A first-in-human, unblinded, phase I trial of Paclitaxel-loaded tumor penetrating microparticles (TPM) in peritoneal carcinomatosis patients who are not eligible for standard-of-care therapeutic interventions.
This is a first in human study of Paclitaxel-loaded TPM, suspended in 0.5 L of 0.1% polysorbate 80 in normal saline instilled into the peritoneal cavity. An enrolled patient will (a) undergo laparoscopy during which time the hydrostatic pressures at different locations within the peritoneal cavity are measured, pretreatment tumors are biopsied and peritoneal catheter is placed, (b) receive intraperitoneal TPM during index hospital stay, and (c) followed-up to evaluate treatment-related toxicity and response. The pharmacokinetics of TPM and paclitaxel in peritoneal fluid and systemic blood samples will be measured. Second dose of TPM is given in clinic if no disease progression or significant AEs. This is a dose escalation study. Dose escalation will proceed using an accelerated titration design (ATD) with intra-patient dose escalation. In the event either: * 1 patient exhibits DLT during the first course of treatment or * 2 patients exhibit grade 2 study drug-related (attribution of probable or definite) toxicity during the first course of treatment. The design switches to a standard 3+3 design at the dose that triggered the switch-two additional patients are accrued at this dose level. Decisions on when and how to escalate if the design switches to a 3+3 are described in the protocol section 6.3
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
4
Paclitaxel-loaded TPM, suspended in 0.5 L of 0.1% (w/v) polysorbate 80 in 0.9% sodium chloride is instilled into the peritoneal cavity over 3 to 5 minutes. Mixing of TPM is achieved by putting patient in 5 different positions for about 80 minutes. Dose escalation, the starting dose of TPM is 50 mg/m\^2 paclitaxel-equivalents. Dose escalation will follow the Accelerated Titration Design. The dose levels to which patients will be assigned in sequential cohorts are listed below. Dose escalation schedule of TPM, Dose Level 1\*: 50 mg/m\^2; Dose Level 2: 100 mg/m\^2; Dose Level 3: 135 mg/m\^2; Dose Level 4: 175 mg/m\^2; Dose Level 5: 200 mg/m\^2 \*Starting Dose
University of Iowa Hospitals & Clinics
Iowa City, Iowa, United States
Assess safety of intraperitoneal Paclitaxel-loaded Tumor Penetrating Microparticles (TPM)
The incidence of treatment-emergent adverse events will be summarized by system organ class and/or preferred term, type of adverse event, severity (based on NCI CTCAE v5.0 grades), and relation to study treatment using the safety population.
Time frame: 12 Weeks
Determine the maximum tolerated dose (MTD) of intraperitoneal Paclitaxel-loaded Tumor Penetrating Microparticles (TPM)
Dose escalation will proceed using an accelerated titration design (ATD). Subjects will be observed for 4 weeks after the first course of TPM treatment for any potential dose limiting toxicities (DLT). The MTD is defined as the highest dose level for which at most 1 out of 6 patients experience a DLT.
Time frame: 4 Weeks
Assess potential therapeutic efficacy of intraperitoneal Paclitaxel-loaded Tumor Penetrating Microparticles (TPM)
Tumor response will be measured by RECIST v1.1 to determine potential effective doses of intraperitoneal Paclitaxel-loaded TPM.
Time frame: 12 Weeks
Measure area-under-drug concentration-time curve of Paclitaxel and tumor penetrating microparticles (TPM) in blood and peritoneal fluid
Paclitaxel-loaded TPM pharmacokinetics will be described using summary statistics, such as mean and range, and graphical displays.
Time frame: 8 Weeks
Measure maximum drug concentration of Paclitaxel and tumor penetrating microparticles (TPM) in blood and peritoneal fluid
Paclitaxel-loaded TPM pharmacokinetics will be described using summary statistics, such as mean and range, and graphical displays.
Time frame: 8 Weeks
Assess whether Paclitaxel-loaded Tumor Penetrating Microparticles (TPM) induce immune response in the peritoneal cavity
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The presence or absence of T cell infiltration in peritoneal cavity.
Time frame: 8 Weeks
Assess whether intra-abdominal pressure is location-dependent
Intra-abdominal hydrostatic pressures at various intraperitoneal locations will be measured at the time of laparoscopy
Time frame: Day 1 on study