A Study of TS-1, Cisplatin (CDDP) and RAD001 (Everolimus)

Summary

Hypothesis: The addition of RAD001 to TS-1/CDDP is safe and can improved the efficacy of TS-1/CDDP. The rationale for combining RAD001 with TS-1/CDDP are: 1. Potential synergism for the combination TS-1/CDDP Activation of the PI3K/AKT/mTOR pathway is frequently a characteristic of worsening prognoses (through increased aggressiveness), resistance to treatment, extension of disease and progression. The antitumour effect of RAD001 is mediated through the antiproliferative and antiangiogenic activity of mTOR inhibition. In preclinical study, RAD001 demonstrated synergism with CDDP in several cancer types including lung (A549; CI 0.47), epidermoid cancer (KB-31; CI 0.74), colon cancer (HCT116; CI 0.47) and gastric cancer (SNU 1; CI 0.204, SNU 216; CI 0.546, SNU 638; CI 0.039, SNU 668; CI 0.396) (IB, Lee 2008 AACR). 2. Potential for overcoming TS-1/CDDP resistance. Upregulation of Akt pathway was found to be an important mechanism for acquired resistance to CDDP (Lee 2005 Gyn Onc, Liu 2007 Cancer Res). In addition, gastric cancers with upregulated Akt pathway are associate with primary resistance to 5- fluorouracil, adriamycin, mitomycin C, and cisplatin (Oki 2007 PASCO) 3. Overlapping antitumour activities with TS-1/CDDP RAD001 is effective and well tolerated against subcutaneous tumours established from a variety of tumour cell lines of diverse histotypes (NSCLC, pancreatic, gastric, colon, renal, melanoma, epidermoid), including a Pgp170-overexpressing, multi-drug resistant tumor line. Partial response to single agent RAD001 was seen in a patient with gastric cancer at the dose of 5mg/day and 2 patients (gastric and oesophageal cancer) at the dose of 10mg/day, in study C2101 and C1101 respectively. A clinical benefit (stable disease, partial response and complete response) was observed in 55% of patient with gastric cancer who had failed 1st line therapy (Yamada 2009 GCS ASCO). A phase III study of RAD001 in patients with 2nd/3rd line gastric cancer has currently opened for recruitment.

Timeline

Start

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Primary completion

2012-09

Completion

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Publications

• Background Liu LZ, Zhou XD, Qian G, Shi X, Fang J, Jiang BH. AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway. Cancer Res. 2007 Jul 1;67(13):6325-32. doi: 10.1158/0008-5472.CAN-06-4261.
• Background Lee S, Choi EJ, Jin C, Kim DH. Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol. 2005 Apr;97(1):26-34. doi: 10.1016/j.ygyno.2004.11.051.

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