Intraperitoneal Paclitaxel for Patients With Primary Malignant Peritoneal Mesothelioma - a Phase I/II Dose Escalation and Safety Study

Malignant Peritoneal Mesothelioma (MPM) is a rare, but unfortunately very aggressive cancer with a poor prognosis. Currently, the only possibly curative treatment is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the majority of patients are not eligible to undergo this treatment, mainly due to extensive local disease. Currently, a palliative treatment with low morbidity is not available. Overall response rates to systemic chemotherapy are low, though morbidity rates are high. Immunotherapy presents similar shortcomings, as the morbidity rate is comparable to that of systemic chemotherapy, while its benefit for MPM patients is not proven. Especially given the high morbidity rate, and the limited effectiveness of systemic treatment with either immunotherapy or chemotherapy, there is lack of treatments suitable as palliative treatment for patients with MPM. Thereby, the majority of MPM patients currently receive no anti-tumor treatment.

As MPM very rarely disseminates outside the abdominal-cavity, the use of intraperitoneal (IP) chemotherapy seems a logical and promising step. This therapy can be delivered through an IP port-a-cath (PAC), and potentially has major advantages over systemic treatment. A higher, more effective dose of chemotherapy can directly be delivered at the site of disease, while systemic uptake is limited likely resulting in fewer toxicity. In rare cases where metastases do develop, a switch can be made to systemic treatment. By first applying local treatment, most patients will be spared a toxic and often ineffective systemic therapy. Another major advantage of the suggested approach is that ascites, a common MPM-symptom that causes major morbidity, can be drained through the same PAC-system. Paclitaxel is a well-known chemotherapeutic agent and is considered extremely favorable for IP use.

The aim of this study is to determine the maximum tolerable dose (MTD) of IP monotherapy with paclitaxel for patients with MPM, and to assess safety and feasibility of this strategy. The investigators will conduct a classic three-plus-three dose escalation study with three dose Three patients are initially enrolled into a given dose cohort. If there is no dose limiting toxicity (DLT) observed in any of these patients, the trial proceeds to enroll additional patients to the next higher dose cohort. If one patient develops a DLT at a specific dose level, three additional subjects are enrolled into that same dose cohort. Development of a DLT in more than 1 patient in a specific dose cohort (≥33%) suggests that the MTD has been exceeded, and further dose escalation is not pursued. The previous dose is considered the MTD. When the MTD is found, an expansion of 3-6 more patients in that dose cohort will be performed, to achieve a total number of 9 patients treated at the MTD-level.

Patients undergo a diagnostic laparoscopy (DLS) according to standard work-up for CRS-HIPEC. If the disease is considered not resectable, a peritoneal PAC will be placed during DLS. Through this PAC intraperitoneal paclitaxel will be administered weekly (dosage according to dose-escalation schedule). The number of cycles depends on toxicity and response to the treatment. The first response evaluation is scheduled after 8 cycles. There is no limit to the number of cycles, in case of continuing response to treatment. During the first and the fourth cycle, additional blood samples and IP-fluid samples will be collected for pharmacokinetic analysis.