| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Malignant pleural mesothelioma (MPM) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Malignant pleural mesothelioma (MPM) |
|
| 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 | 10059518 |
| E.1.2 | Term | Pleural mesothelioma malignant |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate and compare the efficacy of nivolumab and ipilimumab with or without UV1-vaccine in patients with inoperable malignant pleural mesothelioma progressing after first-line platinum-based chemotherapy, as measured by investigator-assessed progression-free survival (PFS). |
|
| E.2.2 | Secondary objectives of the trial |
Objective response rate (ORR), disease control rate (DCR), time to response and duration of response (DOR) will be evaluated in all patients according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (Modified RECIST). To evaluate differences in Overall Survival (OS).
To evaluate and compare patient-reported outcomes (PROs) of lung cancer symptoms, patient functioning, and health-related quality of life (HRQoL) between treatment arms as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) and it's Lung Cancer Module (LC13) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following criteria to be eligible for study entry:
• Histologically and/or cytologically confirmed malignant pleural mesothelioma.
• Unresectable disease (defined as the participant not being a candidate for curative surgery).
• Measurable disease, defined as at least 1 lesion (measurable) that can be accurately assessed at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for repeated assessment (modified RECIST).
• Available unstained archived tumor tissue sample in sufficient quantity to allow for analyses. At least fifteen unstained slides or a tumor block (preferred). NOTE: A fine needle aspiration sample is not sufficient to make the patient eligible for enrollment. Given the complexity of mesothelioma pathological diagnosis , it is expected that they will have a core needle biopsy or surgical tumor biopsy as part of their initial diagnostic work up.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Willing to provide archived tumor tissue and blood samples for research.
• Adequate organ function as defined below
Haemoglobin ≥9.0 g/dL
Absolute neutrophil count (ANC) 1.5 (or 1.0) x (> 1500 per mm3)
Platelet count ≥100 (or 75) x 109/L (>75,000 per mm3)
Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance
• Previously treated with at least one line of platinum -pemetrexed |
|
| E.4 | Principal exclusion criteria |
The subject must be excluded from participating in the trial if the subject has/is:
• Disease suitable for curative surgery
• Previous treatment with a PD-1 or PD-L1 inhibitor, including nivolumab or any other agent targeting immune checkpoints.
• Non-pleural mesothelioma e.g. mesothelioma arising in peritoneum, tunica vaginalis or any serosal surface other than the pleura.
• Active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ.
• Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids (prednisone >10 mg or equivalent). Surgery, radiation and/or corticosteroids (any dose >10 mg prednisone equivalent) must have been completed ≥ 2 weeks prior to registration.
• Uncontrolled seizures.
• Current or prior use of immunosuppressive medication within 28 days before the first dose of nivolumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Standard steroid premedication given prior to chemotherapy or as prophylaxis for imaging contrast allergy should not be counted for this criterion.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease; Wegner syndrome) within the past 2 years. Subjects with vitiligo, alopecia, Grave's disease, or psoriasis not requiring systemic treatment (within the past 3 years) are not excluded.
• History of primary immunodeficiency.
• History of allogeneic organ transplant.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
• Active infection including tuberculosis (clinical evaluation including: physical examination findings, radiographic findings, positive PPD test, etc.), hepatitis B (known positive HBV surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies as defined by a positive ELISA test). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. HIV testing is not required in the absence of clinical suspicion.
• Known history of leptomeningeal carcinomatosis.
• Pregnant or lactating women
• Live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving nivolumab.
• Any condition that, in the opinion of the investigator, would interfere with the evaluation of study treatment or interpretation of patient safety or study results.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Hypothesis: When UV1 is used in combination with nivolumab and ipilimumab, the combination does improve progression-free survival (PFS) compared with nivolumab and ipilimumab alone |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24-month period and followed for a minimum of 2-3 months after the last patient is randomized. |
|
| E.5.2 | Secondary end point(s) |
Objective response rate (ORR), disease control rate (DCR), time to response and duration of response (DOR) will be evaluated in all patients according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (Modified RECIST). To evaluate differences in Overall Survival (OS).
To evaluate and compare patient-reported outcomes (PROs) of lung cancer symptoms, patient functioning, and health-related quality of life (HRQoL) between treatment arms as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire Core 30 (QLQ-C30) and it's Lung Cancer Module (LC13) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 24-month period and followed for a minimum of 2-3 months after the last patient is randomized. |
|
| 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 | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| 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
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 |
| Australia |
| Denmark |
| Norway |
| Sweden |
| Spain |
|
| 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
|
| All subjects will be followed for survival until the end of the study defined as the last expected visit of the last subject on study, approximately 5 years after the last subject initiate treatment with investigational product or when the sponsor stops the study, whichever occurs earlier. |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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