A Phase I Study of Adjuvant Chemotherapy With GS in Biliary Tract Cancer Undergoing Resection Without Major Hepatectomy

A Phase I Study of Adjuvant Chemotherapy With Gemcitabine Plus S-1 in Patients With Biliary Tract Cancer Undergoing Curative Resection Without Major Hepatectomy

To decide maximum tolerated dose and recommended dose of treatment using gemcitabine plus S-1 combination therapy in patients with biliary tract cancer undergoing resection without major hepatectomy

Study Overview

• Status: Completed
• Conditions: Biliary Tract Cancer
• Intervention / Treatment: Drug: Gemcitabine, S-1

Detailed Description

Surgery currently remains the only potentially curative treatment for biliary tract cancer (BTC), and most patients develop recurrence. Therefore, effective adjuvant chemotherapy is required to increase the curability of surgery and to prolong the survival in these patients. However, to date, no standard adjuvant chemotherapy has been established, and a guideline for BTC treatment recommends that trials of adjuvant chemotherapy be carried out.

Recently, there are two reports about gemcitabine (GEM) + S-1 combination (GS)chemotherapy after surgical resection for patients with BTC. At Iwate Medical University, Takahara, et al., performed a phase I study using a regimen of repeating 28 days as 1 course. Patients received GEM on day 1 and day 15, and S-1 from day 1 to day 14. The recommended dose is 1,000 mg/m² of GEM and S-1 80 mg/m² after a pancreatoduodenectomy. The 2-year survival rate of the 34 patients that received the GS therapy was 78.6% (Cancer Chemother Pharmacol. 2012 May;69(5):1127-33). At Hiroshima University, a cycle of chemotherapy consisted of intravenous GEM of 700 mg/m² on day 1 and oral S-1 of 50 mg/m² for 7 consecutive days, followed by a 1-week break from chemotherapy (14days as 1 course). Fifty patients received GS therapy and had a significantly better 3-year survival rate (57%) compared with 53 cases of surgery alone (30%). The GS adjuvant chemotherapy was feasible and the adverse event was minimal (Ann Surg. 2009 Dec;250(6):950-6).

Thus, the regimens of these two studies were 14 or 28 days as 1 course. There was no regimen that consisted of GEM on day 1, 8 and S-1 for 14 consecutive days, followed by a 1-week break from chemotherapy (21days as 1 course), which is frequently used for unresectable BTC and pancreatic cancer.

Though a hepatectomy is frequently performed during surgery for BTC, it is unclear if the effect of the anticancer agent is affected by a hepatectomy. Because GEM is metabolized by cytidine deaminase primarily in the liver, the ability to metabolize GEM after a hepatectomy is thought to decrease. Some clinical studies demonstrated that patients who had undergone a hepatectomy could not tolerate the standard dose and schedule of GEM. For adjuvant chemotherapy with GEM, it is necessary to separately examine whether or not the patient has undergone a hepatectomy.

Considering these present conditions, we aimed to assess the safety and efficacy of GEM + S-1 combination chemotherapy (21days as 1 course regimen, which is frequently used for unresectable BTC) for BTC with the patients undergoing curative resection without a hepatectomy.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Osaka
    • Hirakata, Osaka, Japan, 573-1191
      • Kansai Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Biliary tract cancer (BTC) with more than stage IB
2. BTC undergoing R0 or R1 resection without major hepatectomy
3. Older than 20 years old
4. PS 0 or 1
5. No treatment other than surgery
6. No dysfunction of main organs
7. Possible oral intake
8. Treatment start; after 4 weeks and within 12 weeks after surgery
9. Obtained written informed consent

Exclusion Criteria:

1. Patients with resection of major hepatectomy
2. Patients with double cancers
3. Patients having severe allergy
4. Patients with severe organ dysfunction
5. Patients with active infectious disease
6. Pregnancy
7. Patients with severe psychological disease
8. Patients seem inadequate for this study by investigators

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: gemcitabine , S-1; Level-2 Gem 800mg/msq, S-1 50mg/msq Level-1 Gem 800mg/msq, S-1 65mg/msq Level 1 Gem 1000mg/msq, S-1 65mg/msq Level 2 Gem 800mg/msq, S-1 80mg/msq	Drug: Gemcitabine, S-1; Dose of gemcitabine and S-1 and treatment schedule; Other Names: Gemcitabine;gemzer , S-1;TS-1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose	To establish the maximum tolerated dose of gemcitabine plus S-1 in patients with biliary tract cancer undergoing curative resection without major hepatectomy	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with dose limiting toxicity	Dose limiting toxicity is defined as follows; Grade 4 neutropenia, thrombocytopenia; Grade 3 or 4 febrile neutropenia; Grade 3 or 4 non-hematological adverse events unless unresponsive to treatment; Any adverse events resulting in interruption of dosing on day 8 in both the two courses; Any adverse events resulting in dose modification or delay of longer than 2 weeks	At the end of adjuvant chemotherapy (6 months)

Collaborators and Investigators

• Sponsor: Kansai Hepatobiliary Oncology Group
• Investigators: Study Director: Hideyoshi Toyokawa, MD, PhD, Kansai Medical University

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2012
• Primary Completion (ACTUAL): April 1, 2015
• Study Completion (ACTUAL): March 1, 2017

Study Registration Dates

• First Submitted: September 18, 2012
• First Submitted That Met QC Criteria: October 22, 2012
• First Posted (ESTIMATE): October 24, 2012

Study Record Updates

• Last Update Posted (ACTUAL): October 9, 2017
• Last Update Submitted That Met QC Criteria: October 5, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: adjuvant chemotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Biliary Tract Diseases; Biliary Tract Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine
• Other Study ID Numbers: KHBO1202; UMIN000007454 (REGISTRY: UMIN)