Treatment Pleural Carcinosis of Pressurized IntraThoracic Hyperthermic Aerosol Cisplatin Administration

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

Studienbeginn:
November 2023

Letztes Update:
28.02.2024

Wirkstoff:
Cisplatine Teva®

Indikation (Clinical Trials):
Carcinoma, Mesothelioma, Mesothelioma, Malignant, Carcinoma, Non-Small-Cell Lung, Breast Neoplasms, Hyperthermia, Fever

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
Dr Jean Yannis PERENTES

Collaborator:
-

Studienleiter

Jean-Yannis Perentes
Principal Investigator
Centre Hospitalier Universitaire Vaudois

Kontakt

Jean-Yannis H Perentes
Kontakt:
Phone: 0795560876
E-Mail: jean.perentes@chuv.ch» Kontaktdaten anzeigen

Séverine Devesa-Perez
Kontakt:
Phone: 795567289
Phone (ext.): +41
E-Mail: Severine.Devesa-Perez@chuv.ch» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

Centre Hospitalier Universitaire Vaudois
Lausanne
SwitzerlandRekrutierend» Google-Maps
Ansprechpartner:
Jean-Yannis PERENTES» Ansprechpartner anzeigen

Studien-Informationen

Detailed Description:

Adverse events: the evaluation of the safety of cisplatin administered by PITHAC is the

primary endpoint of both parts of the study Cisplatin administration will be performed on D0.

Postoperative pain management according to the Enhanced Recovery After Surgery program

following the surgical procedure.

Dyspnoea score will be scored at screening, and every day until D10 and checked one last time

at D30 using the CR-10 scale.

Chest X-ray will be performed at screening, D0, 24h post intervention, D10 and D30.

Monitoring of adverse events (AEs), serious and non-serious, will be conducted throughout the

study from the surgery.

Blood samples for cisplatin pharmacokinetics PK will be performed on D0 pre-intervention, 12h

post intervention, 24h and 48h post intervention.

Translational blood tests for immune profiling will be performed on D0 pre-intervention, D10

and D30. Translational blood tests on inflammatory cytokine assessment will be performed on

D0 pre-intervention, 12h post intervention, 24h, 48h and on D10 and D30. Tissue biopsy for

free cisplatin PK and Pleural biopsy for tissue immune infiltration will be performed on D0

before and after treatment administration.

Malignant pleural effusion (MPE) assessment: Immune environment and neoantigen landscape will

be collected before the PITHAC procedure and via the indwelling pleural catheter (D0, at

hospital discharge and D10).

STATISTICAL METHODS:

PART A: Dose escalation and MTD determination: The sample size is set to determine the MTD by

using the 3+3 design. Cohorts of 3-6 patients will be recruited sequentially at each of the

cisplatin doses. The total number of patients is expected to be 12 with a maximum of 24,

depending on the level of MTD. If there are patients who are not evaluable for the objectives

in the study, additional patients will be enrolled. Patients not evaluable will be replaced

but not withdrawal from the study.

Primary Analysis: dose limiting toxicities; To determine the maximum tolerated dose (MTD) of

cisplatin administered with PITHAC, the primary study outcome is the occurrence of Dose

Limiting Toxicities (DLT). The number and proportion of patients with DLTs will be presented

overall and by dose and will be plotted vs dose. The MTD will be graphically displayed.

Secondary Analyses: safety profile of cisplatin administered with PITHAC: The safety analysis

will be performed on the safety population. -Treatment emergent AE frequencies will be

summarised by system organ class and preferred term (MedDRA) overall and by dose. AEs will

also be tabulated by system organ class and preferred term including maximum severity grade

according to the NCI-CTCAE criteria version 5 and relationship to treatment. Incidence of

treatment discontinuations due to AEs and SAEs will be summarised overall and by dose.

-Safety Lab parameters and vital signs at pre-treatment and post-treatment and corresponding

changes from pre-treatment will be presented by dose as descriptive statistics. Efficacy

analysis will be performed on efficacy population. Dyspnoea will be scored from screening to

D30. Dyspnoea score will be presented at pre- and post-treatment and change from pre- to

post-treatment will be presented as descriptive statistics by dose. The pleural infusion

index will be determined by comparing chest X-rays before treatment (D0) and post-treatment

at D1, D10 and 30 days and pleurodesis or indwelling catheter placement. The index will be

presented at pre- and post-treatment and change from pre- to post-treatment will be presented

as descriptive statistics by dose. Exploratory endpoints: exploratory analyses will be

performed by tissue immunostaining and image analysis will be carried out. The concentration

of cisplatin in tumor tissue at the beginning and end of mild hyperthermia PITHAC will be

evaluated by Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) that

will allow visualization of cisplatin distribution and penetration in tumor biopsies. The

correlation between cisplatin concentration and penetration into tumor tissue and clinical

response will be explored. Immune infiltration in tumor tissues will be assessed by

immunostainings and image analysis will be performed. Immune cells proportions in peripheral

blood before and after PITHAC at D0, 10 and 30 will be explored using DURAClone Panels for

flow cytometry.

PART B: Expansion: Determination of Sample Size: the sample in the expansion phase is not

based on a formal hypothesis. To evaluate the safety of cisplatin administered by PITHAC at

the RD and undertake an initial evaluation of efficacy, a total of 15 patients will be

enrolled in this exploratory part of the study. Statistical criteria of termination of trial:

there are no statistical criteria of termination of the trial in this part of the study.

Primary Analysis: dose limiting toxicities; To determine the maximum tolerated dose (MTD) of

cisplatin administered with PITHAC, the primary study outcome is the occurrence of Dose

Limiting Toxicities (DLT). The number and proportion of patients with DLTs will be presented

overall and by dose and will be plotted vs dose. The MTD will be graphically displayed.

Secondary Analyses: safety profile of cisplatin administered with PITHAC: The safety analysis

will be performed on the safety population. -Treatment emergent AE frequencies will be

summarised by system organ class and preferred term (MedDRA) overall and by dose. AEs will

also be tabulated by system organ class and preferred term including maximum severity grade

according to the NCI-CTCAE criteria version 5 and relationship to treatment. Incidence of

treatment discontinuations due to AEs and SAEs will be summarised overall and by dose.

-Safety Lab parameters and vital signs at pre-treatment and post-treatment and corresponding

changes from pre-treatment will be presented by dose as descriptive statistics. Efficacy

analysis will be performed on efficacy population. Dyspnoea will be scored from screening to

D30. Dyspnoea score will be presented at pre- and post-treatment and change from pre- to

post-treatment will be presented as descriptive statistics by dose. The pleural infusion

index will be determined by comparing chest X-rays before treatment (D0) and post-treatment

at D1, D10 and 30 days and pleurodesis or indwelling catheter placement. The index will be

presented at pre- and post-treatment and change from pre- to post-treatment will be presented

as descriptive statistics by dose. Exploratory endpoints: exploratory analyses will be

performed by tissue immunostaining and image analysis will be carried out. The concentration

of cisplatin in tumor tissue at the beginning and end of mild hyperthermia PITHAC will be

evaluated by Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) that

will allow visualization of cisplatin distribution and penetration in tumor biopsies. The

correlation between cisplatin concentration and penetration into tumor tissue and clinical

response will be explored. Immune infiltration in tumor tissues will be assessed by

immunostainings and image analysis will be performed. Immune cells proportions in peripheral

blood before and after PITHAC at D0, 10 and 30 will be explored using DURAClone Panels for

flow cytometry.

QUALITY ASSURANCE AND CONTROL: all data collected will be coded and recorded on the RedCap

search software. The conformity of eCRF with protocol specifications is checked and validated

by the SI and/or qualified individuals, according to ICH GCP. Case Report Forms (eCRF):

electronic data entry will be performed via a web-based application (REDCap). Security

passwords will be provided to each properly trained investigator. An eCRF for data collection

will be developed in Redcap. The REDCap database will record the data obtained with the

coding number specific to each patient: this code will consist of PITHAC-01, PITHAC-02 etc….

A specific subject identification log will be compiled to record the identifying information

of enrolled participants, providing the link to individual attributed codes. This document

(word file) will be kept separately, it will be password protected and saved in a secure

directory on a CHUV server. At the end of the project, the subject identification log will be

kept by the principal investigator. Best practices will be adopted to ensure that data are

complete, reliable, and processed correctly, thus providing high-quality data, keeping the

number of errors and missing data as low as possible, and gathering a maximum amount of

accurate data for analysis. The data collected through RedCap® will be automatically checked

by the implementation of data validation rules (e.g., data-type, maximum/minimum range,

missing data checks, and other logical tests) and automatic alerts. Specification of source

documents: study monitors will perform ongoing source data verification to confirm that

critical protocol data (i.e., source data) entered into the eCRFs by authorized site

personnel are accurate, complete, and verifiable from source documents. Source documents

(paper or electronic) are those in which patient data are recorded and documented for the

first time. They include, but are not limited to, hospital records, clinical and office

charts, laboratory notes, memoranda, evaluation checklists, pharmacy dispensing records,

recorded data from automated instruments, copies of transcriptions that are certified after

verification as being accurate and complete, X-rays, patient files, and records kept at

pharmacies, laboratories, and medico-technical departments involved in the clinical trial.

The Investigator must keep a subject file (medical file, original medical records)

electronically (SOARIAN/ARCHIMEDE) for every subject included in the trial. All documents

containing source data must be filed in the electronic patient file. Electronic subject files

(SOARIAN/ARCHIMEDE) will be accessible to the Monitor to perform source data verification.

Record keeping / archiving: the SI will retain copies of the patient trial records (CRFs,

patient informed consent statement, drug inventory logs and all other information collected

during the trial) and documentation until at least 10 years after the termination of the

trial.It must be available for review by the Monitor and must be ready for Sponsor audit as

well as for inspection by Competent Authorities during and after the trial and must be safely

archived for at least 10 years (or per local requirements or as otherwise notified by the

Sponsor) after the end of the trial. The documents to be thus archived include the Subject

Identification List and the signed subject ICFs.

Safety Monitoring (Dose Escalation Part): a Trial Safety Board (TSB) will be constituted for

the part A of the trial, being responsible for maintaining the scientific integrity of the

trial and safety of patients. This Board will review the DLTs of each cohort and decide

whether to escalate or not to the next dose level (next cohort). Details on the dose

escalation design, rules, and the role of the TSB are provided in the DEP. The TSB will give

the green light to start part B after recommended dose confirmation, based on safety and

efficacy data of all patients enrolled in part A. For Part B, the responsibility for the

safety of the individual patient lies with the investigator and the SI. Clinical Trial

Monitoring: clinical monitoring activities have the ultimate purpose to guarantee that the

rights and well-being of human subjects are protected, that the reported study data are

accurate, complete and verifiable from source documents, and that the conduct of the study

complies with the latest approved version of the study protocol, with ICH-GCP guidelines and

applicable regulations .

Ein-/Ausschlusskriterien

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

Studien-Rationale

Primary outcome:

1. Dose Escalation and Maximum Tolerated Dose determination (Part A): (Time Frame - 18 months approximately):
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).

2. Expansion phase (Part B): (Time Frame - between 10 and 12 months):
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.

Secondary outcome:

1. Dose Escalation and MTD determination (Part A): (Time Frame - 18 months):
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

2. Expansion phase (Part B): (Time Frame - 10 /12 months):
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.

Studien-Arme

Experimental: Cohorte 1 _ 7.5 mg/m2
cohorte 1: 7.5 mg/m2 of cisplatin (once)
Experimental: Cohorte 2 _ 12.5 mg/m2
cohorte 2: 12.5 mg/m2 of cisplatin (once)
Experimental: cohorte 3: 35 mg/m2 of cisplatin
cohorte 3: 35 mg/m2 of cisplatin (once)
Experimental: cohorte 4: 70 mg/m2 of cisplatin
cohorte 4: 70 mg/m2 of cisplatin (once)

Geprüfte Regime

Cisplatine Teva® (Procedure/Surgery):
PITHAC: Cisplatin (Cisplatine Teva®) at a dose between 7.5 and 70 mg/m2 of body surface at a temperature of 39±1°C

Quelle: ClinicalTrials.gov

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