Intraperitoneal Paclitaxel-loaded TPM for Treatment of Peritoneal Carcinomatosis

Phase I Trial of Intraperitoneal Paclitaxel-loaded Tumor Penetrating Microparticles (TPM) for Treatment of Peritoneal Carcinomatosis

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.

Study Overview

• Status: Recruiting
• Conditions: Peritoneal Carcinomatosis
• Intervention / Treatment: Drug: Paclitaxel-loaded tumor penetrating microparticles

Detailed Description

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
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Carlos H.F. Chan, MD, PhD; Phone Number: (319) 356-1727; Email: carlos-chan@uiowa.edu

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Recruiting
      • University of Iowa Hospitals & Clinics
      • Contact: Carlos H.F. Chan, MD, PhD; Phone Number: 319-356-1727; Email: carlos-chan@uiowa.edu
      • Contact: Janelle Born, BSN; Phone Number: 319-356-4797; Email: janelle-born@uiowa.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent document
• Have pathology proven peritoneal carcinomatosis (PC) due to colorectal, ovarian, gastric, pancreatic, appendiceal cancer or mesothelioma, or suspected peritoneal metastasis based on radiological findings. (Patient to come off study if no pathology evidence of peritoneal metastasis at the time of surgery)
• No other standard treatment options are available
• Measurable intraperitoneal disease by RECIST v1.1 criteria , or by radiological PCI scoring when RECIST is not feasible, on imaging studies
• 18 to 75 years of age
• Have an ECOG performance of 0 to 2
• Have adequate organ and bone marrow functions as indicated by:
• Leukocytes ≥ 3000/mcL
• Absolute neutrophil count ≥ 1500/mcL
• Platelets ≥ 100000/mcL
• Total bilirubin within normal institutional limits
• AST (SGOT) < 3 x institutional upper limit of normal
• ALT (SPGT) < 3 x institutional upper limit of normal
• Medically fit for surgery. Defined as: Patients who are able to undergo general anesthesia for abdominal surgery and have a metabolic equivalent (METs) ≥ 4

• Have adequate contraception, as follows:

  1. Women of child-bearing potential and men with partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 10 months beyond the last dose of TPM. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  2. A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
• has not undergone a hysterectomy or bilateral oophorectomy; or

• has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

  c. Men with partners of child bearing potential must use barrier contraceptive

  d. Men of child-bearing potential must not donate sperm while on this study and for 7 months after the last dose of TPM

Acceptable forms of birth control are listed below:

• One Barrier method (cervical cap with spermicide plus male condom; diaphragm with spermicide plus male condom) OR
• Hormonal method (oral contraceptives, implants, or injections) or an intrauterine device (e.g., Copper-T)

Exclusion Criteria:

• Presence of mucinous ascites
• Evidence of extra-peritoneal metastases
• Current or expected use of other investigational agents
• Received systemic chemotherapy or radiotherapy within 3 weeks prior to study enrollment or not recovering from adverse events (e.g., recovery to ≤ Grade 1)
• Abdominal cavity deemed not accessible by treating surgeon due to prior abdominal surgery
• History of allergic reactions to paclitaxel, PLG co-polymer, mannitol, or polysorbate 80
• Uncontrolled intercurrent illness
• Currently active second malignancy other than non-melanoma skin cancer
• Pregnancy, nursing, or plans to become pregnant for the duration of study participation including 10 months beyond the last dose of TPM
• Grade 2 or higher peripheral neuropathy
• CrCL ≤ 4 mL/min
• Actively treated for other malignancy
• Patients with HIV or Hepatitis B/C requiring the use of ART agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Intraperitoneal paclitaxel-loaded tumor penetrating microparticles (TPM); Paclitaxel-loaded tumor penetrating microparticles (TPM), dose escalation starting at 50 mg/m^2 instilled in the peritoneal cavity at study start and again 6-8 weeks after the first TPM treatment.

Drug: Paclitaxel-loaded tumor penetrating microparticles; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	4 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	8 Weeks
Assess whether Paclitaxel-loaded Tumor Penetrating Microparticles (TPM) induce immune response in the peritoneal cavity	The presence or absence of T cell infiltration in peritoneal cavity.	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	Day 1 on study

Collaborators and Investigators

• Sponsor: Carlos Chan
• Collaborators: Institute of Quantitative Systems Pharmacology (IQSP)
• Investigators: Principal Investigator: Carlos Chan, MD, PhD, University of Iowa

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2022
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): November 1, 2024

Study Registration Dates

• First Submitted: November 8, 2021
• First Submitted That Met QC Criteria: December 1, 2021
• First Posted (Actual): December 15, 2021

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Peritoneal Diseases; Digestive System Neoplasms; Abdominal Neoplasms; Carcinoma; Peritoneal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Paclitaxel
• Other Study ID Numbers: 202105008

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No