Nivolumab and Ipilimumab +/- UV1 Vaccination as Second Line Treatment in Patients With Malignant Mesothelioma

Study Overview
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Brief Summary
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The objective of the study is to induce a meaningful progression-free survival benefit in patients with Malign Pleural Mesothelioma (MPM) after progression on first line standard platinum doublet chemotherapy, by treating with nivolumab and ipilimumab with or without UV1 vaccine.

Detailed Description
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Several studies have investigated the use of checkpoint inhibition in Malign Pleural Mesothelioma (MPM). Most of them are small studies investigating the efficacy of single-agent immunotherapy in few patients. Given that the combination of anti-PD-1 or anti-PD-L1 therapy with CTLA-4 has been shown in other cancers to enhance treatment effect, combined checkpoint inhibitor treatment has also been investigated in patients with MPM. Although these results are encouraging, the response rates seen are moderate compared to what has been documented for the combination of checkpoint inhibitors in other cancer indications. An approach to further enhance the PFS and response rate in MPM may be to use a vaccine aiming to activate an immune response directed against tumor-related antigens, and to combine the vaccine with checkpoint inhibitors. The proposed study will evaluate the use of the therapeutic cancer vaccine UV1 in combination with nivolumab and ipilimumab after progression on standard first-line chemotherapy in patients with malignant pleural mesothelioma. The objective of the study is to induce a meaningful progression-free survival benefit in patients with MPM after progression on first line standard platinum doublet chemotherapy, by treating with nivolumab and ipilimumab with or without UV1. The primary end-point (PFS) is expected to be analyzed in 2023.

Official Title
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Nivolumab and Ipilimumab +/- UV1 Vaccination as Second Line Treatment in Patients With Malignant Mesothelioma (the NIPU-study)

Conditions
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Cancer, Cancer, Lung, Cancer of Lung, Mesothelioma, Mesothelioma; Lung, Mesothelioma; Pleura, Mesotheliomas Pleural

Intervention / Treatment
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* Biological: UV1 vaccine + leukine
* Biological: ipilimumab
* Biological: nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically and/or cytologically confirmed malignant pleural mesothelioma. Unresectable disease 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 Calculated creatinine CL>40 mL/min (Cockcroft-Gault formula) 24-hour urinecollection for determination of CL Males: Creatinine CL (mL/min) =Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL) Females:Creatinine CL (mL/min)=Weight (kg) x (140 - Age)x0.85 72 x serum creatinine (mg/dL) Previously treated with at least one line of platinum -pemetrexed Exclusion Criteria: 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. History of allergy or hypersensitivity to any of the active substances or excipients in the study drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized, multi-center, open-label, proof of concept study comparing the efficacy and safety of nivolumab and ipilimumab with or without UV1 in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Ipilimumab and nivolumab + UV1 | Biological: UV1 vaccine + leukine<br>* The mode of action of UV1 is to activate the immune system to induce T cells directed against telomerase (hTERT). UV1 vaccination amplifies the pool of hTERT specific tumor-reactive T cells from the naive repertoire and has the potential to increase the breadth and diversity of the tumor-reactive T cell response (epitope spreading). Vaccination with UV1 can thus provide the basis for increased efficacy of checkpoint inhibition therapy, by augmenting the pool of tumor specific T cells in patients with limited or insufficient numbers of T cell clones spontaneously primed by tumor antigens. Reciprocally, the efficacy of UV1 vaccination may be enhanced in combination with checkpoint inhibitors, since the clonal expansion and effector activity of UV1 induced T cells will otherwise be restricted by intrinsic immune regulatory and tumor induced suppressor mechanisms.<br>Biological: ipilimumab<br>* The responses to ipilimumab and nivolumab combination therapy seen in MPM is encouraging.<br>* Other names: Yervoy;Biological: nivolumab<br>* The responses to ipilimumab and nivolumab combination therapy seen in MPM is encouraging.<br>* Other names: Opdivo;|
| Active Comparator: Arm B<br>Ipilimumab and nivolumab | Biological: ipilimumab<br>* The responses to ipilimumab and nivolumab combination therapy seen in MPM is encouraging.<br>* Other names: Yervoy;Biological: nivolumab<br>* The responses to ipilimumab and nivolumab combination therapy seen in MPM is encouraging.<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of efficacy of ipilimumab and nivolumab With or without UV1 vaccine in patients With inoperable malignant pleural mesothelioma progressing after first-line platinum-based chemotherapy. | Progression-free survival (PFS) per Modified Response Evaluation Criteria in Solid Tumors (RECIST) as determined by blinded independent central review (BICR) assessed by radiologic assessments | Monitoring for change in imaging evalated tumor lesions indicating progression throughout the trial until 5 years of follow-up has past. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response evaluation | Comparison of response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (Modified RECIST), in patients who receive nivolumab and ipilimumab with patients who receive nivolumab and ipilimumab in combination with UV1. | Throughout the trial. Radiological assessments every 6th week during the first year, every 12th week for the next 5 years. | 
| Evaluation of patient reported outcomes (PRO) | To evaluate changes from baseline in patient-reported outcomes (PROs) in patients who receive nivolumab and ipilimumab compared to patients who receive nivolumab and ipilimumab in combination with UV1. | every other week for the first 12 weeks, every 6th week thereafter | 
| Evaluation of Adverse Events and discontinuation rate of patients | To determine the safety and tolerability of patients receiving ipilimumab and nivolumab With or without UV1 vaccination by monitoring AEs and study drug discontinuation due to AEs. tolerability in patients who receive nivolumab and ipilimumab compared to patients who receive nivolumab and ipilimumab in combination with UV1, measured by adverse events (AE) and study drug discontinuations due to AEs. | Continuously, and until 90 days after discontinuation of study treatment. |