A prospective, open-label, single-center, phase-1 study with a classic threeplus-three dose escalation design.

According to standard of care work-up for CRS-HIPEC, patients will undergo diagnostic laparoscopy to determine the feasibility of complete cytoreduction with HIPEC. In case CRS-HIPEC is not considered feasible, a peritoneal port-a-cath (PAC) system will be placed. Through this PAC, 8-16 weekly cycles of intraperitoneal chemotherapy will be administered.

As we aim to provide IP-paclitaxel as first line monotherapy for patients with MPM, we first need to determine the maximum tolerable dose, safety and feasibility, in this setting. To achieve this, we will perform a classic three-plus-three dose-escalation study in MPM patients.

Primary Objective: To determine the maximum tolerable dose (MTD) of intraperitoneal paclitaxel monotherapy for patients with MPM that are ineligible to undergo CRS-HIPEC.

Secondary Objective(s):

• To assess the safety and toxicity of this treatment
• To explore the feasibility of this treatment
• To establish the pharmacokinetic profile of IP-paclitaxel.

The primary endpoint of the study is to assess the MTD of IP paclitaxel monotherapy for patients with MPM that are ineligible to undergo CRSHIPEC. Secondary endpoints are to assess safety and toxicity, feasibility, and the pharmacokinetic profile of this treatment.

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

• Histological confirmed diagnosis of malignant peritoneal mesothelioma
• Patients that are not eligible (or willing) to undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC)
• Age ≥ 18 years
• Written informed consent by the patient according to the ICH-GCP and national/local regulations
• Patients must be ambulatory (WHO-ECOG performance status 0 or 1) (25)
• Ability to return to the Erasmus MC for adequate follow-up as required by this protocol
• Patients must have normal organ function and adequate bone marrow reserve as assessed by the following laboratory requirements; absolute neutrophil count >1.5 * 10^9/l, platelet count >100*10^9/l and Haemoglobin >6.0mmol /l. Patients must have a Bilirubin < 1½ x upper limit of normal (ULN), Serum AST and ALT < 2.5 x ULN

A potential subject who meets any of the following criteria will be excluded from participation in this study:

• Incapacitated patients
• Extra-abdominal disease/metastatic disease established by preoperative CT-scan of thorax-abdomen and/or PET-scan. Imaging not older than two months at time of surgery
• Medical or psychological impediment to probable compliance with the protocol
• Serious concomitant disease or active infections
  History of auto-immune disease or organ allografts, or with active or chronic infection, including HIV and viral hepatitis
• Serious intercurrent chronic or acute illness such as pulmonary (COPD or asthma) or cardiac (NYHA class III or IV) or hepatic disease or other illness considered by the study coordinator to constitute an unwarranted high risk for participation in this study
• Pregnant or lactating women; for all women of child-bearing potential a negative urine pregnancy test will be required as well as the willingness to use adequate contraception during the study until 4 weeks after finishing treatment
• Absence of assurance of compliance with the protocol
• An organic brain syndrome or other significant psychiatric abnormality which would comprise the ability to give informed consent, and preclude participation in the full protocol and follow-up