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.

• Patients must have a histologically or cytologically proven NSCLC, including adenocarcinoma, broncho-alveolar cell and large cell anaplastic carcinoma
• Patients need not have measurable disease to be eligible for this study. Patients with non-measurable lesions will be eligible. Measurable and non-measurable disease will be defined by RECIST criteria
• Age ≥18 years
• ECOG 0-2
• Life Expectancy: ≥3 months
• Patients who have had prior therapy must have completed chemotherapy at least 3 weeks, and radiotherapy at least 2 weeks, prior to study drug administration, with all side effects resolved. Patients who have not received prior therapy are eligible if they are not good candidates for standard treatment with cytotoxic chemotherapy, or do not wish to receive cytotoxic chemotherapy.
• Patients may not have undergone major surgery within 4 weeks prior to starting study drug administration. In addition, any surgical complications must be resolved, and the surgical scar must be determined by the surgeon to be healing appropriately
• Patients must have recovered from uncontrolled intercurrent illness including, but not limited to, ongoing active infection
• Patients may not have had any of the following within 6 months prior to study drug administration: MI, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic CHF, CVA, TIA or PE
• Patients may not have had a grade 3 hemorrhage within 4 weeks of study drug administration
• Patients may not have a history of or active spinal cord compression or carcinomatous meningitis. In addition, any previous brain metastases should be adequately treated, and there should be no evidence of new brain or leptomeningeal metastases on a screening CT or MRI scan
• Patients may not have ongoing cardiac dysrhythmias of grade ≥2. In addition, they may not have a prolonged QTc interval on baseline EKG
• Patients may not have uncontrolled hypertension or thyroid disease
• Patients may not have a severe acute or chronic medical or psychiatric condition, or laboratory abnormality
• Patients must have adequate bone marrow function defined as an absolute neutrophil count ≥ 1,500 cells/mm3, Hgb ≥ 9g/dl and platelet count ≥ 100,000 cells/mm3
• Patients must have adequate liver function defined as bilirubin <=2 x the upper limit of institutional normal and SGOT and SGPT <=2.5 x the upper limit of institutional normal, or SGOT and SGPT <=5 x the upper limit of institutional normal if liver function abnormalities are due to underlying malignancy
• Patients must have adequate renal function defined as serum creatinine <=1.5 x the upper limit of institutional normal
• Patients must have serum calcium ≤12.0 mg/dL
• No previous history of severe hypersensitivity reaction attributed to a receptor tyrosine kinase inhibitor.
• For all patients with reproductive potential, the use of adequate contraception and will be required for the duration of treatment and the 3 months following treatment
• Pregnant and nursing women are not eligible
• After being informed of the treatment involved, patients must give written consent. The patient should not have any serious medical or psychiatric illness that would prevent either the giving of informed consent or the receipt of treatment
• Entry to this study is open to both men and women and to all racial and ethnic subgroups