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
- 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
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To define the optimal dose of sunitinib when given in combination with rapamycin 2mg daily.
Ramaswamy Govindan, M.D.
Washington University School of Medicine
United States: Food and Drug Administration
07-0562 / 201101709
|Washington University School of Medicine||Saint Louis, Missouri 63110|