Low-dose RAD001(Everolimus) Plus Cisplatin-HDFL Chemotherapy for the First-line Treatment of Advanced Gastric Cancer

August 19, 2013 updated by: National Taiwan University Hospital

Phase II Study of Low-dose RAD001(Everolimus) Plus Cisplatin and HDFL (Weekly 24-Hour Infusion of High-dose 5-Fluorouracil and Leucovorin) Chemotherapy for First-line Treatment of Unresectable, Recurrent or Metastatic Gastric Cancer

The primary end-point of this study is to evaluate the objective response rates, and the secondary end-points are overall survival, progression-free survival and safety profile of low-dose RAD001 (everolimus) plus cisplatin and HDFL (weekly 24-hour infusion of high-dose 5-FU and leucovorin) chemotherapy in the first-line treatment for patients with unresectable, recurrent, or metastatic gastric cancer.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Non-resectable gastric cancer is an incurable disease, with a median survival of 4 months if untreated. Systemic chemotherapy confers prolongation of survival and improvement of quality of life. Regimens containing cisplatin and 5-fluorouracil (5-FU) are widely adopted in the world. The overall response rate and median overall survival of the P-HDFL regimen (cisplatin and weekly 24-hour infusion of high-dose 5-FU and leucovorin) for advanced gastric cancer are 60% (45%-76%, 95% C.I.) and 10 months, respectively. This regimen (P-HDFL) is very popular in Taiwan because of high objective response rates and low treatment-related toxicities. Adding a third active chemotherapeutic agent to cisplatin and 5-FU doublet does not seem to improve efficacy. Further, most of the patients with recurrent or metastatic gastric cancer are frequently associated with a poor general condition which prohibits intensive chemotherapy. Therefore, combination of P-HDFL with biologic agents(such as everolimus, etc.)is an attractive alternative.

PI3K/Akt/mTOR pathway is actively participating in cell proliferation and survival of human gastric cancers. We have recently demonstrated that RAD001(everolimus),an mTOR inhibitor, although with only modest growth inhibitory effects as a single agent, has significant synergistic cytotoxicity with cisplatin and 5-FU in gastric cancer cells. The concentration of RAD001 needed for synergism with cisplatin and 5-FU is as low as 0.5 to 5 nM. And, as expected, RAD001 has significant inhibition of downstream molecules such as 4E-BP1 and S6Kinase, in human gastric cancer cells. It is therefore reasonable to conduct a phase II study to examine if the combination of a relatively low dose of RAD001 and P-HDFL may improve the outcome of advanced gastric cancer.

This is an open-label, multi-center, phase II trial using low-dose RAD001 (10 mg po on D1,D8,&D15) plus P-HDFL chemotherapy (cisplatin 35 mg/m2 ivd 24 hrs on D1 & D8; 5-FU 2,000 mg/m2 and leucovorin 300 mg/m2 ivd 24 hrs on D1,D8,&D15) in chemotherapy-naïve patients with unresectable locally advanced, recurrent or metastatic gastric cancer. The treatment will be repeated every 28 days. The primary end-point is objective response rates evaluated by RECIST criteria, and the secondary end-points are overall survival, progression-free survival and safety profile. Approximately 41 patients will be enrolled in order to obtain the 37 evaluable patients required by Simon two-stage minimax design. All enrolled patients will be subjected to toxicity evaluations, but optionally to the correlative translational study of biomarkers in peripheral blood mononuclear cells. Patients with massive malignant ascites will optionally participate the study of biomarkers in neoplastic cells in ascites.

Study Type

Interventional

Enrollment (Actual)

40

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Taiwan
      • Taipei, Taiwan, 10002
        • Department of Oncology, National Taiwan University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 75 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Patients must have a histologically proven adenocarcinoma of the stomach, with unresectable locally advanced, recurrent or metastatic disease;
  2. Patients must receive no prior chemotherapy for unresectable locally advanced, recurrent or metastatic gastric cancer. Previous post-gastrectomy adjuvant therapy should be completed more than 6 months before enrollment;
  3. Patients must have at least one "measurable" lesion (by RECIST);
  4. Patients must have adequate baseline organ functions, and fasting triglyceride level >/= 70 mg/mL;
  5. Patients must be younger than 75 years of age;
  6. Patients must have an ECOG performance status </= 2;
  7. Patients' life expectancy should be expected >/= 3 months;
  8. Patients must sign an informed consent form.

Exclusion Criteria:

  1. Patients who have received radiotherapy, chemotherapy, or other experimental therapy within the previous 4 weeks or who are planning to receive such therapies simultaneously with RAD001 plus P-HDFL;
  2. Patients who have known hypersensitivity to everolimus, sirolimus or to its derivative;
  3. Patients who should not withdrawal from medication which can induce or inhibit activity of CYP3A4 during study period;
  4. Patients who have uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations;
  5. Patients with CNS metastasis;
  6. Patients who refuse port-A implantation;
  7. Women who are currently pregnant or breast feeding, and women of child-bearing potential without adequate contraception;
  8. Patients who have another prior malignancy, except for adequately treated basal cell, cervical carcinoma in situ, or any cancer from which the patient has been disease-free for 5 years.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: A
Drug:RAD001 Drug:Cisplatin Drug:5-FU
Drug: RAD001; Cisplatin; 5-FU; Leucovorin
RAD001: oral 10mg/day on Day 1,8,15 Cisplatin:infusion 35mg/m2/day on Day 1,8 5-FU:infusion 2000mg/m2/day on Day 1,8,15

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To evaluate the confirmed objective response rates (complete and partial responses)
Time Frame: 2008 ~2009
2008 ~2009

Secondary Outcome Measures

Outcome Measure
Time Frame
To assess the overall survival(OS), progression-free survival(PFS), treatment-related toxicities, and pharmacokinetic profile of RAD001 used in combination with 5-FU and cisplatin
Time Frame: 2009~2010
2009~2010

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Taiwan University Hospital

Collaborators

Taipei Veterans General Hospital, Taiwan
National Cheng-Kung University Hospital

Investigators

  • Principal Investigator: Kun-Huei Yeh, M.D.,Ph.D., Department of Oncology, National Taiwan University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2008

Primary Completion (Actual)

September 1, 2012

Study Completion (Actual)

December 1, 2012

Study Registration Dates

First Submitted

March 3, 2008

First Submitted That Met QC Criteria

March 7, 2008

First Posted (Estimate)

March 10, 2008

Study Record Updates

Last Update Posted (Estimate)

August 21, 2013

Last Update Submitted That Met QC Criteria

August 19, 2013

Last Verified

August 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 200612015M

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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