| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| type B3 thymoma and thymic carcinoma |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 10061031 |
| E.1.2 | Term | Thymoma malignant |
| 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 assess PFS rate (PFSR) at 6 months in patients treated with nivolumab or the combination of nivolumab and ipilimumab, with relapsed/advanced thymic carcinoma and type B3 thymoma not amenable to curative-intent radical treatment and previously treated with platinum-based chemotherapy |
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| E.2.2 | Secondary objectives of the trial |
♦To assess Overall Response Rate (ORR), Disease Control Rate (DCR) and duration of response of nivolumab or nivolumab in combination with ipilimumab in this study population;
♦To assess OS and PFS in this study population treated with nivolumab;
♦To assess the safety of nivolumab in this study population.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
♦Relapsed/advanced thymoma B3 or thymic carcinoma not amenable to curative-intent radical treatment;
♦At least one previous line of platinum-based chemotherapy for advanced disease
- Patients treated with neo-adjuvant or adjuvant platinum-based chemotherapy combined with radical surgery or as part of radical chemoradiotherapy are eligible if chemotherapy was completed less than 6 months before enrollment;
♦Radiological progression documented per RECIST 1.1 during or after completion of previous line therapy;
♦Presence of measurable disease according to RECIST 1.1.;
-Disease status must be documented by full chest and upper abdomen (including adrenal glands) CT and/or MRI and brain CT and / or MRI within 28 days prior study enrollment.
♦At least 18 years;
♦WHO Performance Status (PS) 0-2;
♦Availability of FFPE tumor tissue (preferentially a tumor block or 10 unstained slides), notably for PD-L1 immunohistochemistry (IHC) expression assessment. Archival material is allowed. Tissue must be considered adequate (assessed by a local pathologist) for characterization of PD-L1 status as per procedure manual;
♦Adequate hematological function:
-White blood count ≥ 2 × 109/L;
-Haemoglobin >9 g/dL;
-Platelet count >100 × 109/L;
♦Adequate liver function:
-Total bilirubin <1.5 × ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL);
-LT and/or AST <2.5 × ULN (< 4 x ULN in case of liver metastasis)
-Alkaline phosphatase <5 × ULN;
♦Adequate renal function: calculated creatinine clearance ≥50 mL/min (according to Cockroft-Gault, see 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;
♦Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to the first dose of study treatment;
-Note: women of childbearing potential are defined as premenopausal females capable of becoming pregnant (i.e. females who have had any evidence of menses in the past 12 months, with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, low body weight, ovarian suppression or other reasons;
♦Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 5 months for a woman and 7 months for a man after the last study treatment.
Note:A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:
-Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
-Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
-Intrauterine device (IUD)
-Intrauterine hormone-releasing system (IUS)
-Bilateral tubal occlusion
-Vasectomized partner
-Sexual abstinence (sexual abstinence is only acceptable if this is in line with the preferred and usual lifestyle of the patient)
Acceptable birth control methods that result in a failure rate of more than 1% per year include:
-Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action
-Male or female condom with or without spermicide
-Cap, diaphragm or sponge with spermicide
A combination of male condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are also considered acceptable, but not highly effective, birth control methods
♦Female patients who are breast feeding should discontinue nursing prior to the first dose of study medication and must not breast feed during the trial treatment and for a period of at least 5 months following the last administration of trial drug(s);
♦Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.
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| E.4 | Principal exclusion criteria |
♦Any evidence of active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable (i.e. without evidence of progression by imaging for at least four weeks prior to enrollment and any neurologic symptoms have returned to baseline), and have not received steroids (for a total equivalent dose of more than 10 mg of prednisone per day) for at least 7 days prior to enrollment;
♦Prior treatment with anti-PD-1, anti-PD-L1/2, anti-CD137, CTLA-4 modulators;
♦Presence of acetylcholine receptor antibodies;
♦Current participation in any other clinical research or treatment with an investigational agent or use of an investigational device within 4 weeks of enrollment;
♦Known
active Hepatitis B (e.g., positive HBsAg result) or C (e.g., HCV RNA[qualitative] is detected) or known history or current evidence of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies);
♦If CT has to be used, known contra-indications for CT with IV contrast;
♦Chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 15 days prior to enrollment;
-Corticosteroid use as premedication for IV contrast allergies/reactions is allowed;
-Daily prednisone at doses up to 10 mg or equivalent doses of any other corticosteroid is allowed for example as replacement therapy;
♦History of interstitial lung disease (ILD) OR pneumonitis (other than COPD exacerbation) that has required oral or IV steroids;
♦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 (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed;
♦Live vaccines within 30 days prior to the first dose of study therapy and while participating in study. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, H1N1 flu, rabies, BCG, and typhoid vaccine.
♦Autoimmune paraneoplastic syndrome requiring immunosuppressive or dedicated treatment. Particular attention should be given to detecting any minor myasthenia signs or positive autoantibodies at enrollment;
♦History of any other hematologic or primary solid tumor malignancy, unless in remission for at least 5 years. pT1-2 prostatic cancer Gleason score < 6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix are allowed;
♦Previous allogeneic tissue/solid organ transplant;
♦Active infection requiring therapy;
♦Surgery or chemotherapy related toxicity that have not resolved to a grade 1, with the exception of alopecia, fatigue, neuropathy and lack of appetite /nausea;
♦Severe comorbidities that in the opinion of the investigator might hamper participation to the study and/or treatment administration;
♦Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival Rate at 6 months (PFSR-6) per independent radiological review |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From Baseline/Registration until to 27 th week (+/- 7 days) |
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| E.5.2 | Secondary end point(s) |
1.Progression Free Survival Rate at 6 months (PFSR-6) according to RECIST 1.1 per local investigator assessment.
2.Safety according to CTCAE v4.0;
3.Overall Response Rate (ORR) according to RECIST 1.1 per local investigator assessment ;
4.Disease Control Rate according to RECIST 1.1 per local investigator assessment (DCR);
5.Duration of response according to RECIST 1.1 per local investigator assessment;
6.Progression Free Survival (PFS) according to RECIST 1.1 per local investigator assessment;
7.Overall Survival (OS).
8.Progression Free Survival for patients continuing treatment after progression
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.From Baseline/Registration until to 27 th week (+/- 7 days)
2.From Baseline/Registration until to 1.5 months after end of treatment,
3. From Baseline/Registration until to progressions or if not progress till end of study
4.From Baseline/Registration until to progressions or if not progress till end of study
5.from the time measurement criteria are met for CR/PR [whichever is first recorded] until to progressions or if not progress till end of study
6.From Baseline/Registration until to progressions or if not progress till end of study
7.From Baseline/Registration until death or end of study
8.From the initial progression till the time of the next progression or death
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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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 | No |
| 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 |
| Belgium |
| France |
| Germany |
| Netherlands |
| Spain |
| Switzerland |
| United Kingdom |
| Czechia |
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| 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
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End of study occurs when all of the following criteria have been satisfied:
1. 5 months after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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