Intracavitary Cisplatin-Fibrin Localized Chemotherapy After P/D or EPP for Malignant Pleural Mesothelioma

Study Overview
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Brief Summary
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The aim is to introduce a new therapeutic method of intracavitary chemotherapy (cisplatin) combined with a fibrin carrier (Vivostat®) after pleurectomy/decortication or extrapleural pneumonectomy in a phase I and II study for Malignant Pleural Mesothelioma patients by evaluation of the safety in a dose-escalating model (phase I), and confirmation of safety and efficacy in phase II with the maximum tolerated dose in phase I.

Official Title
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Phase I Dose-Escalation /Phase II Monocentric Open Trial for Evaluation of Safety and Efficacy of Intracavitary Cisplatin-Fibrin Localized Chemotherapy After Pleurectomy/Decortication or Extrapleural Pneumonectomy for the Treatment of Patients With Malignant Pleural Mesothelioma

Conditions
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Malignant Pleural Mesothelioma

Intervention / Treatment
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* Combination Product: intracavitary cisplatin-fibrin


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patient is able to understand and willing to sign a written informed consent document. Male or female, age >=18 years ECOG performance status =<2 (ECOG = Eastern Cooperative Oncology Group) Resectable MPM (Malignant Pleural Mesothelioma) histologically confirmed (phase I: stage cT1-cT4 cN0-cN3 cM0-cM1 / phase II: stage cT1-cT3 cN0-cN1 cM0) (TNM Tumor staging abbreviations: c = clinical; T = Tumor, N = lymph Nodes, M = Metastases; numbers = quantity) Only Phase II: Mediastinal staging (cytological or histological) Only Phase II: Induction chemotherapy (3 or more cycles cisplatin or carboplatin (also in combination with other therapeutic agents) Patient qualifying for (extended) pleurectomy/decortication ((e)P/D) or extrapleural pneumonectomy (EPP) for resection of MPM, which has to be assessed during a multidisciplinary tumor board including a thoracic surgeon Patient must have appropriate organ and bone marrow function as defined: hematologic function: hemoglobin ≥100 g/L, WBC (white blood cell count) ≥3.5 G/L, neutrophils ≥1.5 G/L, thrombocytes ≥100 G/L; liver function: total bilirubin and LDH (lactate dehydrogenase) ≤1.5 x ULN (upper limit of normal); AST (aspartate aminotransferase), ALT (alanine aminotransferase), GGT (gamma glutamyltransferase), and AP (alkaline phosphatase) ≤2.5 x ULN; renal function: creatinine ≤130 μmol/L or, if greater, creatinine clearance ≥60 ml/min/1.73m2. Patient must have an appropriate blood coagulation for P/D or EPP (Quick-test > 50%, INR (international normalized ratio) <=1.2) The patient agrees to use an efficient contraceptive treatment up to 3 months after cisplatin application if required (pre-menopausal women and men in a sexually mature age). Heart and lung function allowing P/D under general anesthesia Exclusion criteria: Known or suspected unwillingness of the patient to follow the rules of the protocol Patient who has not recovered from side effects from prior chemotherapy or radiotherapy. Any known hypersensitivity against cisplatin or other platinum containing substances or any other components used for the preparation of the drugs. Patient must not receive any other investigational agents 4 weeks before treatment and until the end of the observation period (2 months after treatment). Patient with prior ipsilateral pleurectomy Only Phase II: Multimodality Prognostic Score (MMPS) > 2: 4 items with a maximum possible score of 4 if the patient presented all four conditions and 0 if none were present: Tumor volume before induction chemotherapy > 500 ml, non-epithelioid histotype in the diagnostic biopsy before induction chemotherapy, CRP (C reactive protein) value > 30 mg/l before induction chemotherapy, and progressive disease after induction chemotherapy according to RECIST criteria Patient with uncontrolled intercurrent illnesses that would limit the operative procedure of P/D / EPP or compliance with study requirements Tinnitus impairment of more than severity grade I (slight) evaluated by the tinnitus questionnaire MiniTF12_CH (Mini Tinnitus Fragebogen 12, CH = Confoederatio Helvetica (Swiss version)), and/or restricted power of hearing until 4 kHz (kilohertz) confirmed by audiometry, unless age-related presbyacusis in a normal range confirmed by an audiologist. Known alcohol and/or drug abuse at the time of screening Pregnant or lactating woman

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
Intervention Model: Single Group Assignment
Interventional Model Description: Open Label, single dose local intracavitary application of Cisplatin bound to Fibrin after surgery (removal of Tumor)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intracavitary cisplatin-fibrin<br>single dose local intracavitary cisplatin-fibrin application after pleurectomy/decortication | Combination Product: intracavitary cisplatin-fibrin<br>* single dose, local intracavitary application of cisplatin-fibrin after pleurectomy/decortication<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (Safety) | (Serious) Adverse Events & safety blood parameters (hematology and clinical chemistry) | during 6 weeks after surgery with local cisplatin-fibrin application | 
| Cisplatin concentration in the superficial chest wall tissue | local cisplatin concentration in the superficial chest wall biopsy measured by inductively coupled plasma sector field mass spectrometric (ICP-MS) detection | 90 min after application | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival | time between date of treatment and time point of death or last follow-up, method of Kaplan and Meier | up to 5 years (phase I), up to 2 years (phase II) | 
| FFR (= Freedom From Recurrence) | time to tumor progression by CT or PET-CT/MRI, method of Kaplan and Meier | 4, 16 weeks, then every 4 months up to 5 (phase I) / 2 years (phase II) | 
| in-treatment-field FFR (= Freedom From Recurrence) | time to tumor progression by CT or PET-CT/MRI in the chest cavity where the investigational medicinal product was applied, method of Kaplan and Meier (PET-CT = positron emission computed tomography) | up to 2 years (phase II) | 
| Quality of Life SF-36 (= Short Form-36) | change from baseline in SF-36 quality of life questionnaire | phase I: 0, 4, 8, 16 weeks and every 4w up to 5y; phase II: 0, 6, 16w and every 4w up to 2y | 
| Quality of Life EORTC QLQ-C15/LC13 (QLQ = Quality of Life Questionnaire, C = Cancer, LC = Lung Cancer) | change from baseline in EORTC Lung Cancer Questionnaire QLQ-C15/LC13 | phase I: 0, 4, 8, 16 weeks and every 4w up to 5y; phase II: 0, 6, 16w and every 4w up to 2y | 
| pharmacokinetics cisplatin concentration in blood serum | cisplatin concentration in blood serum by inductively coupled plasma sector field mass spectrometric (ICP-MS) detection | baseline, and 0, 2, 6, 10, 24, 48, 120 h postoperative | 
| pharmacokinetics cisplatin concentration in urine | pharmacokinetics, cisplatin concentration in urine by inductively coupled plasma sector field mass spectrometric (ICP-MS) detection | baseline, collection of first 48h, day 14 postoperative | 
| TUNEL assay | markers for apoptosis in superficial chest wall tissue | before and 90 min after cisplatin-fibrin application | 
| PAI-1 and p21 (PAI-1 = Plasminogen Activator Inhibitor Typ 1, p21 = CDK-Inhibitor 1 = Cyclin Dependent Kinase Inhibitor 1)) | markers for senescence in superficial chest wall tissue | before and 90 min after cisplatin-fibrin application |