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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

Phase 2
75 Years
Open (Enrolling)
Advanced Gastric Cancer

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Trial Information

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

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.

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
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

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.

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the confirmed objective response rates (complete and partial responses)

Outcome Time Frame:

2008 ~2009

Safety Issue:


Principal Investigator

Kun-Huei Yeh, M.D.,Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Department of Oncology, National Taiwan University Hospital


Taiwan: Department of Health

Study ID:




Start Date:

February 2008

Completion Date:

December 2012

Related Keywords:

  • Advanced Gastric Cancer
  • mTOR inhibitor
  • RAD001
  • everolimus
  • chemotherapy
  • cisplatin
  • high-dose 5-FU
  • Stomach Neoplasms