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. To
date, there are no studies investigating IP chemotherapy in MPM patients.

This study has been transitioned to CTIS with ID 2024-516738-36-00 check the CTIS register for the current data.

The primary purpose of this study is to determine the maximum tolerable dose
(MTD) of IP monotherapy with paclitaxel for patients with MPM. Secondary
objectives are to assess safety and feasibility of this strategy, and to study
the pharmacokinetics of paclitaxel in this setting. The broader, long-term aim
of this research, is to provide a better palliative treatment for patients with
MPM, resulting in less toxicity, improved quality of life, and possibly
prolonged survival.

We will conduct a classic three-plus-three dose escalation study with three
dose levels. In short: 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.

Patiënts 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.

The intervention is an alternative for the standard of care with systemic
chemotherapy. Patients who participate will receive a peritoneal access port,
that will be implanted subcutaneously. This will be done during diagnostic
laparoscopy, which is part of standard of care. Patients do not have to undergo
extra surgery. There is a small chance of complications due to the peritoneal
port, like (wound)infection or obstruction. However, experience from an ongoing
study with the same type of peritoneal access port (INTERACT study) shows that
there are no or few complications of the peritoneal port. The most important
risk of participation is the occurrence of toxicity due to the administration
of intraperitoneal chemotherapy. However, administration of intraperitoneal
chemotherapy is expected to cause less toxicity than the current systemic
chemotherapy. The current systemic treatment consists of cycles of 3 weeks,
with a maximum of 6 cycles. Patients who participate in this study will have
additional hospital visits. Also, they will have to undergo additional invasive
procedures, like venapunction or intravenous catheter. The risks of these
procedures are limited.