To define the optimal dose of sunitinib when given in combination with rapamycin 2mg.
To determine the maximum tolerated dosage of sunitinib and rapamycin given in this fashion.
To determine the how many times and how severe other toxicities of this combination therapy.
To determine how quickly the patient(s) will respond the the drug, overall survival and time
to progression for this combination therapy.
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
- 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
- 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
- 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