| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| MM and NSCLC patients resistant to anti-PD-1/PD-L1 therapy |
| pazienti con melanoma metastatico (MM) e tumore del polmone non a piccole cellule (NSCLC) in stadio IV, che hanno ricevuto e sono progrediti a precedenti trattamenti con farmaci immunoterapici anti-PD-1/(-PD-L1) |
|
| E.1.1.1 | Medical condition in easily understood language |
| MM and NSCLC patients resistant to anti-PD-1/PD-L1 therapy |
| pazienti con melanoma metastatico (MM) e tumore del polmone non a piccole cellule (NSCLC) in stadio IV, che hanno ricevuto e sono progrediti a precedenti trattamenti immunoterapici anti-PD-1/(-PD-L1) |
|
| 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 | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| 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 assess the immune-related Objective Response Rate (i-ORR) of nivolumab combined with ipilimumab and guadecitabine or nivolumab combined with ipilimumab, in MM and NSCLC patients resistant to anti-PD-1/PD-L1 therapy. |
| L’obiettivo primario dello studio è di accertare tasso di risposta obiettiva immuno-correlata ( immune-related Objective Response Rate: i-ORR) del nivolumab combinato con ipilimuamb e guadecitabina, o nivolumab combinato con ipilimuamb in pazienti con melanoma metastatico (MM) e tumore del polmone non a piccole cellule (NSCLC), resistenti a terapia anti-PD-1/(-PD-L1). |
|
| E.2.2 | Secondary objectives of the trial |
To assess safety, tolerability and feasibility of the combinations
To assess the objective response rate (ORR), (assessed using RECIST v. 1.1 criteria) of nivolumab combined
with ipilimumab and guadecitabine or nivolumab combined with ipilimumab, in MM and NSCLC patients
resistant to anti-PD-1/PD-L1 therapy.
To further describe efficacy using the following tumor response indicators (assessed using iRECIST/RECIST v
1.1 criteria) and clinical endpoints: Disease Control Rate, Duration of response, Time to response and
Progression-Free Survival, Overall Survival (OS) as summarized by median Survival and Survival rate at one
and two years. |
• sicurezza, tollerabilità e fattibilità delle combinazioni
• valutazione del tasso di risposta oggettiva (ORR), (tramite i criteri RECIST v. 1.1) di nivolumab combinato con ipilimumab e guadecitabina o nivolumab combinato con ipilimumab, in pazienti MM and NSCLC resistenti alla terapia anti-PD-1/PD-L1.
• ulteriore valutazione dell’efficacia tramite i seguenti indicatori di risposta del tumore: (valutati tramite i criteri iRECIST/RECIST v 1.1) e endpoint clinici: Disease Control Rate, Duration of response, Time to response and Progression-Free Survival, Overall Survival (OS), calcolati come sopravvivenza mediana e tasso di sopravvivenza a uno e due anni |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Signed Written Informed Consent
Willing and able to give written informed consent.
Target Population Subjects must fulfill all of the following inclusion criteria:
Men and women of and over 18 years old
1) Target Population Melanoma cohort A
a) Histologic diagnosis of malignant melanoma
b) Unresectable Stage III/Stage IV melanoma patients with resistance to anti-PD-1/PD-L1 and measurable lesions
by CT or MRI per iRECIST/RECIST criteria that can be amenable to biopsy
c) Only one line of immunotherapy for advanced (unresectable Stage III or Stage IV) disease with anti-PD-1/PDL1
and its combinations; if BRAF mutant one line of targeted therapy is allowed prior to anti-PD-1/PDL1therapy.
2) Target Population NSCLC cohort B
a) Histologic or cytologic diagnosis of NSCLC lacking EGFR-sensitizing mutation and/or ALK/ROS1
translocation.
b) Stage IV NSCLC patients with primary resistance to anti-PD-1/PD-L1 and measurable lesions by CT or MRI
per iRECIST/RECIST criteria that can be amenable to biopsy.
c) Only one line of immunotherapy for advanced (unresectable Stage III or Stage IV) disease with anti-PD-1/PDL1
or its combinations; one line of chemotherapy is allowed prior to anti-PD-1/PDL-1 therapy.
3) confirmed PD
4) 4 weeks or greater since last treatment and
5) Must have recovered from any acute toxicity associated with prior therapy
6) Life expectancy greater than 16 weeks
7) Subjects with adequate organ function defined as:
a) WBC =3500/uL
b) ANC =2000/uL
c) Platelets = 100 x 103/uL
d) Hemoglobin = 9 g/dL
e) Creatinine < or <= 2.5 x ULN AND creatinine clearance (CrCl) = 40 mL/min (if using the Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) x weight in kg x 0.85
72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dL
f) AST
- < or <= 2.5 x ULN for patients without liver metastasis
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- < or <= 5 x ULN for patients with liver metastasis
g) Bilirubin
- < or <= 3 x ULN for patients with liver metastasis
- <3.0 mg/mL for patients with Gilbert’s Syndrome
- 1.5 x ULN for patients without liver metastasis
8) Negative screening tests for HIV, HepB, and HepC. If positive results are not indicative of true active or chronic
infection, the patient can enter the study after discussion and agreement between the Investigator and the Medical Monitor.
9) Women of child-bearing potential must not be pregnant or breastfeeding, must have a negative pregnancy test at
Screening and all men must be practicing two medically acceptable methods of birth control. Men should not father a
child while receiving treatment with guadecitabine+ ipilimumab, and for 2 months following completion of treatment.
Men with female partners of childbearing potential should use effective contraception during this time. |
- Uomini e donne >= 18 anni
- Capacità di fornire il consenso allo studio
Cohort A: pazienti con Melanoma
- Diagnosi istologico di melanoma maligno
- Melanoma di Stadio III/Stadio IV inoperabile resistente a anti-PD-1/PD-L1 e lesioni misurabili con CT o MRI per i criteri iRECIST/RECIST raggiungibile alla biopisa.
- Una linea di immunoterapia per malattia avanzata (Stadio III/Stadio IV inoperabile) con anti-PD-1/PD-L1 e sue combinazioni; se BRAF è mutante, una linea di terapia target è consentita prima della terapia anti-PD-1/PD-L1.
Cohort B: pazienti NSCLC
- a) diagnosi istologica o citologica di NSCLC mancante della mutazione EGFR-sensibilizzante e della traslocazione ALK/ROS1.
- b) Pazienti NSCLC di stadio IV con resistenza primaria a anti-PD-1/PD-L1 e lesioni misurabili tramite CT o MRI per criteri iRECIST/RECIST raggiungibili alla biospia.
- c) - Una linea di immunoterapia per malattia avanzata (Stadio III/Stadio IV inoperabile) con anti-PD-1/PD-L1 o sue combinazioni: una linea di chemio terapia è permessa prima della terapia anti-PD-1/PDL-1.
- 3) PD confermata
- 4) almeno 4 settimane dall’ultimo trattamento e
- 5) completo recupero da qualsiasi tossicità acuta associata a precedente terapia
041275025/E;
-
- 6) aspettativa di vita maggiore di 16 settimane
- 7) adeguata funzionalità organica definita come::
- a) WBC =3500/uL
- b) ANC =2000/uL
- c) Piastrine = 100 x 103/uL
- d) Emoglobina = 9 g/dL
- e) Creatinina < o <= 2.5 x ULN E clearance di creatinina
CrCl) = 40 mL/min (in accordo alla seguente formula di Cockcroft-Gault formula):
- Donna CrCl = (140 – età in anni) x peso in kg x 0.85
- 72 x creatinina serica in mg/dL
- Uomo CrCl = (140 – età in anni) x peso in kg x 1.00
- 72 x creatinina serica in mg/dL
- f) AST
- < o <= 2.5 x ULN per pazienti senza metastasi epatiche
- < o <= 5 x ULN per pazienti con metastasi epatiche
- g) Bilirubina
- < o <= 3 x ULN per pazienti senza metastasi epatiche
- <3.0 mg/mL per pazienti con sindrome di Gilbert’s
- 1.5 x ULN per pazienti senza metastasi epatiche
- 8) negatività all’HIV, HepB, a HepC. Se il risultato positivo non è indicativo di infezione attiva o cronica franca, il paziente può essere arruolato dopo accordo tra Sperimentatore e Medical Monitor
- 9) Le donne fertili non devono essere in gravidanza o in allattamento, devono avere un test di gravidanza negativo allo screening e accettare di usare valida contraccezione
- Gli uomini devono accettare di usare valida contraccezione nel periodo di trattamento e per i due mesi successivi al trattamento |
|
| E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
a) Women who are pregnant or breastfeeding;
b) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period
and for up to 6 months after the study;
c) Women with a positive pregnancy test on enrollment or prior to investigational product administration;
d2) Target Disease Exceptions
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a) Any malignancy from which the patient has been disease-free for less than 2 years, with the exception of
adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ
of the cervix
b) Primary ocular melanoma.
3) Medical History and Concurrent Diseases
a) Symptomatic brain metastases requiring immediate local intervention (radiotherapy (RT) and/or surgery);
b) Leptominingeal involvement by disease;
c) Autoimmune disease: Patients with a documented history of Inflammatory Bowel Disease, including ulcerative
colitis and Crohn’s disease are excluded from this study as are patients with a documented history of
symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma],
Systemic Lupus Erythematosus, autoimmune vasculitis [e.g., Wegener’s Granulomatosis] and autoimmune
hepatitis. Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome) are
also excluded from this study;
d) Any underlying medical condition, which in the opinion of the investigator, will make the administration of
study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent
diarrhea.
4) Prohibited Treatments and/or Therapies
a) Concomitant therapy with any anti-cancer agent; immunosuppressive agents; any non-oncology vaccine therapy
used for prevention of infectious diseases (for up to 1 month prior to or after any dose of study drug); surgery or
radiotherapy (except palliative surgery and/or radiotherapy to treat a non-target symptomatic lesion or to the
brain after Sponsor approval); other investigational anti-cancer therapies; or chronic use of systemic
corticosteroids (used in the management of cancer or non-cancer-related illnesses);
b) Previous treatment with other investigational products, including cancer immunotherapy, within 30 days;
c) Prior treatment with anti-CTLA-4, except in adjuvant setting) Sexually active fertile men not using effective birth control if their partners are WOCBP |
Criteri di esclusione
1. Donne in gravidanza o in allattamento
2. Donne fertili che non vogliono o possono utilizzare un adeguato metodo contraccettivo per l’intero periodo di studio e per 6 mesi dopo lo studio.
3. Donne con test di gravidanza positivo allo screening o prima di iniziare il trattamento
4. Uomini che non usano un adeguato metodo contraccettivo se le loro partner sono fertili.
5. Qualsiasi tumore che è durato più di due anni, con l’eccezione del tumore della pelle basale o squamoso, tumore superficiale della vescica, carcinoma in situ della cervice, adeguatamente trattati e curati
6. Melanoma primario oculare
7. Metastasi cerebrali sintomatiche che richiedono immediato intervento locale ( radioterapia o chirurgia)
8. Coinvolgimento leptomenigeale;
9. Malattie autoimmuni
10. Qualsiasi condizione medica sottostante che nell’opinione dello sperimentatore possa rendere pericolosa la somministrazione dei farmaci in studio, o non sicura l’interpretazione degli eventi avversi, come ad esempio condizioni associati a frequenti diarree.
11. Terapie concomitanti anticancro
12. Precedenti trattamenti con altri prodotti sperimentali, inclusa immunoterapia oncologica, nei precedenti 30 giorni
13. Precedente trattamento con anti-CTLA-4, eccetto che come adiuvante
14. Pazienti prigionieri on incarcerati involontariamente
15. Pazienti con patologie psicologiche o psichiatriche |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To assess the immune- related objective response rate (i-ORR) (assessed using iRECIST criteria) of nivolumab combined
with ipilimumab and guadecitabine or nivolumab combined with ipilimumab, in MM and NSCLC patients resistant to
anti-PD-1 therapy. |
Valutare il tasso di risposta oggettiva immuno-correlata (i-ORR) (tramite i criteri iRECIST ).
iORR è la proporzione di pazienti trattati con un iBOR di iCR o iPR confermati. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Objectives:
- To assess safety, tolerability and feasibility of the combinations
- To assess the objective response rate (ORR) (assessed using RECIST v. 1.1 criteria) of nivolumab combined
with ipilimumab and guadecitabine or nivolumab combined with ipilimumab, in MM and NSCLC patients
resistant to anti-PD-1 therapy.
- To further describe efficacy using the following tumor response indicators (assessed using RECIST v 1.1and
iRECIST criteria) and clinical endpoints: Disease Control Rate, Duration of response, Time to response and
Progression-Free Survival, Overall Survival as summarized by median Survival and Survival rate at one and two years |
- sicurezza, tollerabilità e fattibilità delle combinazioni tramite raccolta di AE, SAE, risultati di laboratorio, segni vitali e esame fisico.
- valutazione del tasso di risposta oggettiva (ORR),
ORR è la proporzione di soggetti trattati con BOR of CR or PR per RECIST 1.1. (tramite i criteri RECIST v. 1.1)
- • ulteriore valutazione dell’efficacia tramite i seguenti indicatori di risposta del tumore: (valutati tramite i criteri iRECIST/RECIST v 1.1) e endpoint clinici: Disease Control Rate, Duration of response, Time to response and Progression-Free Survival, Overall Survival (OS), calcolati come sopravvivenza mediana e tasso di sopravvivenza a uno e due anni. |
|
| 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 | No |
| 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 | 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 |
| randomizzato non controllato |
| Randomized, run in |
|
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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 | Information not present in EudraCT |
| 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 | 2 |
| 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 | 2 |
| 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 |
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