A Phase I Study of SUNITINIB and Rapamycin in Advanced Non-Small Cell Lung Cancer (NSCLC)

We propose to conduct a phase I study of sunitinib and rapamycin administered daily for weeks 1-4)in a 6-week cycle. The rationale for this study includes:

• Sunitinib is a tyrosine kinase inhibitor that targets multiple receptor pathways critical for cell growth. It has both antiangiogenic and direct antitumor activities.
• Resistance to receptor tyrosine kinase inhibitors is well-documented. The mammalian target of rapamycin (mTOR) pathway may play a critical role in imatinib-refractory GIST. Rapamycin and other agents that inhibit mTOR demonstrate antiangiogenic and antitumor properties by decreasing VEGF production and decreasing responsiveness to VEGF.
• Sunitinib is approved and well-tolerated at doses as high as 75mg daily. The typical dose in most Phase II and III trials has been 50mg/day, given on a four weeks on/two weeks off schedule. There are, however, recent trials looking at a lower dosage, 37.5 mg, in NSCLC.
• Rapamycin at doses greater than 2 mg daily is documented to be well-tolerated in renal transplant patients. In renal transplant patients, 2mg daily is the typical starting dose. This dose was used in one of the phase I studies of rapamycin in glioblastoma.
• The administration of two oral medications, taken once daily, may be more convenient to patients than iv administration of chemotherapy at an infusion center every 1-3 weeks.
• Based on these data, initial dosing of sunitinib beginning at 37.5 mg orally everyday for 4 weeks, followed by 2 weeks off, in combination with rapamycin 2 mg/day orally for 6 weeks during a 6 week cycle should be well tolerated and allow for dose-finding escalation.