Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) and Electrostatic PIPAC (ePIPAC) With Paclitaxel In Patients With Peritoneal Carcinomatosis

Peritoneal Carcinomatosis Clinical Trial

Official title:

Phase 1 Study of Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) and Electrostatic PIPAC (ePIPAC) With Paclitaxel for Peritoneal Carcinomatosis - PIPAC2 Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05395910
• Other study ID #: DSRB 2020/01447
• Status: Recruiting
• Phase: Phase 1
• Start date: August 4, 2023
• Est. completion date: December 31, 2025

Study information

• Verified date: May 2024
• Source: National University Hospital, Singapore
• Contact: Bok Yan Jimmy So, MBChB
• Phone: +65 6772 5555
• Email: sursbyj[@]nus.edu.sg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Peritoneal carcinomatosis (PC) is a miserable disease with poor treatment outcome. Intraperitoneal administration of anticancer drugs enables an extremely high concentration of drugs to directly contact the target cancer lesions in the peritoneal cavity. However, its effectiveness is limited by the intraperitoneal distribution and penetration of the drug. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an innovative intraperitoneal chemotherapy concept that enhances efficacy by taking advantage of the physical properties of gas and pressure. Electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (ePIPAC) may further enhance these benefits.

This research study serves to determine the safety profile and tolerability of PIPAC/ePIPAC with paclitaxel. It will determine the maximal tolerated dose (MTD) and evaluate the safety and tolerability, and pharmacokinetics of PIPAC/ePIPAC paclitaxel in pre-treated patients with peritoneal carcinomatosis (PC). It may offer a novel and effective option of treatment for patients with PC, who, at present have limited options involving the use of systemic chemotherapy and who suffer from poor life expectancy and poor quality of life.

Description:

In patients with histologically proven unresectable or recurrent gastric cancer limited to the peritoneum, the combination of intraperitoneal (IP) paclitaxel with systemic chemotherapy reported a one-year survival rate of 78%. However, the effectiveness of IP chemotherapy may be limited by its distribution, tissue penetration and associated catheter-related complications.

Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a novel drug delivery technique for PC taking advantage of physical laws (gaseous nature, hydrostatic pressure) with superior pharmacological properties (homogeneous distribution, deeper tissue penetration). It is applied through laparoscopy and is minimally invasive. Adding electrostatic loading (ePIPAC) as an adjunct would further improve the pharmacological properties of PIPAC since it should induce precipitation of the aerosolized drug, increasing the ratio between the dose applied and the dose in the target tissue.

Systemic toxicity is significantly reduced due to the peritoneum/blood barrier and the low dose applied (about 20% of the usual systemic dose). A systematic review highlighted that PIPAC combines the benefits of a minimally invasive approach with pharmacokinetic advantages of intraperitoneal administration and pressurized vaporization. It concluded that PIPAC is feasible, safe, and warrants further prospective studies. PIPAC may be combined with systemic palliative chemotherapy with minimal additional organ toxicity. This method of treatment avoids the morbidity and mortality of HIPEC. PIPAC has been shown in pre-clinical studies to be potentially more efficacious than catheter-based IP-chemotherapy due to better drug distribution and penetration. In clinical use, PIPAC can be repeated at intervals of 6 weeks to 3 months. This allows repeated objective assessment of therapy effect over time.

To date, PIPAC has only been utilized to administer Oxaliplatin or a combination of Doxorubicin/Cisplatin. Paclitaxel is an approved drug for systemic chemotherapy for several cancers, and also has well-documented intraperitoneal use for ovarian cancer and gastric cancer. It is a hydrophobic, high molecular weight compound resulting in low absorption through the lymphatic system after IP administration with a much higher peritoneal to plasma peak concentration and AUC ratios (>1000 versus 25 and >1000 versus 16 respectively). As such, IP Paclitaxel may be potentially more efficacious with less systemic toxicity than IP Oxaliplatin. However, no clinical data exists in the published literature for PIPAC/ePIPAC paclitaxel.

This proposed prospective study is the first clinical study of PIPAC/ePIPAC with Paclitaxel. It will determine the maximal tolerated dose (MTD) and evaluate the safety and tolerability, and pharmacokinetics of PIPAC/ePIPAC paclitaxel in pre-treated patients with PC. Peritoneal biopsies will be collected prior to and after PIPAC/ePIPAC to assess tissue drug concentration and depth of drug penetration. Collection of biospecimens including peritoneal tissue, peritoneal fluid and blood will be used for correlative studies including paclitaxel resistance analysis and development of cancer modelling platforms. For the individual patient, repeated biopsies and molecular profiling may also facilitate individualized therapy. For medical research, PIPAC/ePIPAC may deliver measurable progress in 3-5 years because the assessment interval is short (6 weeks) in this disease with rapid progression (6-12 months to death).

This study will determine the safety dose range of PIPAC/ePIPAC paclitaxel. This will allow us to design a phase II trial to evaluate clinical efficacy. On a larger scale, the success of this PIPAC/ePIPAC trial would add a valuable treatment option to our arsenal in the treatment of PC.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 99 Years

Eligibility

Inclusion Criteria:

• All solid cancer patients with peritoneal metastasis on peritoneal cytology/histology.

• Patients who refuse, are unable to tolerate, or have completed at least 1st line systemic chemotherapy

• Patients who have completed chemotherapy/targeted therapy > 21 days or at least 5 half-lives (whichever is longer) prior to PIPAC/ePIPAC

• Patients must have recovered (= grade 1) from all reversible treatment toxicity from prior chemotherapy, radiotherapy or surgery.

• Age =21 years

• Eastern Cooperative Oncology Group performance status 0-2

• Adequate bone marrow function (neutrophil count =1500/mm3, hemoglobin =8.0 g/dl and platelet count =100 000/mm3)

• Adequate liver function (bilirubin = 1.5x ULN (upper limit normal) and AST/ALT =3x ULN or =5x ULN in the presence of liver metastases)

• Adequate renal function (serum creatinine =1.5x ULN)

• Expected survival >3 months

• Able to understand and the willingness to sign a written informed consent document

• The effects of proposed regimen on the developing human fetus at the recommended therapeutic dose are unknown. For this reason and because antitumor agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

• Patients with treated skin cancer besides melanoma may be included.

Exclusion Criteria:

• Predominant extra-peritoneal metastases at the discretion of the study team after discussion at the multidisciplinary tumor board

• Patients with clinical or radiological evidence of hollow viscera perforation or impending perforation, including but not limited to gastric, small bowel, colon, gallbladder. Decision will be made at the discretion of the study team in consultation with multidisciplinary tumour board or with necessary specialists

• Good response to systemic chemotherapy based on RECIST guidelines version 1.1 with complete or partial response to systemic chemotherapy

• Known allergy to paclitaxel

• Previous malignancy unrelated to current peritoneal carcinomatosis diagnosed in the last 2 years

• Patients with reproductive potential who refuse to use an adequate means of contraception (including male patients)

• Significant disease or conditions which, in the investigator's opinion, would exclude patient from the study

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant or lactating female

• Patients with bowel obstruction, total dependence on parenteral nutrition, or who are undergoing gastrointestinal resection in the same setting

Related Conditions & MeSH terms

• Carcinoma
• Peritoneal Carcinomatosis
• Peritoneal Neoplasms

Intervention

Drug:
• Paclitaxel
This is a prospective, two armed phase I trial in a 3 + 3 dose escalation evaluating the safety and tolerability of PIPAC/ePIPAC using paclitaxel in patients with peritoneal carcinomatosis.

Locations

Country	Name	City	State
Singapore	National University Hospital	Singapore

Sponsors (1)

Lead Sponsor	Collaborator
National University Hospital, Singapore

Country where clinical trial is conducted

Singapore, 

References & Publications (10)

Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA; Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006 Jan 5;354(1):34-43. doi: 10.1056/NEJMoa052985. — View Citation

Chan DY, Syn NL, Yap R, Phua JN, Soh TI, Chee CE, Nga ME, Shabbir A, So JB, Yong WP. Conversion Surgery Post-Intraperitoneal Paclitaxel and Systemic Chemotherapy for Gastric Cancer Carcinomatosis Peritonei. Are We Ready? J Gastrointest Surg. 2017 Mar;21(3):425-433. doi: 10.1007/s11605-016-3336-3. Epub 2016 Dec 15. — View Citation

Grass F, Vuagniaux A, Teixeira-Farinha H, Lehmann K, Demartines N, Hubner M. Systematic review of pressurized intraperitoneal aerosol chemotherapy for the treatment of advanced peritoneal carcinomatosis. Br J Surg. 2017 May;104(6):669-678. doi: 10.1002/bjs.10521. — View Citation

Ishigami H, Fujiwara Y, Fukushima R, Nashimoto A, Yabusaki H, Imano M, Imamoto H, Kodera Y, Uenosono Y, Amagai K, Kadowaki S, Miwa H, Yamaguchi H, Yamaguchi T, Miyaji T, Kitayama J. Phase III Trial Comparing Intraperitoneal and Intravenous Paclitaxel Plus S-1 Versus Cisplatin Plus S-1 in Patients With Gastric Cancer With Peritoneal Metastasis: PHOENIX-GC Trial. J Clin Oncol. 2018 Jul 1;36(19):1922-1929. doi: 10.1200/JCO.2018.77.8613. Epub 2018 May 10. — View Citation

Ishigami H, Kitayama J, Kaisaki S, Hidemura A, Kato M, Otani K, Kamei T, Soma D, Miyato H, Yamashita H, Nagawa H. Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis. Ann Oncol. 2010 Jan;21(1):67-70. doi: 10.1093/annonc/mdp260. Epub 2009 Jul 15. — View Citation

Kobayashi D, Kodera Y. Intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis. Gastric Cancer. 2017 Mar;20(Suppl 1):111-121. doi: 10.1007/s10120-016-0662-9. Epub 2016 Nov 1. — View Citation

Kono K, Yong WP, Okayama H, Shabbir A, Momma T, Ohki S, Takenoshita S, So J. Intraperitoneal chemotherapy for gastric cancer with peritoneal disease: experience from Singapore and Japan. Gastric Cancer. 2017 Mar;20(Suppl 1):122-127. doi: 10.1007/s10120-016-0660-y. Epub 2016 Oct 20. — View Citation

Reymond M, Demtroeder C, Solass W, Winnekendonk G, Tempfer C. Electrostatic precipitation Pressurized IntraPeritoneal Aerosol Chemotherapy (ePIPAC): first in-human application. Pleura Peritoneum. 2016 Jun 1;1(2):109-116. doi: 10.1515/pp-2016-0005. Epub 2016 Apr 29. — View Citation

Solass W, Herbette A, Schwarz T, Hetzel A, Sun JS, Dutreix M, Reymond MA. Therapeutic approach of human peritoneal carcinomatosis with Dbait in combination with capnoperitoneum: proof of concept. Surg Endosc. 2012 Mar;26(3):847-52. doi: 10.1007/s00464-011-1964-y. Epub 2011 Nov 1. — View Citation

Solass W, Hetzel A, Nadiradze G, Sagynaliev E, Reymond MA. Description of a novel approach for intraperitoneal drug delivery and the related device. Surg Endosc. 2012 Jul;26(7):1849-55. doi: 10.1007/s00464-012-2148-0. Epub 2012 May 12. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Tolerability of PIPAC /ePIPAC with Paclitaxel by monitoring dose limiting toxicities	Dose limiting toxicities are monitored to evaluate the tolerability of PIPAC /ePIPAC	1 - 2 years
Primary	Safety Profile of PIPAC/ePIPAC with Paclitaxel by monitoring adverse events	Adverse events are monitored to evaluate the safety profile of PIPAC/ePIPAC	1 - 2 years
Secondary	Clinical response of PIPAC/ePIPAC with Paclitaxel according to Peritoneal Cancer Index (PCI)	Peritoneal Cancer Index (PCI) is used to measure Clinical response of PIPAC/ePIPAC with Paclitaxel	1 - 2 years
Secondary	Pathological response of PIPAC/ePIPAC with Paclitaxel according to Peritoneal Regression Grade Scoring (PRGS) System	Peritoneal Regression Grade Scoring (PRGS) System is used to measure Pathological response of PIPAC/ePIPAC	1 - 2 years
Secondary	Maximum concentration (Cmax) of Paclitaxel administered via PIPAC/ePIPAC using blood drawn from patient.		Pre-dose; 30 and 45 minutes; and 1, 2, 4, 8, 24, 30, 48 hour
Secondary	Half-life (t1/2) of Paclitaxel administered via PIPAC/ePIPAC using blood drawn from patient		Pre-dose; 30 and 45 minutes; and 1, 2, 4, 8, 24, 30, 48 hour
Secondary	Area under the curve (AUC) of Paclitaxel administered via PIPAC/ePIPAC using blood drawn from patient.		Pre-dose; 30 and 45 minutes; and 1, 2, 4, 8, 24, 30, 48 hour