
Hg for diastolic blood pressure.
• A brain MRI at Screening is required for all patients with metastatic
NSCLC, and for patients with other tumor types who have known brain
metastasis.
• Patients with brain metastases are eligible if all the criteria below are
fulfilled:
- Brain metastases must be treated at least 2 weeks prior to study
treatment initiation. Treatment may include stereotactic radiosurgery,
whole brain radiotherapy, or neurosurgical resection.
- Brain imaging after treatment and within the screening period must
demonstrate no new or progressing brain metastases.
- No requirement for systemic corticosteroids >10 mg/day prednisone
equivalents. Stable doses of anticonvulsants are allowed.
- No clinically significant symptoms associated with brain metastases.
• Tumor tissue sample is required for all patients. Acceptable samples
include archival tissue obtained no more than 12 months prior to
enrollment if the patient has not received systemic treatment between
the time of biopsy/resection and enrollment. Otherwise, a fresh tumor
biopsy taken during screening is required.
Dose Expansion Cohort (Cohort 2)
1L Non- Small Cell Lung Cancer (Cohorts 2.1, 2.2, and 2.3)
• Histologically or cytologically confirmed diagnosis of NSCLC.
• Patients must have tumor tissue samples available and sent to a
central laboratory for PD-L1 testing using an FDA-approved test or
validated assay. Approximately 20 patients will be enrolled in each
subgroup of PD-L1 negative (PD-L1 < 1%; Cohort 2.1), PD-L1
low/intermediate (PD-L1 1% to 49%; Cohort 2.2) or PD-L1 highly
positive (PD-L1 = 50%; Cohort 2.3).
• Patients with epidermal growth factor receptor (EGFR) or anaplastic
lymphoma kinase (ALK) genomic tumor aberrations are excluded.
• Must not have received anti-cancer therapy for advanced or metastatic
lung cancer.
• Must not have progressed on or within 6 months of completing
adjuvant PD-L1 therapy. |
• Fornire il consenso informato scritto alla partecipazione allo studio e seguire le procedure dello studio.
• Età pari o superiore a 18 anni al momento della firma del modulo di consenso informato (ICF).
• Aspettativa di vita >12 settimane, secondo quanto determinato dallo Sperimentatore.
• I pazienti possono aver ricevuto non più di una precedente linea di terapia sistemica per il tumore localmente avanzato o metastatico.
• La terapia precedente a base di IL-2 è consentita per i pazienti delle coorti di ottimizzazione della dose, ma non della coorte di espansione della dose.
• Stato prestazionale dell’Eastern Cooperative Oncology Group (ECOG) di 0 o 1.
• Saturazione dell'ossigeno =92% all'aria ambiente per tutte le indicazioni; saturazione dell'ossigeno = 90% in aria ambiente per il carcinoma polmonare considerata dovuta a metastasi polmonari.
• Malattia misurabile in base a RECIST 1.1.
• I pazienti con ipertensione devono essere trattati con =2 farmaci antipertensivi e senza modifiche per i 14 giorni precedenti alla randomizzazione. La pressione arteriosa allo screening deve essere sistolica <150 mm Hg e <90 mmHg per la pressione arteriosa diastolica.
• È richiesta una risonanza magnetica cerebrale allo screening per tutti i pazienti affetti da NSCLC metastatico e per i pazienti con altri tipi di tumore che presentano metastasi cerebrali note.
• I pazienti con metastasi cerebrali sono idonei se soddisfano tutti i criteri seguenti:
- Le metastasi cerebrali devono essere trattate almeno 2 settimane prima dell’avvio del trattamento dello studio. Il trattamento può comprendere radiochirurgia stereotassica, radioterapia cerebrale completa o resezione neurochirurgica.
- Gli esami di imaging cerebrale dopo il trattamento ed entro il periodo di screening non devono dimostrare alcuna nuova o progressione delle metastasi cerebrali.
- Assenza di necessità di corticosteroidi sistemici >10 mg/giorno di equivalenti di prednisone. Sono ammesse dosi stabili di anticonvulsivanti.
- Nessun sintomo clinicamente significativo associato alle metastasi cerebrali.
• Il campione di tessuto tumorale è necessario per tutti i pazienti. I campioni accettabili includono tessuto d’archivio ottenuto non più di 12 mesi prima dell’arruolamento se il paziente non ha ricevuto un trattamento sistemico tra il momento della biopsia/resezione e l'arruolamento. In caso contrario, è necessaria una nuova biopsia del tumore durante lo screening.
Coorte di espansione della dose (Cohort 2)
1L Non- small Cell Lung Cancer (Cohorts 2.1, 2.2 e 2.3)
• Diagnosi di NSCLC confermata istologicamente o citologicamente.
• Le pazienti devono essere sottoposte a campioni di tessuto tumorale disponibili e inviati a un laboratorio centrale per l'analisi di PD-L1 utilizzando un test approvato dalla FDA o un test convalidato. Verranno arruolati circa 20 pazienti in ciascun sottogruppo con risultato negativo per PD-L1 (PD-L1 <1%; coorte 2.1), PD-L1 a basso/intermedio (PD-L1 1% rispetto al 49%; coorte 2,2) o PD-L1 (PD-L1 = 50%; coorte 2.3).
• Sono esclusi i pazienti con aberrazioni tumorali genomiche del recettore del fattore di crescita epidermico (EGFR) o della chinasi del linfoma anaplastico (ALK).
• Non deve aver ricevuto una terapia antitumorale per il carcinoma polmonare avanzato o metastatico.
• Nessuna progressione della malattia nei 6 mesi precedenti al completamento della terapia adiuvante a base di PD-L1. |
|
| E.4 | Principal exclusion criteria |
1. Use of an investigational agent or an investigational device within 28
days prior to enrollment.
2. Women who are pregnant or breastfeeding.
3. Patients who have an active, known or suspected autoimmune
disease. Exceptions include patients with type I diabetes mellitus,
hypothyroidism only requiring hormone replacement, skin disorders
(such as vitiligo, psoriasis, or alopecia) not requiring systemic
treatment, autoimmune conditions not expected to recur, or with Medical
Monitor approval.
4. History of allergy or hypersensitivity to study drug components.
5. Prior malignancy within the previous 3 years. Exceptions include nonmelanoma
skin cancer and carcinoma in situ of bladder, breast, cervix,
colon, prostate, stomach, and melanoma treated with curative intent,
with minimal risk of recurrence or requiring therapy during study
participation. Patients with prostate cancer are allowed if one of the
following criteria is met:
Stage T2N0M0 or lower; Gleason score = 3+4, and prostate-specific
antigen (PSA) below lower limit of normal by local laboratory.
6. Patients in the dose expansion cohort must not have received prior IL2 therapy.
7. Chronic systemic corticosteroid at >10 mg prednisone or equivalent or
other immunosuppressive agents. Patient on inhaled steroids for asthma
or local steroid injections are allowed.
8. Evidence of clinically significant interstitial lung disease or active,
noninfectious pneumonitis.
9. Surgery or radiotherapy within 14 days of enrollment. Patients who
had surgery or radiotherapy outside of 14 days must have recovered
from associated complications and toxicities.
10. Chemotherapy or biological therapy within 28 days of enrollment.
Targeted therapy (e.g., tyrosine kinase inhibitors) within 14 days of
enrollment.
11. Prior treatment with immune checkpoint inhibitor.
12. Active infection requiring systemic therapy.
13. Known hepatitis B virus (HBV) infection (e.g., positive hepatitis B
surface antigen [HBsAg]) or hepatitis C virus (HCV) infection (e.g.,
positive HCV ribonucleic acid [RNA]).
14. Known immunodeficiency or active human immunodeficiency virus
(HIV-1/2 antibodies).
15. Prolonged Fridericia's corrected QT interval (QTcF) > 450 ms for men
and > 470 ms for women at Screening.
16. History of unstable or deteriorating cardiac disease or
cerebrovascular disease within the 2 years prior to screening including
but not limited to the following:
a. Unstable angina or myocardial infarction.
b. Congestive heart failure (New York Heart Association [NYHA] Class
III or IV).
c. Uncontrolled clinically significant arrhythmias.
d. Cerebrovascular accident or transient ischemic attack
17. Current drug or alcohol abuse.
18. Any condition including medical, emotional, psychiatric, or logistical
that, in the opinion of the Investigator, would preclude the patient from
adhering to the protocol or would increase the risk of adverse events
while participating in study. |
1. Use of an investigational agent or an investigational device within 28 days prior to enrollment.
2. Women who are pregnant or breastfeeding.
3. Patients who have an active, known or suspected autoimmune disease. Exceptions include patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, autoimmune conditions not expected to recur, or with Medical Monitor approval.
4. History of allergy or hypersensitivity to study drug components.
5. Prior malignancy within the previous 3 years. Exceptions include nonmelanoma
skin cancer and carcinoma in situ of bladder, breast, cervix,
colon, prostate, stomach, and melanoma treated with curative intent,
with minimal risk of recurrence or requiring therapy during study
participation. Patients with prostate cancer are allowed if one of the
following criteria is met:
Stage T2N0M0 or lower; Gleason score = 3+4, and prostate-specific
antigen (PSA) below lower limit of normal by local laboratory.
6. Patients in the dose expansion cohort must not have received prior IL2 therapy.
7. Chronic systemic corticosteroid at >10 mg prednisone or equivalent or
other immunosuppressive agents. Patient on inhaled steroids for asthma
or local steroid injections are allowed.
8. Evidence of clinically significant interstitial lung disease or active,
noninfectious pneumonitis.
9. Surgery or radiotherapy within 14 days of enrollment. Patients who
had surgery or radiotherapy outside of 14 days must have recovered
from associated complications and toxicities.
10. Chemotherapy or biological therapy within 28 days of enrollment.
Targeted therapy (e.g., tyrosine kinase inhibitors) within 14 days of
enrollment.
11. Prior treatment with immune checkpoint inhibitor.
12. Active infection requiring systemic therapy.
13. Known hepatitis B virus (HBV) infection (e.g., positive hepatitis B
surface antigen [HBsAg]) or hepatitis C virus (HCV) infection (e.g.,
positive HCV ribonucleic acid [RNA]).
14. Known immunodeficiency or active human immunodeficiency virus
(HIV-1/2 antibodies).
15. Prolonged Fridericia's corrected QT interval (QTcF) > 450 ms for men
and > 470 ms for women at Screening.
16. History of unstable or deteriorating cardiac disease or
cerebrovascular disease within the 2 years prior to screening including
but not limited to the following:
a. Unstable angina or myocardial infarction.
b. Congestive heart failure (New York Heart Association [NYHA] Class
III or IV).
c. Uncontrolled clinically significant arrhythmias.
d. Cerebrovascular accident or transient ischemic attack
17. Current drug or alcohol abuse.
18. Any condition including medical, emotional, psychiatric, or logistical
that, in the opinion of the Investigator, would preclude the patient from
adhering to the protocol or would increase the risk of adverse events
while participating in study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- ORR by RECIST 1.1 of NKTR-214 plus pembrolizumab in patients with
untreated metastatic NSCLC |
| • Determinare l’ORR secondo RECIST 1.1 di NKTR-214 più pembrolizumab in pazienti con NSCLC metastatico non trattato. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| screening then every 9 weeks (± 7 days) from Cycle 1 Day 1, EOT (unless scan done within 4 weeks) and at the 90-day long-term followup visits |
| Le misurazioni tumorali verranno eseguite ogni 9 settimane ± 7 giorni, all'EOT e alle visite di follow-up a lungo termine di 90 giorni. |
|
| E.5.2 | Secondary end point(s) |
Efficacy endpoints : Tumor response evaluation :
o duration of response (DOR) by RECIST 1.1
o clinical benefit rate (CBR) by RECIST 1.1
o time to response (TTR) by RECIST 1.1
o progression-free survival (PFS) by RECIST 1.1
o overall survival (OS)
Secondary Safety endpoints :
incidence of adverse events (AEs), including serious AEs (SAEs)
• clinical laboratory tests (blood and urine sampling)
• vital signs
• electrocardiograms (ECG) and echocardiograms (ECHO) or multigated
acquisition (MUGA)
• physical examination |
Efficacy endpoints : Tumor response evaluation :
o duration of response (DOR) by RECIST 1.1
o clinical benefit rate (CBR) by RECIST 1.1
o time to response (TTR) by RECIST 1.1
o progression-free survival (PFS) by RECIST 1.1
o overall survival (OS)
Secondary Safety endpoints :
incidence of adverse events (AEs), including serious AEs (SAEs)
• clinical laboratory tests (blood and urine sampling)
• vital signs
• electrocardiograms (ECG) and echocardiograms (ECHO) or multigated
acquisition (MUGA)
• physical examination |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy: screening then every 9 weeks (± 7 days) from Cycle 1 Day 1,
EOT (unless scan done within 4 weeks) and at the 90-day long-term
follow-up visits
Safety: Throughout the study |
Efficacia: Le misurazioni tumorali verranno eseguite ogni 9 settimane ± 7 giorni, all'EOT e alle visite di follow-up a lungo termine di 90 giorni.
Sicurezza: Durante il corso dello studio |
|
| 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 |
|
| 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 | 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 |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Australia |
| Israel |
| Russian Federation |
| United States |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
|
| 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
|
End of study is defined as no more than 3 years after the last patient
received their first dose of NKTR-214, lost to follow-up, or Sponsor
decision to terminate the study, whichever comes first. Survival data
may be collected beyond end of study. |
End of study is defined as no more than 3 years after the last patient
received their first dose of NKTR-214, lost to follow-up, or Sponsor
decision to terminate the study, whichever comes first. Survival data
may be collected beyond end of study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 18 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 10 |
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