Clinical trial NCT01644994: Intracavitary Cisplatin-Fibrin Localized Chemotherapy After P/D or EPP for Malignant Pleural Mesothelioma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Malignant Pleural Mesothelioma
Lead sponsor: University of Zurich
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
name: Swiss Accident Insurance Fund SUVA
First posted: 2012-07-19
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open Label, single dose local intracavitary application of Cisplatin bound to Fibrin after surgery (removal of Tumor)
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events (Safety)
timeFrame: during 6 weeks after surgery with local cisplatin-fibrin application
measure: Cisplatin concentration in the superficial chest wall tissue
timeFrame: 90 min after application
Secondary outcomes:
measure: overall survival
timeFrame: up to 5 years (phase I), up to 2 years (phase II)
measure: FFR (= Freedom From Recurrence)
timeFrame: 4, 16 weeks, then every 4 months up to 5 (phase I) / 2 years (phase II)
measure: in-treatment-field FFR (= Freedom From Recurrence)
timeFrame: up to 2 years (phase II)
measure: Quality of Life SF-36 (= Short Form-36)
timeFrame: phase I: 0, 4, 8, 16 weeks and every 4w up to 5y; phase II: 0, 6, 16w and every 4w up to 2y
measure: Quality of Life EORTC QLQ-C15/LC13 (QLQ = Quality of Life Questionnaire, C = Cancer, LC = Lung Cancer)
timeFrame: phase I: 0, 4, 8, 16 weeks and every 4w up to 5y; phase II: 0, 6, 16w and every 4w up to 2y
measure: pharmacokinetics cisplatin concentration in blood serum
timeFrame: baseline, and 0, 2, 6, 10, 24, 48, 120 h postoperative
measure: pharmacokinetics cisplatin concentration in urine
timeFrame: baseline, collection of first 48h, day 14 postoperative
measure: TUNEL assay
timeFrame: before and 90 min after cisplatin-fibrin application
measure: PAI-1 and p21 (PAI-1 = Plasminogen Activator Inhibitor Typ 1, p21 = CDK-Inhibitor 1 = Cyclin Dependent Kinase Inhibitor 1))
timeFrame: before and 90 min after cisplatin-fibrin application
Other outcomes:
measure: pharmacokinetics cisplatin concentration in pleural effusion
timeFrame: Pleural effusion collection: 0-48 h postoperative
Locations:
city: Zurich
country: Switzerland
facility: University Hospital Zurich, Division of Thoracic Surgery
state: ZH
Study officials:
affiliation: University Hospital Zurich, Division of Thoracic Surgery
name: Isabelle Opitz, Professor MD
role: PRINCIPAL_INVESTIGATOR
References: