Primary Outcome Measures
1. Outcome Measure
Dose Escalation and Maximum Tolerated Dose determination (Part A):
Measure Description
In order to determine the maximum tolerated dose (MTD) of cisplatin administered by PITHAC, the primary study outcome will be the occurrence of Dose Limiting Toxicities (DLT).
Time Frame
18 months approximately
2. Outcome Measure
Expansion Phase
Measure Description
Safety profile of cisplatin administered by PITHAC will be assessed by the incidence of Adverse Events and Serious Adverse Events according to NCI-CTCAE criteria (v5). Incidence and severity of intraoperative and post-operative complications will be measured using the Clavien-Dindo classification up to 30 days after the intervention.
Safety profile of cisplatin administered by PITHAC will be assessed by the incidence of Adverse Events and Serious Adverse Events according to NCI-CTCAE criteria (v5). Incidence and severity of intraoperative and post-operative complications will be measured using the Clavien-Dindo classification up to 30 days after the intervention.
Time Frame
between 10 and 12 months
Secondary Outcome Measures
Outcome Measure
Dose Escalation and MTD determination (Part A):
Measure Description
Safety profile of cisplatin administered with moderate hyperthermic PITHAC will be assessed by the incidence of Adverse Events and Serious Adverse Events according to NCI-CTCAE criteria (v5).
Dyspnoea will be scored every day until Day 10 and re-evaluated at Day 30 after the procedure
The pleural effusion index will be determined by comparing chest X-rays before, 24 hours (Day 0), at Day 10 and at Day 30 after PITHAC and pleurodesis or indwelling catheter placement
Time Frame
18 Months
Outcome Measure
Expansion phase (Part B):
Measure Description
Dyspnoea will be scored every day until Day 10 and re-evaluated at Day 30 after the procedure.
The pleural effusion index will be determined by comparing chest X-rays before PITHAC procedure, 24 hours after, at Day 10 and Day 30 after PITHAC and pleurodesis or indwelling catheter placement.
Time Frame
10 /12 months
Other Outcome Measures
Outcome Measure
Dose Escalation and MTD determination (Part A):Exploratory outcomes
Measure Description
Tissue immune infiltration will be assessed by comparing penetration depth and resulting immune infiltrate in pleural biopsy specimens at the beginning and at the end of PITHAC.
The correlation between plasma concentrations of administered intrapleural cisplatin by PITHAC and acute secondary side effects will be evaluated.
Tissue distribution of free cisplatin will be compared in pleural biopsy specimens at the beginning and at the end of PITHAC by gaz phase chromatography.
Correlation between treatment outcome, percentage of cancer cell death, cisplatin concentration in pleural biopsies, release of pro-inflammatory proteins and the activation status of effector T-cell will be assessed.
Assess the immune environment and immune responses mediated by neoantigen directed cytotoxic T cells (neoantigen landscape) in patient malignant pleural effusion (MPE) before and after PITHAC ((D0, 72h post intervention, Day 10 and D30).
Time Frame
18 months approximately
Outcome Measure
Expansion phase (Part B):Exploratory outcomes
Measure Description
Tissue immune infiltration will be assessed by comparing penetration depth and resulting immune infiltrate in pleural biopsy specimens at the beginning and at the end of PITHAC.
The correlation between plasma concentrations of administered intrapleural cisplatin by PITHAC and acute secondary side effects will be evaluated.
Tissue distribution of free cisplatin will be compared in pleural biopsy specimens at the beginning and at the end of PITHAC by gaz phase chromatography.
Correlation between treatment outcome, percentage of cancer cell death, cisplatin concentration in pleural biopsies, release of pro-inflammatory proteins and the activation status of effector T-cell will be assessed.
Assess the immune environment and immune responses mediated by neoantigen directed cytotoxic T cells (neoantigen landscape) in patient malignant pleural effusion (MPE) before and after PITHAC ((D0, 72h post intervention, Day 10 and D30).
Time Frame
between 10 and 12 months
Inclusion Criteria
- At least 18 years of age
- Body weight at least 30 kg
- Eastern cooperative oncology group performance status score of 0-2 at enrolment
- Patient with pleural carcinosis that qualify for a surgical intervention for pleurodesis or placement of an indwelling permanent catheter.
- Life expectancy of at least 3 months
- Pathology-confirmed pleural carcinosis with malignant pleural effusion (either histological confirmation is already available based on a previous tru-cut pleural biopsy or previous pleural fluid cytology is positive for malignant cells or high suspicion of pleural carcinosis based on computed tomography imaging which must be confirmed by fresh frozen section analyses of tissue harvested during pithac operative procedure)
- Non-small cell lung cancer, breast cancer, lymphoma, ovarian cancer, oesophageal cancer, gastric cancer, and malignant tumour of the serous membranes (mesothelioma) confirmed by pathology either as part of a diagnostic workup of suspected pleural carcinosis OR available from other previous examinations patients undergoing a planned videothoracoscopy to perform pleurodesis or a placement of a tunnelled catheter
- Adequate liver, kidney, and bone marrow functions as assessed by laboratory tests (serum total bilirubin <1.5 mg/dl, aspartate transaminase and alanine transaminase less than 2.5 times the upper limit of the normal range, creatinine clearance ≥60 ml/min, absolute neutrophil count ≥1,500/μl, haemoglobin ≥90 g/L, platelets ≥100,000/μl)
- I) Patients with past/resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible, if HBV DNA test is negative. Ii) HBV DNA must be obtained in patients with positive hepatitis B core antibody prior start of study treatment.
- Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA
- Adequate cardiac functions as assessed by echocardiography
- Adequate birth control measures
- Signed informed consent
Exclusion Criteria
- Patients with active or chronic hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at pre-screening)
- Patients with active hepatitis C
- Any known formal contra-indication for video-assisted thoracoscopy (VATS) according to pulmonary and cardiac preliminary investigations.
- Systemic cytotoxic anticancer treatment within 10 days before and after enrolment except for inhibitors of vascular endothelial growth factor for which this period should be decided according to the used drug (for bevacizumab the period involves 4 weeks before and after enrolment, for lenvatinib 1 week before and 2 weeks after, and for sorafenib 1 week before and after), no limitations applied for immune checkpoint inhibitors
- Major surgery within 28 days prior to enrolment
- Any unresolved toxicity from previous anticancer therapy of grade ≥2 according to the CTCAE except for alopecia, vitiligo, and laboratory values considered as adequate in the inclusion criteria and any irreversible toxicity that is expected to have impact on the study results or be a contraindication for the planned surgical intervention or be worsened by the investigational procedure
- Long lasting exposure to corticosteroids
- Known allergy to platinum compounds
- Non-small cell lung cancer with egfr or alk mutations unless refractory to tyrosine kinase inhibitor (thus off treatment)
- Uncontrolled intercurrent illness
- Clinically relevant hearing loss or tinnitus
- Clinically relevant neuropathy
- Life-threatening conditions (uncontrolled systemic infection etc.)
- Previous administration (by any route) of a total cumulative dose of more than 500 mg/m2 of cisplatin
- Secondary resistance to platinum compounds defined as tumour progression during platinum treatment or within 6 months after its cessation
- pregnancy
- judgement of the investigator that the patient is unlikely to comply with the study requirements
- current enrolment in another prospective clinical trial
- Incapacity of judgement
- Patients in emergency situation
- Myelossupression
- Yellow fever vaccine
- Concurrent prophylactic use of phenytoin
