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Docetaxel

Cisplatin

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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

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

Intraperitoneal docetaxel

Ka-On Lam, MBBS

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

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.

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

Feasibility Study of Intraperitoneal Docetaxel Combined With Intravenous Cisplatin and Oral TS-ONE for Gastric Cancer Patients With Peritoneal Carcinomatosis

Taiho Pharmaceutical Co., Ltd.

The University of Hong Kong

Clinical Assistant Professor

Micronutrients

Oxaliplatin

Leucovorin

Fluorouracil

Participants will receive intraperitoneal docetaxel combined with the standard of care. A standard 3 + 3 dose escalation design will be used according to the dose escalation plan.

Up to 3 dose levels of intraperitoneal docetaxel will be studied (25mg/m2, 35 mg/m2, 45 mg/m2).

Fabian M Johnston, MD, MHS

Sherry Leung

Fabian M Johnston, M.D., M.H.S., F.A.C.S

Sherry G Leung

This is a single-center, open-label, non-randomized, uncontrolled Phase 1 study of intraperitoneal docetaxel in combination with systemic mFOLFOX6 for patients who have gastric cancer with gross peritoneal carcinomatosis (GC-PC).

Gastric cancer (GC) is one of the leading causes of cancer-related deaths in the United States and has a five-year survival of 40% after surgical resection. Metastatic gastric cancer has an even poorer prognosis and most patients die within the first year of diagnosis. Most patients are diagnosed in advanced stages of the disease due to non-specific or lack of symptomatology and treatment options are then limited to systemic chemotherapy. The peritoneum is the most frequent site of metastasis as well as cancer recurrence. Peritoneal Carcinomatosis (PC) results in adverse clinical sequelae and is ultimately responsible for 60% of all gastric cancer-related deaths. While visceral metastases originating from primary gastric cancer are relatively chemosensitive, peritoneal carcinomatosis is particularly challenging to treat because of inadequate drug delivery from systemic circulation. The primary purpose of this trial is to determine the safety of administering intraperitoneal docetaxel in conjunction with the standard of care treatment regimen of intravenous mFOLFOX6 (5-Fluorouracil, leucovorin, and oxaliplatin) in patients with primary gastric cancer with gross peritoneal carcinomatosis.

Intraperitoneal Docetaxel in Combination With mFOLFOX6 for Gastric Cancer Patients With Peritoneal Carcinomatosis

A Phase I Study of Intraperitoneal Docetaxel in Combination With 5-Fluorouracil, Leucovorin, and Oxaliplatin (mFOLFOX6) for Gastric Cancer Patients With Peritoneal Carcinomatosis

To determine the Maximum Tolerated Dose (MTD) of intraperitoneal docetaxel in conjunction with the standard of care treatment regimen of intravenous mFOLFOX6 in patients with primary gastric cancer with gross peritoneal carcinomatosis

Progression-free survival rate at 20 weeks, which is defined as the percentage of patients alive and free of disease progression at 20 weeks.

Johns Hopkins University

Symptoms and General Pathology

Neoplasm Metastasis

Ascites

Docetaxel is diluted in 1litre normal saline and administered intraperitoneal（IP）at a dose of 60 mg/m2 over 1 hour on day 1. S-1 was administered orally twice daily at a dose of 40mg/m2 per day for 14 consecutive days, followed by 7 days of rest.

Intervention: Drug: Intraperitoneal docetaxel Intervention：Drug：Oral S-1

One peritoneal access port will be implanted in subcutaneous space of patients' abdominal wall after laparoscopic exploration.Then intraperitoneal docetaxel in 1litre normal saline will be administered through the port

intraperitoneal docetaxel

40mg/m² twice daily on day 1-14 every 3 weeks

oral S-1

jun wang, Doctor

This is a clinical Study to evaluate the effect, survival benefit and safety of intraperitoneal docetaxel combined with oral S-1 for advanced gastric cancer with malignant ascites.

Peritoneal metastasis(PM) is common in advanced gastric cancer and associated with a poor prognosis. The median survival time is 3 to 4 months and even shorter in the patients with malignant ascites. Systemic chemotherapy is considered to be less effective against peritoneal metastasis (PM) due to the existence of the blood-peritoneal barrier (BPB), which inhibits the movement of drugs from systemic circulation to the peritoneal cavity.

S-1 is one kind of oral fluoropyrimidine derivatives and has been reported to be effective on PM. Docetaxel (DTX) has a pharmacokinetic advantage after intraperitoneal（IP）delivery which is hundreds of times higher than systemic administration. The use of S-1 and docetaxel has been studied in some phase II trials. Fujiwara and Fushida reported the usefulness of IP docetaxel combined with oral S-1 regimen in gastric cancer with PM respectively，the median survival time can exceed 16 months and one year survival rate was over 70%. Therefore, the investigators suppose IP docetaxel and oral S-1 can also be effective for gastric cancer with malignant ascites and start this study.

This is a single center, open-label, prospective clinical trial. Patients with histological proven gastric cancer with ascites, who fulfill the inclusion and exclusion criteria, can be recruited in this study. Patients will be firstly received laparoscopic exploration for Peritoneal Cancer Index (PCI）score, extraction of 100ml ascites for cytology examination, and one peritoneal access port is implanted in the subcutaneous space of the lower abdomen. Then patients were treated with chemotherapy on the first day after operation, the regimen as follows: DTX is administered IP at a dose of 60 mg/m2 on day 1. DTX is diluted in 1 litre normal saline and administered through the implanted peritoneal access port over 1 hour. S-1 was administered orally twice daily at a dose of 80 mg/m2 per day for 14 consecutive days, followed by 7 days of rest. The treatment course will be repeated every three weeks until observation of disease progression or unacceptable toxicity. Before each intraperitoneal chemotherapy, investigators extract 50-100 ml ascites for cytology pathologic examination, the abdominal CT will be reviewed after every three course to evaluate the volume of ascites.

The volume of ascites before and after therapy, PCI scores, ascites cytology results, complications, side effects and conditions of survival state and follow-up will be recorded and analyzed to evaluate the effect, survival benefit and safety of this study.

The Study of Intraperitoneal Docetaxel Plus S-1 for Malignant Ascites

The Study of Intraperitoneal Docetaxel Plus S-1 for Malignant Ascites Due to Far Advanced Gastric Cancer

From date of enrollment to three cycles of treatment，the ascites is evaluated by the Japanese conventional five-point method

Grade refers to Common Terminology Criteria for Adverse Events（CTCAE）Version4.0

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Intraperitoneal Docetaxel With Cisplatin and TS-ONE for Gastric Cancer With Peritoneal Carcinomatosis	NCT02024841	Gastric Cancer Peritoneal Carc...	Intraperitoneal...	18 Years -	The University of Hong Kong
Intraperitoneal Docetaxel in Combination With mFOLFOX6 for Gastric Cancer Patients With Peritoneal Carcinomatosis	NCT04583488	Peritoneal Carc...	Intraperitoneal...	18 Years -	Johns Hopkins University
The Study of Intraperitoneal Docetaxel Plus S-1 for Malignant Ascites	NCT02779608	Stomach Neoplas... Peritoneal Meta...	intraperitoneal... oral S-1	20 Years - 75 Years	Fudan University

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