A Randomized, Double Blind Study Evaluating Paclitaxel With and Without RAD001 in Patients With Gastric Carcinoma After Prior Chemotherapy

This is a randomized, double-blind, phase III two-arm multi-center study aiming at estimating the relative efficacy of the combination of RAD001 and paclitaxel versus that of paclitaxel alone as second-, third- or fourth-line treatment in terms of hazard ratio of overall survival in patients with gastric cancer who have relapsed after one treatment regimen containing a fluoropyrimidine (e.g., 5-FU, S-1, capecitabine and other 5-FU prodrugs or derivatives). Patients will be randomized in a 1:1 ratio for a total of 240 patients per treatment arm. Randomization will be stratified according to performance status (0-1 versus 2), prior taxan use (yes vs. no) and treatment line (2nd versus 3rd/4th line).

Study treatment will be continued until progression or intolerable toxicity. Patients will be seen at baseline/screening, and weekly for paclitaxel administration and safety assessment until disease progression or discontinuation of trial therapy for other reasons. Radiological tumor assessment will be performed every second cycle (every 8 weeks) or earlier if clinically indicated. Post-study follow-up will be completed every 8 weeks for survival.

Inclusion criteria

• Male or female patients ≥ 18 years old
• Histologically or cytologically confirmed and documented gastric adenocarcinoma. Adenocarcinomata of the gastro-esophageal junction will be allowed, if they have advanced disease (inoperable, recurrent or metastatic disease).
• Documented progressive disease during/after one, two or three prior treatments containing 5FU and/or its precursors or derivatives in the palliative setting
• At least one measurable or evaluable lesion by RECIST as determined by Computed Tomography (CT) Scan or Magnetic Resonance Imaging (MRI)
• ECOG performance status of 0, 1 or 2
• The following laboratory parameters:

• Absolute neutrophil count ≥ 1.5 x 109/L
• Platelets ≥ 100 x 109/L
• Hemoglobin (Hgb) ≥ 9 g/dL
• Serum creatinine ≤ 2 x Upper Limit of Normal (ULN)
• Adequate liver function:
• Total serum calcium (corrected for serum albumin) or ionized calcium ≥ LLN
• Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first administration of study treatments and must be willing to use adequate methods of contraception during the study and for 3 months after last study drug administration.
• Written informed consent

Exclusion criteria

• Current treatment with any anti cancer therapy or treatment with anti cancer therapy ≤ 2 weeks prior to study treatment start unless rapidly progressing disease is measured
• Known hypersensitivity to RAD001 (everolimus) or to its excipients, or to other rapamycins (e.g. sirolimus, temsirolimus)
• Known prior history of hypersensitivity to paclitaxel.
• Paclitaxel refractory disease, which is defined as a disease progression under or within 12 weeks of last taxan treatment
• Chronic treatment with steroids (except for oral, topical or local injection) or another immunosuppressive agent
• Major surgery ≤ 2 weeks prior to starting study treatment or patients who have not recovered from such therapy
• Lack of resolution of all acute toxic effects (excluding alopecia) of prior chemotherapy, prior radiotherapy, or surgical procedure to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade <= 1. Note: Neuropathy due to prior chemotherapy is allowed.
• Unstable CNS disease

• Requiring increasing doses of steroids to maintain stable neurological status
• Deteriorating / changing neurological status
• Known history of HIV seropositivity (HIV testing is not mandatory) or Hepatitis B or C.
• Active, bleeding diathesis or on oral anti-vitamin K medication (except low dose warfarin, as long as the INR is <= 2.0)
• Any other severe and/or uncontrolled medical conditions