Intraperitoneal Docetaxel With Cisplatin and TS-ONE for Gastric Cancer With Peritoneal Carcinomatosis

NCT ID: NCT02024841

Last Updated: 2018-05-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-31
• Study Completion Date: 2018-03-31

Brief Summary

Phase I study on the maximum tolerated dose (MTD) and the recommended dose (RD) of intraperitoneal docetaxel combined with intravenous cisplatin and oral TS-ONE in gastric cancer patients with peritoneal carcinomatosis

Detailed Description

Peritoneal carcinomatosis (PC) is common in advanced gastric cancer, and it carries a poor prognosis; the median survival time is 3 to 6 months. Gastric cancer with PC is considered incurable and patients are subjected to non-surgical treatment, mainly chemotherapy. Currently, there is no established standard treatment for these patients.

Multidisciplinary approach to the treatment of gastric cancer including chemotherapy, radiotherapy and surgery has been developed and survival benefit has been demonstrated in the adjuvant setting. Novel chemotherapeutic agents: taxanes (paclitaxel and docetaxel), irinotecan, oxaliplatin, fluoropyrimidine (TS-ONE and capecitabine) have shown activity in gastric cancer. Various combination chemotherapy regimens for unresectable and metastatic gastric cancer are practised in different parts of the world. Epirubicin, cisplatin and 5-fluorouracil (ECF) are used in Europe, while TS-ONE and cisplatin are commonly used in Asian countries such as Japan and Korea. The median survival time (MST) with these regimens was 8.9 and 13 months, respectively. Use of docetaxel, cisplatin and 5-fluorouracil (DCF) was proposed in the V325 study, MST was 9.2 months but the toxicity (grade 3-4 neutropenia) was reported to be significantly higher in DCF group when compared with CF group. However, there are few trials to study the specific efficacy of these regimens on PC.

Systemic chemotherapy is considered to be less effective against PC due to the existence of the blood-peritoneal barrier (BPB). The barrier inhibits the movement of drugs from systemic circulation to the peritoneal cavity. Intraperitoneal (IP) chemotherapy has the advantage of maintaining a high drug concentration in the peritoneal cavity, and reduces the systemic toxicity. Paclitaxel and docetaxel have been shown to have high peritoneal concentration in animal studies and are considered ideal drugs for IP administration.

Neoadjuvant intraperitoneal/systemic chemotherapy (NIPS) is a new bidirectional induction chemotherapy for treatment of PC from gastric cancer. The aim of NIPS is to induce a reduction of PC volume. Bidirectional means that NIPS could attack PC from both the peritoneal cavity and the subperitoneal blood vessels. Patients with good response to NIPS may undergo subsequent gastrectomy. The use of TS-ONE and IP taxane (paclitaxel/docetaxel) had been studied in phase I and II trials. Ischigami et al. reported 1-year survival rate of 78% and overall response rate of 56% using weekly intravenous and IP paclitaxel combined with TS-ONE. Fujiwara et al. reported 78% patients had negative peritoneal cytology after NIPS and 16 out of 18 patients (88.9%) underwent subsequent gastrectomy, with a MST of 24.6 months. No treatment-related mortality has been reported.

Systemic DCF is associated with significant toxicity, yet it is superior to CF alone in terms of survival (9.2 months vs. 8.6 months, p<0.02). Grade III/IV neutropenia was reported to be 82%. It is postulated that switching from intravenous docetaxel to IP docetaxel may improve its efficacy against PC and reduce the systemic toxicity. TS-ONE contains tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo). Dihydropyrimidine dehydrogenase (DPD), which is found in liver, rapidly degrades 5-FU. The presence of CDHP, a specific inhibitor of DPD, allows a high intraperitoneal drug concentration after oral administration of TS-ONE that has been demonstrated in an experimental model.

Therefore we propose a modification of the DCF regimen using IP docetaxel, intravenous cisplatin and oral TS-ONE in the treatment of gastric cancer patients with PC. We aim to study the maximum tolerated dose (MTD) and the recommended dose (RD) of IP docetaxel while using fixed doses of cisplatin and TS-ONE. Data on treatment efficacy will also be recorded. By far there is no study on IP chemotherapy in Hong Kong.

Conditions

Gastric Cancer; Peritoneal Carcinomatosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intraperitoneal docetaxel

Intraperitoneal docetaxel in 1litre normal saline infused over 1 hour on day 1 every 3 weeks:

• Level I: 40mg/m2; Level II: 50mg/m2; Level III: 60mg/m2

Intravenous cisplatin: 60mg/m2 on day 1 every 3 weeks

Oral TS-ONE: 40-60mg twice daily on day 1 -14 every 3 weeks

Group Type: EXPERIMENTAL

Intraperitoneal docetaxel

Intervention Type: DRUG

Intraperitoneal docetaxel, intravenous cisplatin and oral TS-ONE every 3 weeks for 3 cycles then stop

Interventions

Intraperitoneal docetaxel

Intraperitoneal docetaxel, intravenous cisplatin and oral TS-ONE every 3 weeks for 3 cycles then stop

Intervention Type: DRUG

Other Intervention Names

Intraperitoneal taxotere

Eligibility Criteria

Inclusion Criteria

• Age≥18
• Histologic confirmation of gastric adenocarcinoma
• Positive peritoneal cytology or histological proven PC
• Absence of other distant metastases except peritoneum and lymph node(s)
• Adequate bone marrow and organ functions as defined below:
• Leucocyte ≥3.00 x 109/L
• Absolute neutrophil counts ≥ 1.50 x 109/L
• Platelet ≥ 100 x 109/L
• Total bilirubin ≤2 x ULN
• AST/ALT ≤2.5 x ULN
• Creatinine clearance ≥60ml/min
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Subjects of child-bearing potential must agree to contraception from screening to 6 months after completion of treatment
• Provision of written informed consent

Exclusion Criteria

• Any prior anti-cancer therapy for gastric cancer
• Previous exposure to taxane, fluoropyrimidine or platinum chemotherapy
• Previous radiotherapy to abdomen or pelvic region
• Known hypersensitivity to study medication
• Known dihydropyrimidine dehydrogenase (DPD) deficiency
• Any prior or synchronous malignancy, except,
• Malignancy treated with curative intent and with no evidence of disease for ≥5 years prior to enrollment and considered to be at low risk for recurrence by the treating physician
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Subject is pregnant or breast feeding
• Any serious concomitant illness

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Taiho Pharmaceutical Co., Ltd.

INDUSTRY

Sponsor Role: collaborator

The University of Hong Kong

OTHER

Sponsor Role: lead

Responsible Party

Dr. Lam Ka On

Clinical Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ka-On Lam, MBBS

Role: PRINCIPAL_INVESTIGATOR

The University of Hong Kong

Locations

The University of Hong Kong

Hong Kong, Hong Kong, China

Countries

China

Other Identifiers

HKUGCDTC01

Identifier Type: -

Identifier Source: org_study_id