Safety Study of Rapamycin Administered Before and During Radiotherapy to Treat Rectum Cancer

A Clinical Trial Testing Rapamycin, an mTOR-inhibitor, in Combination With Preoperative Radiotherapy in Operable Rectum Cancer: a Phase I and Phase II Study

Investigating the safety and the activity of Rapamycin, administered before and during preoperative radiotherapy in patients with an operable colorectal carcinoma. The phase I dose escalation study will be performed in three steps (2, 4 and 6 mg). Patients entered in phase II will follow the same tolerable treatment regimen as patients in phase I study.

Treatment regimen Phase I A daily dose of Rapamycin will be taken during 13 days. At step 1 a dose of 2 mg will be given once a day; at step 2 a dose of 4 mg will be given once a day; at step 3 a dose of 6 mg will be given once a day.

Preoperative radiotherapy (5x 5 Gy) will be administered at day 8-12, followed by TME-surgery at day 15.

Phase II A daily dose of 6 mg Rapamycin will be taken for 14 days (unless the optimal dose found in the phase I study is lower).

Preoperative radiotherapy (5x 5 Gy) will be administered at day 9-15, followed by TME-surgery 7-8 weeks post RT.

Sample size Phase I dose-escalation study Minimum 3 eligible patients per step, maximum 6 eligible patients per step. Phase II A total of 47 patients will be entered in this part of the study.

Inclusion Criteria:

• Histologically proven rectum cancer
• UICC TNM I-III
• WHO performance status 0-2
• Less than 10% weight loss the last 6 months
• No recent (< 3 months) severe cardiac disease
• Normal serum bilirubin and serum creatinin

Exclusion Criteria:

• Concurrent chemotherapy with radiation
• History of prior pelvis radiotherapy
• Recent (<3 months) myocardial infarction
• Uncontrolled infectious disease
• Concurrent medication known as inhibitors of CYP3A4 susceptible to increase Rapamycin blood concentrations