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

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

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.

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