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. 2022 Jun 21;7(4):169-177.
doi: 10.1515/pp-2022-0116. eCollection 2022 Dec.

Multicenter dose-escalation Phase I trial of mitomycin C pressurized intraperitoneal aerosolized chemotherapy in combination with systemic chemotherapy for appendiceal and colorectal peritoneal metastases: rationale and design

Mustafa Raoof  1 , Kevin M Sullivan  1 , Paul H Frankel  2 , Marwan Fakih  3 , Timothy W Synold  4 , Dean Lim  3 , Yanghee Woo  1 , Isaac Benjamin Paz  1 , Yuman Fong  1 , Rebecca Meera Thomas  5 , Sue Chang  6 , Melissa Eng  7 , Raechelle Tinsley  7 , Richard L Whelan  8 , Danielle Deperalta  8 , Marc A Reymond  9 , Jeremy Jones  10 , Amit Merchea  11 , Thanh H Dellinger  1
Affiliations

Multicenter dose-escalation Phase I trial of mitomycin C pressurized intraperitoneal aerosolized chemotherapy in combination with systemic chemotherapy for appendiceal and colorectal peritoneal metastases: rationale and design

Mustafa Raoof et al. Pleura Peritoneum. .

Abstract

Objectives: Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC.

Methods: This is a multicenter Phase I study of MMC-PIPAC (NCT04329494). Inclusion criteria include treatment with at least 4 months of first- or second-line systemic chemotherapy with ineligibility for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Exclusion criteria are: progression on chemotherapy; extraperitoneal metastases; systemic chemotherapy intolerance; bowel obstruction; or poor performance status (ECOG>2). Escalating MMC-PIPAC doses (7-25 mg/m2) will be administered in combination with standard dose systemic FOLFIRI. Safety evaluation will be performed on 15 patients (dose escalation) and six expansion patients: 21 evaluable patients total.

Results: The primary endpoints are recommended MMC dose and safety of MMC-PIPAC with FOLFIRI. Secondary endpoints are assessment of response (by peritoneal regression grade score; Response Evaluation Criteria in Solid Tumors [RECIST 1.1], and peritoneal carcinomatosis index), progression free survival, overall survival, technical failure rate, surgical complications, conversion to curative-intent CRS-HIPEC, patient-reported outcomes, and functional status. Longitudinal blood and tissue specimens will be collected for translational correlatives including pharmacokinetics, circulating biomarkers, immune profiling, and single-cell transcriptomics.

Conclusions: This Phase I trial will establish the recommended dose of MMC-PIPAC in combination with FOLFIRI. Additionally, we expect to detect an early efficacy signal for further development of this therapeutic combination.

Keywords: Phase I study; appendiceal cancer; colorectal cancer (CRC); mitomycin C (MMC); peritoneal metastasis (PM); pressurized intraperitoneal aerosolized chemotherapy (PIPAC).

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Conflict of interest statement

Competing interests: Authors state no conflict of interest.

Figures

Figure 1:
Figure 1:
Study schema. Schema and overview of the Phase I trial of mitomycin C PIPAC in combination with systemic chemotherapy for colorectal and appendiceal cancers. Three PIPAC procedures are planned 6 weeks apart with two doses of IV systemic chemotherapy (FOLFIRI) every two weeks between PIPAC procedures. The starting dose of mitomycin C will be 7 mg/m2 and escalate to 12.5, 19, and finally 25 mg/m2. Following the procedures, progression-free survival, overall survival, radiographic response, quality of life, and treatment with cytoreductive surgery will be monitored. Samples will be taken at each PIPAC procedure for correlative transcriptional and genomic studies. PIPAC, pressurized intraperitoneal aerosolized chemotherapy; FOLFOX, folinic acid (leucovorin), fluorouracil (5-FU), oxaliplatin; FOLFIRI, folinic acid (leucovorin), fluorouracil (5-FU), irinotecan; MMC, mitomycin C; FOLFOXIRI, folinic acid (leucovorin), fluorouracil (5-FU), oxaliplatin, irinotecan; AE, adverse event; DLT, dose limiting toxicity; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; DL, dose level
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