E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Osteosarcoma, not eligible for curative surgery |
Osteosarcoma metastatico o in ricaduta non candidato a chirurgia |
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E.1.1.1 | Medical condition in easily understood language |
Osteosarcoma |
Osteosarcoma in fase avanzata, non operabile |
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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 | PT |
E.1.2 | Classification code | 10031291 |
E.1.2 | Term | Osteosarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10031294 |
E.1.2 | Term | Osteosarcoma metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the percentage of patients who achieve clinical response; complete response (CR), partial response (PR), or stable disease (SD) at 18 weeks |
Valutare la percentuale di pazienti che raggiunge la risposta clinica; la risposta completa, parziale o stabilità di malattia a 18 settimane valutata secondo RECIST 1.1 |
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E.2.2 | Secondary objectives of the trial |
•Overall response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), and progression-free survival (PFS), assessed by the Investigator using RECIST v1.1. •To evaluate the percentage of patients who have achieved clinical response; CR, PR, or SD at 18 weeks , ORR, CBR, DOR, and PFS assessed by the Investigator using immune-related response criteria, irRC. •To evaluate the percentage of patients who achieve response by 18F-FDG PET/CT measured by changes in maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and/or total lesion glycolosis (TLG). •To evaluate overall survival (OS). •To evaluate the safety and tolerability of pembrolizumab in patients with osteosarcoma. •To evaluate health-related quality of life changes from baseline in patients with osteosarcoma, receiving pembrolizumab, using EORTC QLQ-C30.
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•Valutare il tasso di risposta globale, tasso di beneficio clinico durata della risposta, and sopravvivenza libera da progressione, valuata in accordo ai criteri RECIST 1.1 •Valutare la percentuale di pazienti che raggiunge risposta clinica, risposta completa, parziale o stabilità di malattia a 18 settimane in accordo agli immune-related response criteria, irRC. • Valutare la percentuale di pazienti che raggiunge risposta valuatata mediante PET (variazioni del maximum standardized uptake value (SUVmax), del volume metabolico del (MTV) e/o la glicolisi totale della lesione (TLG). •Valutare la sopravivvenza globale (OS) •Valutare la sicurezza e la tollerabilità di pembrolizumab in pazienti con osteosarcoma •Valutare i cambiamenti correlati alla qualità di vita rispetto al basale mediante il questionario EORTC QLQ-C30, in pazienti con osteosarcoma che hanno ricevuto pembolizumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically confirmed osteosarcoma. 2. Disease relapse or progression after at least one line of systemic treatment. 3. Surgical resection with curative intent not possible. 4. Be willing and able to provide written informed consent/assent for the trial. 5. Be 18 years of age on day of signing informed consent. 6. Have measurable disease based on RECIST, version 1.1. 7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. 8. Have a performance status of 0 or 1 on the ECOG Performance Scale. 9. Demonstrate adequate organ function as defined in Table 1.
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1. Osteosarcoma istologicamente confermato. 2. Ricaduta o progressione di malattia dopo almeno 1 linea di trattamento sistemico 3. Impossibilità di resezione chirurgica con intento curativo o chirurgia non fattibile |
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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. 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. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.Hypersensitivity to pembrolizumab or any of its excipients. 5. Hypersensitivity to pembrolizumab or any of its excipients. 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. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 9. Has known active central nervous system (CNS) metastases and/or sarcomatous meningitis. 10. 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). 11. Has known history of, or any evidence of active, non-infectious pneumonitis. 12. Has an active infection requiring systemic therapy. 13. 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. 14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 15. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). 19. Has received a live vaccine within 30 days of planned start of study therapy.
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1. Pazienti che ricevono altri farmaci sperimentali o che hanno terminato il trattamento sperimentale entro le 4 settimane. 2. Diagnosi di immunodeficienza o che prendono steroidi o altri agenti immunosopressivi nei 7 giorni prima della prima dose di IMP. 3. Storia di tubercolosi attiva 4. Storia di polmonite non infettiva che richiede l'uso di steroidi o polmonite in corso 5. Ipersensibilità al pembrolizumab e/o ai suoi eccipienti . 6. Precedente terapia antitumorale con anticorpi monoclonali nelle 4 settimane prima dell'inizio trattamento o con tossicità superiore al grado 1. 7. Precedente chemioterapia con farmaci target, radioterapia entro le 2 settimane o con tossità non risolta 8. Concomitante patologia maligna con eccezione del cacrinoma delle cellule basali della pelle o del carcinoma squamoso che è stato trattato con intento curativo o carcinoma della cervice in sito. 9. Metastasi a livello del SNC. |
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E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate the percentage of patients who achieve clinical response; complete response (CR), partial response (PR), or stable disease (SD) at 18 weeks as assessed by the Investigator, using RECIST v1.1. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Clinical response at 18 weeks: The percentage of patients with unresectable osteosarcoma who have achieved clinical response; complete response (CR), partial response (PR), or stable disease (SD) at 18 weeks as assessed using RECIST v1.1 |
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E.5.2 | Secondary end point(s) |
• Overall response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), and progression-free survival (PFS), assessed by the Investigator using RECIST v1.1. • To evaluate the percentage of patients who have achieved clinical response; CR, PR, or SD at 18 weeks , ORR, CBR, DOR, and PFS assessed by the Investigator using immune-related response criteria, irRC. • To evaluate the percentage of patients who achieve response by 18F-FDG PET/CT measured by changes in maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and/or total lesion glycolosis (TLG). • To evaluate overall survival (OS). • To evaluate the safety and tolerability of pembrolizumab in patients with osteosarcoma. • To evaluate health-related quality of life changes from baseline in patients with osteosarcoma, receiving pembrolizumab, using EORTC QLQ-C30. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS will be calculated from the date of first dose of pembro until death. Patients alive at the time of data analysis 24 M after last enrolled patient will be treated as censored. OS will be estimated by Kaplan Meier method. PFS will be measured as the time from first dose of pembrolizumab to the first progression recorded, or Death. If patients undergo curative surgical resection after start of treatment, PFS will be measured as time from first dose of pembro to disease recurrence after surgery, or death. Patients who have not yet progressed or died at the time of data analysis 24 M after last enrolled patient will be treated as censored. PFS will be estimated by Kaplan Meier Method. Safety Endpoints Safety will be assessed by reporting adverse experiences using CTCAE v4.0 |
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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 | 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 | 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.8.3 |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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 | No |
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
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The overall trial ends when the last subject completes the last study related phone call or visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator) |
LVLS |
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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 | 7 |
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 | 7 |
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 |