| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable melanoma with superficial or superficial and visceral metastases |
| Melanoma avanzato con lesioni superficiali (Cutanee/Sottocutanee) in presenza o meno di metastasi viscerali |
|
| E.1.1.1 | Medical condition in easily understood language |
| Unresectable melanoma |
| Melanoma Avanzato |
|
| 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 | 10053571 |
| E.1.2 | Term | Melanoma |
| 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 evaluate safety and efficacy (in terms of improvement of the local and systemic response rates) of the combined treatment with pembrolizumab e elettrochemotherapy |
| valutare la sicurezza e l'efficacia (in termini di miglioramento dei tassi di risposta locale e sistemica) del trattamento concomitante con Pembrolizumab e elettrochemioterapia |
|
| E.2.2 | Secondary objectives of the trial |
1) Disease control rate (complete response + partial response + SD)
2) Progression Free Survival
3) Correlation between clinical and radiological immune responses.
4) Durable local disease progression-free survival at 36 weeks (day 252 = Visit 13), 48 weeks (Visit 16), 60 (Visit 19) and every 12 weeks up two years
5) Survival at 2 years (Follow-up will be continued every 12 weeks for 2 years).
6) Safety of the combination
7) Toxicity of the combination
8) Quality of life (EORTC questionnaire Pain Visual Scale) |
1. Tasso di controllo della malattia (CR+PR+SD)
2. Sopravvivenza libera da progressione
3. Correlazione tra la risposta clinica e radiologica
4. Valutazione della PFS alla settimana 36,48,60 e ogni 12 settimane per due anni
5. Sopravvivenza a due anni
6. Sicurezza
7. Tossicità
8. Qualità di vita |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have a histologically confirmed advanced melanoma stages III b/c or IV, with at least the following superficial lesions: 5 lesions if diameter < 1 cm or 3 lesions if diameter > 1 cm.
2. Could have received previous therapy included CT, antiCTLA4 or antiBRAF/antiMEK treatment or be treatment naïve.
3. Be willing and able to provide written informed consent/assent for the trial.
4. Be ¿ 18 years of age on day of signing informed consent.
5. Have measurable disease based on RECIST 1.1.
6. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.
7. Have a performance status = 2 on the ECOG Performance Scale. (Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.)
8. Demonstrate adequate organ function as defined in
9. Have a baseline total body CT scan (brain MRI if brain metastasis are suspected)
a. Patients with brain metastasis are allowed to participate if previously treated and brain lesion stability or inactivity is demonstrated. Patients with a history of brain metastasis are required to have a pre-baseline brain MRI at least 60 days (2 months) before the Screening/Baseline visit (Visit 1) for comparison to the Screening (Visit 1) MRI. Patients for whom MRI is contraindicated will undergo head CT. Stable/inactive disease is determined by comparing the pre baseline and screening/baseline MRI/CT results.
b. Patients presenting with brain metastasis at Screening/Baseline who had no known previous brain involvement and who had no brain MRI/CT tests at least 60 days (2 months) before Screening/Baseline are considered screening failures and will be excluded from study enrollment.
10. Have cutaneous or subcutaneous metastases from melanoma that are accessible for the application of electric pulses using the single use, sterile CLINIPORATOR™ electrodes (5 lesions if diameter <1 cm or 3 lesions if diameter >1 cm). For patients presenting with more than 7 lesions, the lesions with the largest diameters that fall within the <10 to 30 mm size requirements will be considered "target" lesions for RECIST criteria and study purposes. The others will be recorded and monitored but will not considered as Target.
11. Have lesions clearly requiring palliative treatment [e.g., symptomatic (bleeding, draining, painful), disfiguring or causing distress to the patient].
12. A treatment-free period of three (3) weeks before enrolling in the study. NOTE: Patients receiving concomitant treatments for unrelated existing pathologies are eligible for enrollment.
13. Life expectancy > 3 months.
14. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
15. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 – Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
16. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. |
1. Diagnosi istologica confermata di melanoma avanzato stadio III b/c o IV, con almeno le seguenti lesioni superficiali: 5 lesioni se diametro < 1 cm o 3 lesioni se diametro > 1 cm.
2. Precedente trattamento con CT, antiCTLA4 or antiBRAF/antiMEK o treatment naïve.
3. Volontà e capacità di dare un consenso informato scritto allo studio.
4. Età >= 18 anni
5. Malattia misurabile in base ai RECIST 1.1.
6. Volontà di essere sottoposto a una nuova biopsia (core biopsy o excisional) della lesione tumorale (entro 6 settimane dall’inizio del trattamento). Per i pazienti per i quali non è possibile ottenere una nuova biopsia sarà sufficiente inviare una precedente biopsia dopo approvazione dello sponsor.
7. ECOG = 2
8. Adeguati valori di laboratorio come definiti in tab 1 (esami dello screening eseguiti entro 10 gg dall’inizio del trattamento)
9. Total body CT scan basale (MRI encefalo se sospetto di metastasi cerebrali)
a. I pts con metastasi cerebrali possono essere inclusi se precedentemente trattati e si dimostra la stabilità o inattività delle lesioni. Per i pts con una storia di metastasi cerebrali è richiesta una pre-baseline MRI encefalica almeno 60 gg (2 mesi) prima della visita 1 per paragonarla alla MRI dello screening. I pts per i quali è controindicata la MRI potranno eseguire una TC scan.
b. I pazienti con metastasi cerebrali allo screening senza un precedente coinvolgimento e senza una precedente MRI/CT tests saranno considerati screening failures e saranno esclusi dallo studio.
10. Metastasi da melanoma cutanee o subcutanbee accessibili per l’elettroporazione con CLINIPORATOR™ (5 lesioni se diametro < 1 cm o 3 lesioni se diametro > 1 cm). Per i pts con più di 7 lesioni, sarà considerate lesioni “target” quella con il diametro maggiore <10 fino a 30 mm. Le altre lesioni saranno monitorate ma non considerate Target.
11. Presenza di lesion che richiedano un trattamento palliative [sintomatiche (sanguinanti, dolorose), deturpate o che causano afflizione per il paziente].
12. Periodo libero da trattamento di 3 settimane prima dell’arruolamento nello studio. NOTE: sono includibili I pts che ricevono trattamenti concomitanti per pre-esistenti patologie.
13. Aspettativa di vita > 3 mesi.
14. Donne in pre menopausa devono avere un test di gravidanza (siero o urine) negativo entro 72 ore prima di ricevere il trattamento. Se il test delle urine è positivo o non può essere confermato come negativo è richiesto un test di gravidanza su siero.
15. Donne in pre menopausa (Section 5.7.2) devono essere d’accordo nell’usare un adeguato metodo contraccettivo. La contraccezione deve continuare 120 gg dopo l’ultima dose del farmaco in studio. Note: L’astinenza è accettata.
16. Soggetti maschi (Section 5.7.1) devono essere d’accordo nell’usare un adeguato metodo contraccettivo - La contraccezione deve continuare 120 gg dopo l’ultima dose del farmaco in studio. Note: L’astinenza è accettata |
|
| E.4 | Principal exclusion criteria |
1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment or has any ongoing treatment for melanoma or with any non-study anticancer therapy or immunosuppressive agent.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
3. Has a known history of active TB (Bacillus Tuberculosis)
4. Hypersensitivity to pembrolizumab or any of its excipients or known allergies to Bleomycin.
5. Has received a cumulative lifetime dose of Bleomycin exceeding 250 mg/m2
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to a previously administered agent.
8. Patient has a history of a malignancy (other than the disease under treatment in the study) within 5 years prior to first study drug administration. This should exclude adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers. Shorter intervals can be considered after discussion with Merck.
9. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
10. Has epilepsy.
11. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
12. Has a history of (no-infectious) pneumonitis that require steroids or current pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. |
1. Pts che stanno partecipando ad altri studi o che vi hanno partecipato entro 4 settimane dalla prima dose di trattamento o che hanno trattamenti per il melanoma in corso.
2. Diagnosi di immunodeficienza o che ricevono terapia sistemica con steroidi o alter forme di terapia immunosoppressiva entro 7 gg dall’inizio del trattamento in studio.
3. Storia nota di TB attiva (Bacillus Tuberculosis)
4. Ipersensibilità al pembrolizumab o ai suoi eccipienti o allergie note alla Bleomycin.
5. Aver ricevuto nel corso della propria vita una dose di Bleomycin eccedente 250 mg/m2
6. Aver ricevuto un precedente anticorpo monoclonale entro 4 settimane dal giorno 1 di studio o non aver recuperate precedenti tossicità da agenti ricevuti da più di 4 settimane prima.
7. Precedente chemioterapia, targeted small molecule therapy, o radiazione entro 2 settimane prima del giorno 1 di studio o che non hanno recuperate da precedenti eventi avversi.
8. Pazienti con tumori entro i 5 anni dall’inizio del trattamento in studio; eccetto carcinoma squamoso/basale della cute adeguatamente trattato stadio 1 o 2, crcinoma in situ della cervice o della mammella o altri carcinomi in situ. Intervalli più brevi possono essere considerati dopo discussione con il promotore.
9. Metastasi a livello del CNS e/o meningiti carcinomatose. Soggetti con precedenti metastasi encefaliche trattate possono partecipare se stabili (senza evidenza di progressione da immagini per almeno 4 settimane prima della prima dose di trattamento e in assenza di sintomi neurologici al basale) senza evidenza di nuove metastasi e senza l’uso di steroidi per almeno 14 gg prima dell’inzio del trattamento. Questa eccezione non riguarda le meningiti carcinomatose che sono escluse a meno di stabilità clinica.
10. Epilessia.
11. Malattia autoimmune che abbia richiesto un trattamento sistemico nei precedenti 2 anni
12. Storia di (no-infectious) pneumonitis che abbia richiesto steroidi o pneumonitis corrente.
13. Infezioni attive che richiedano terapia sistemica.
14. Storia o evidenza corrente di qualsiasi condizione, terapia o anormalità di laboratorio che potrebbero confondere i risultati del trial, interferire con la partecipazione del soggetto per tutta la durata dello studio o che non sia nel migliore interesse del soggetto per la partecipazione del soggetto nell’opinione dell’investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate (complete response + partial response) |
Tasso di risposta globale (risposta completa + risposta parziale)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 3 months |
| Ogni 3 mesi |
|
| E.5.2 | Secondary end point(s) |
| Disease control rate (complete response + partial response + SD) ; Correlation between clinical and radiological immune responses; Progression Free Survival; Durable local disease progression-free survival ; Overall Survival ; safety; Toxicity; Quality of life |
| Tasso di controllo della malattia (CR+PR+SD); Correlazione tra immunorisposta clinica e radiologica; Sopravvivenza libera da progressione; Durata dell’intervallo libero dalla malattia; Sopravvivenza globale; Sicurezza; Tossicità; Qualità di vita |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| end of treatment; 2 years; End of treatment; at 36 weeks (day 252 = Visit 13), 48 weeks (Visit 16), 60 (Visit 19) and every 12 weeks up two years ; Survival at 2 years (Follow-up will be continued every 12 weeks for 2 years) ; end of treatment; end of treatment; end of treatment |
| fine del trattamento; 2 anni; Fine del trattamento; a 36 settimane (gg252= visita 13), 48 settimane (visita 16), 60 settimana (visita 19) e ogni 12 settimane fino a 2 anni; sopravvivenza a 2 anni (follow up continuerà ogni 12 settimane per 2 anni; fine del trattamento; fine trattamento; fine trattamento |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| traslational research to identify biomarkers predictive of favorable clinical outcome and to evaluate immunological modification due to treatment |
| è prevista una ricerca translazionale per identificare eventuali marker associati ad un risultato clinico più favorevole e valutare cambiamenti immunologici associati al trattamento |
|
| 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 | 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 | 4 |
| 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 | 5 |
| 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 | 5 |
| 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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