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.
Interventional
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To evaluate the confirmed objective response rates (complete and partial responses)
2008 ~2009
Yes
Kun-Huei Yeh, M.D.,Ph.D.
Principal Investigator
Department of Oncology, National Taiwan University Hospital
Taiwan: Department of Health
200612015M
NCT00632268
February 2008
December 2012
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