Phase I/II Clinical Trial of Weekly Intraperitoneal Paclitaxel (IP-PTX) with Monthly Intravenous Carboplatin (IV-CBDCA) for Minimal Residual Disease of Ovarian, Tubal, and Peritoneal Carcinoma

Takeuchi S,Miyamoto T,Tanimura K,Omichi M,Takeuchi K,Terai Y

doi:10.18314/gjct.v5i1.1809

Abstract

We conducted weekly intraperitoneal administration of paclitaxel (IP-PTX) with monthly intravenous administration of carboplatin (IV-CBDCA), as a prospective phase 1/2 setting. The purpose of this study was to assess the pharmacokinetics and to decide the recommended dose (RD) according to modified Fibonacci method. Patients aged 20-75 years old with histological confirmed mullerian cancers (epithelial ovarian cancer; EOC, fallopian tubal cancer; FTC, and primary peritoneal cancer; PPC) from stage IC to IV or the patients with recurrent disease with small residual disease (including retention of ascetic fluid, para-aortic nodes recurrence after optimal debulked after interval debulking surgery; IDS) were eligible. The protocol regimen consisted of IP-PTX on day1 (D1), 8, and 15, at a starting dose level 1(DL1) of 45 mg/m2, with 15 mg/ m2 incremental, and IV-CBDCA was fixed dose AUC 5.0 mg/mL.min on D1, monthly. The accrual period was from August 2000 until September 2005. As for result, twelve patients were enrolled. No dose limiting toxicity (DLT) was observed in DL1. In dose level 2 (DL2, 60 mg/m2), one grade 3 (G3) hypersensitive reaction to CBDCA was detected. Further 5 patients had been enrolled but additional DLT was not identified. The RD was decided as DL2, which was the same dose of RD in weekly IP-PTX reported by Francis et al. The serum AUCs of PTX in DL1 and DL2 were 1605 nM.min and 2365 nM.min, respectively. By serum CA125, five complete responses were observed out of 8 evaluable patients by Rustin’s criteria. In conclusion, the combination of weekly IP-PTX and monthly IV-CBDCA at AUC 5.0 mg/mL.min was feasible and the recommended dose of IP-PTX was 60 mg/m2. The therapy was moderate effective for optimal debulking mullerian carcinomas. From our pharmacokinetic results, as for the patients with extra-pelvic lesions, additional IV-PTX would be necessary like GOG 172 experimental arm.

Highlights

Despite the fact that the establishment of standard regimen such as paclitaxel (PTX) plus carboplatin (CBDCA) with/without dose dense setting or bevacizumab or maintenance of Poly Adenosine diphosphateRibose Polymerase (PARP) inhibitors, cure rate of advanced ovarian cancer (OC), Fallopian Tube Cancer (FTC) and Primary Peritoneal Cancer (PPC) has not been improved satisfyingly
In case of using intraperitoneal administration of some cytotoxic agents, it has been well known that the area under the curve (AUC) of peritoneal fluid becomes much higher than that of peritoneal fluid when the agents were administered via intravenous (IV) way
Markman et al reported that the relative AUC (IP AUC/ IV AUC ratio) in peritoneal fluid reached about 1,000 folds higher in intraperitoneal administration of paclitaxel (IP-PTX), and it was 12-15 folds in intraperitoneal administration of carboplatin (IP-CBDCA) [2]

Summary

Introduction

Despite the fact that the establishment of standard regimen such as paclitaxel (PTX) plus carboplatin (CBDCA) with/without dose dense setting or bevacizumab or maintenance of PARP inhibitors, cure rate of advanced ovarian cancer (OC), Fallopian Tube Cancer (FTC) and Primary Peritoneal Cancer (PPC) has not been improved satisfyingly. In spite of the announcement, it has not prevalent even in US In such advanced patients, the recurrence rate has reached 85% or more during longer observation [1]. In order to control such peritoneal disease, intraperitoneal administration (IP) was considered as one of modalities. Markman et al reported that the relative AUC (IP AUC/ IV AUC ratio) in peritoneal fluid reached about 1,000 folds higher in intraperitoneal administration of paclitaxel (IP-PTX), and it was 12-15 folds in intraperitoneal administration of carboplatin (IP-CBDCA) [2]. PTX in itself is lipophilic agent and considered to be absorbed into adipose tissue of the abdominal visceral organs such as diaphragm, connective tissues, visceral adipose tissue, as well as lymphatic systems when it is administered into peritoneal cavity. The IP-PTX may be superior to IV-PTX in control the peritoneal disease and para-aortic nodal disease

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