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.

Study Overview

• Status: Completed
• Conditions: Malignant Pleural Mesothelioma
• Intervention / Treatment: Combination product: intracavitary cisplatin-fibrin

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • ZH
    • Zurich, ZH, Switzerland, 8091
      • University Hospital Zurich, Division of Thoracic Surgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: intracavitary cisplatin-fibrin; single dose local intracavitary cisplatin-fibrin application after pleurectomy/decortication	Combination product: intracavitary cisplatin-fibrin; single dose, local intracavitary application of cisplatin-fibrin after pleurectomy/decortication

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
pharmacokinetics cisplatin concentration in pleural effusion	cisplatin concentration in pleural effusion by inductively coupled plasma sector field mass spectrometric (ICP-MS) detection	Pleural effusion collection: 0-48 h postoperative

Collaborators and Investigators

• Sponsor: University of Zurich
• Collaborators: Swiss National Science Foundation; Swiss Accident Insurance Fund SUVA
• Investigators: Principal Investigator: Isabelle Opitz, Professor MD, University Hospital Zurich, Division of Thoracic Surgery

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2012
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): August 1, 2021

Study Registration Dates

• First Submitted: July 17, 2012
• First Submitted That Met QC Criteria: July 17, 2012
• First Posted (Estimate): July 19, 2012

Study Record Updates

• Last Update Posted (Actual): September 29, 2021
• Last Update Submitted That Met QC Criteria: September 28, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Mesothelioma; Mesothelioma, Malignant; Antineoplastic Agents; Cisplatin
• Other Study ID Numbers: INFLuenCe - Meso

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No