Photo-induction as a Means to Improve Cisplatin Delivery to Pleural Malignancies

Study Overview
=================
Brief Summary
-----------------
This clinical study aims to explore intrapleural low-dose Visudyne®-mediated photodynamic therapy (photo-induction) as a pathway to promote the uptake of systemically administered Lipoplatin™ in pleural malignancies of patients undergoing video-assisted talcage for their malignant pleural effusions. Photo-induction is expected to overcome the chemo-resistance of pleural malignancies for cisplatin-based chemotherapeutics and thereby improve local tumor control.

Detailed Description
-----------------
The primary objective of the study is to assess the safety and tolerability of intrapleural Visudyne®-mediated photo-induction as a means to selectively increase tumor uptake of systemically administered Lipoplatin™ in patients with primary or secondary pleural malignancies. The secondary objectives are: Assessment of treatment efficacy as measured by dyspnea reduction, pleural effusion free survival as well as local relapse rate, progression free and median overall survival. Analysis of the pleural intratumor penetration of Lipoplatin™ by repeated biopsies for Lipoplatin concentration measurements before and after Visudyne® treatment as well as vessel modulation related parameters (pericyte coverage, vessels morphology).

Official Title
-----------------
Photo-induction as a Means to Improve Cisplatin Delivery to Pleural Malignancies: a Clinical Phase I Trial

Conditions
-----------------
Pleural Effusion, Malignant

Intervention / Treatment
-----------------
* Drug: Cisplatin, liposomal
* Drug: Verteporfin
* Device: Device for Intrapleural Visudyne-mediated Low-Dose Photodynamic Therapy with integrated in situ light dosimetry


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria Stage IV breast, ovarian, gastric, colorectal, germ cell, lung, bladder, sarcoma or head and neck carcinoma requiring systemic chemotherapy OR alternatively Stage I/II malignant pleural mesothelioma OR alternatively Stage III/IV mesothelioma requiring systemic chemotherapy OR alternatively Stage IVa thymic malignancies AND Cytologically proven malignant pleural effusion requiring VATS pleurodesis PS 0-1 Age 18-80 Written informed content Life expectancy >3 months Laboratory Requirements - within 28 days prior to enrollment: Haematology: absolute granulocytes ≥1× 109/L platelets ≥100 × 109/L leukocytes ≥3 × 109 Biochemistry: Bilirubin ≤3 × upper limit of normal (<5x if liver metastasis present) AST(SGOT) ≤2.5 × upper limit of normal (<5x if liver metastasis present) Creatinine clearance ≥50 mL/min according to Cockroft and Gault No major cardio-pulmonary co-morbidity precluding a surgical approach according to local standards Enrollment decision at the institutional multidisciplinary tumor board Patient must be willing to use effective methods of contraception. Female patients must be postmenopausal, surgically sterile, or they must agree to use a physical barrier method of contraception in addition to either an intrauterine device or hormonal contraception until at least of 3 months after the study treatment. Male patients must agree to use a barrier method (condom) for 3 months after study treatment. Exclusion criteria Grade >2 peripheral neuropathy Any concurrent anticancer systemic therapy within 14 days before the study intervention Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study e.g. Known or suspected allergy to the investigational agent or any agent given in association with this trial. Clinically serious infections requiring systemic antibiotic (e.g antiviral, antimicrobial, antifungal) therapy. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results Severe interstitial pneumonia or pulmonary fibrosis Chronic corticosteroid use at equivalent dose of >30mg/d methylprednisolone Pregnancy or breast-feeding Porphyria Severe liver insufficiency

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lipoplatin/Visudyne-mediated photodynamic therapy<br>200 mg/m2 Lipoplatin™ will be delivered as iv perfusion. Then, intrapleural photo-induction will be realized through a classical video-assisted thoracoscopic (VATS) approach using 3 mg/m2 Visudyne® activated at 689 nm. At the end of the procedure, the patients will receive chemical pleurodesis by VATS as per standard-of-care treatment for malignant pleural effusion. | Drug: Cisplatin, liposomal<br>* Lipoplatin IV 200 mg/m2<br>* Other names: Lipoplatin™;Drug: Verteporfin<br>* Visudyne® IV 3 mg/m2<br>* Other names: Visudyne®;Device: Device for Intrapleural Visudyne-mediated Low-Dose Photodynamic Therapy with integrated in situ light dosimetry<br>* Intrapleural photo-induction will be realized in the chest cavity with low-dose PDT using Visudyne® 3mg/m2 as photosensitizer, activated by 689 nm laser light with a fluence of 10J/cm2 and a fluence rate of <10mWcm2.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of the treatment as assessed by 30-day postoperative mortality | survival status at 30 days | 30 days | 
| Tolerability of the treatment as assessed by 30-day postoperative mortality | survival status at 30 days | 30 days | 
| Feasibility | survival status at 30 days | 30 days | 
| Acute respiratory failure rate |  | 30-day postoperative | 
| Dyspnea according to CTCAE v4.0 |  | 30-day postoperative | 
| Chest pain rate according to CTCAE v4.0 |  | 30-day postoperative | 
| Dyspnea according to Medical Research Council (MRC) chronic dyspnea scale (5-point) |  | 30-day postoperative | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Malignant effusion recurrence-free - percentage of patients without recurrent pleural effusion at 30 days |  | 30 days after treatment | 
| Dyspnea reduction according to CTCAE v4.0 | CTCAE v4.0 | 30 days after treatment | 
| Tumor response | Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | according to local standard | 
| Overall survival (OS) |  | every 3 months up to 3 years | 
| Overall response rate (ORR) based on investigator assessment according to Response | Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | according to local standard | 
| Progression-free survival (PFS) | Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | according to local standard | 
| Duration of Response (DOR) | Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | according to local standard |