Malignant Pleural Mesothelioma
Conditions
Brief summary
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.
Interventions
COMBINATION_PRODUCTintracavitary cisplatin-fibrin
single dose, local intracavitary application of cisplatin-fibrin after pleurectomy/decortication
Sponsors
Swiss National Science Foundation
Swiss Accident Insurance Fund SUVA
University of Zurich
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open Label, single dose local intracavitary application of Cisplatin bound to Fibrin after surgery (removal of Tumor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cisplatin concentration in the superficial chest wall tissue | 90 min after application | local cisplatin concentration in the superficial chest wall biopsy measured by inductively coupled plasma sector field mass spectrometric (ICP-MS) detection |
| Incidence of Treatment-Emergent Adverse Events (Safety) | during 6 weeks after surgery with local cisplatin-fibrin application | (Serious) Adverse Events & safety blood parameters (hematology and clinical chemistry) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TUNEL assay | before and 90 min after cisplatin-fibrin application | markers for apoptosis in superficial chest wall tissue |
| overall survival | up to 5 years (phase I), up to 2 years (phase II) | time between date of treatment and time point of death or last follow-up, method of Kaplan and Meier |
| FFR (= Freedom From Recurrence) | 4, 16 weeks, then every 4 months up to 5 (phase I) / 2 years (phase II) | time to tumor progression by CT or PET-CT/MRI, method of Kaplan and Meier |
| in-treatment-field FFR (= Freedom From Recurrence) | up to 2 years (phase II) | 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) |
| Quality of Life EORTC QLQ-C15/LC13 (QLQ = Quality of Life Questionnaire, C = Cancer, LC = Lung Cancer) | phase I: 0, 4, 8, 16 weeks and every 4w up to 5y; phase II: 0, 6, 16w and every 4w up to 2y | change from baseline in EORTC Lung Cancer Questionnaire QLQ-C15/LC13 |
| pharmacokinetics cisplatin concentration in blood serum | baseline, and 0, 2, 6, 10, 24, 48, 120 h postoperative | cisplatin concentration in blood serum by inductively coupled plasma sector field mass spectrometric (ICP-MS) detection |
| pharmacokinetics cisplatin concentration in urine | baseline, collection of first 48h, day 14 postoperative | pharmacokinetics, cisplatin concentration in urine by inductively coupled plasma sector field mass spectrometric (ICP-MS) detection |
| Quality of Life SF-36 (= Short Form-36) | phase I: 0, 4, 8, 16 weeks and every 4w up to 5y; phase II: 0, 6, 16w and every 4w up to 2y | change from baseline in SF-36 quality of life questionnaire |
| PAI-1 and p21 (PAI-1 = Plasminogen Activator Inhibitor Typ 1, p21 = CDK-Inhibitor 1 = Cyclin Dependent Kinase Inhibitor 1)) | before and 90 min after cisplatin-fibrin application | markers for senescence in superficial chest wall tissue |
Other
| Measure | Time frame | Description |
|---|---|---|
| pharmacokinetics cisplatin concentration in pleural effusion | Pleural effusion collection: 0-48 h postoperative | cisplatin concentration in pleural effusion by inductively coupled plasma sector field mass spectrometric (ICP-MS) detection |
Countries
Switzerland
Outcome results
None listed