Inclusion Criteria

- INCLUSION CRITERIA:

1. Histologically documented NSCLC that is confirmed by the Laboratory of Pathology
at the Clinical Center/NIH or the Laboratory of Pathology at NNMC.

2. Tumor biopsy will be requested from all study subjects unless the procedure
poses too great a risk. If the subject declines, he or she may still participate
in the study. We will ask subjects not undergoing biopsy to provide 6 unstained
slides or a tissue block of archived tissue for immunohistochemistry (IHC)
evaluation. Tumors from subjects enrolling in the phase II portion of the study
will be analyzed retrospectively to demonstrate mTOR activation as assessed by
immunohistochemistry in a fresh biopsy. mTOR activation will be defined using
distribution andintensity of staining for phosphorylation of mTOR, or its
downstream substrates S6K, and S6. SOPs describing the acquisition and handling
of PBMCs and tissues are outlined in appendix 10.3 and 10.4. At a minimum, a
total score (sum of intensity and distribution scores) of 2 for phospho-S6 or
phospho-mTOR (S2448) mTOR will be required to determine that mTOR is active.
Either measurement will be sufficient to ascertain that mTOR is active.
Measurement of phosphorylation of Akt, 4E-BP1, and total levels of thymidylate
synthase (TS) will also be measured, but are not part of the eligibility
requirements. In the event of limited tissue availability, the stains will be
prioritized as follows: S6, mTOR, S6K, Akt (S473), Akt (T308), and TS.
Phosphorylation of S6 correlates most closely with mTOR activity, while
phosphorylation of mTOR at S2448 best predicts response to sirolimus.

3. Tissue from the time of original diagnosis will be adequate for enrollment on
study. Optional fresh tissue biopsy must be obtained AFTER their most recent
chemotherapy (including small molecule or targeted therapy) or radiation
therapy. Tumors that can be biopsied percutaneously (with or without
CT/ultrasound guidance) or via bronchoscopy will be considered accessible if
there are no other competing risk factors such as coagulopathy, hypoxemia,
unstable cardiovascular disease, uncontrolled pain, or inability to give
informed consent.

4. Individuals with relapsed NSCLC who have received at least one standard
chemotherapeutic regimen are eligible. Patients who received adjuvant
chemotherapy and then relapse or recur less than or equal to 12 months after
completion of chemotherapy will be eligible. Patients who received adjuvant
chemotherapy and relapse greater than 12 months after completion of chemotherapy
should receive frontline therapy for metastatic disease before enrollment, as
should individuals who initially present with incurable disease that is
chemotherapy naive. Individuals unwilling to receive standard front line therapy
for metastatic lung cancer may enroll.

5. Patients must have not received any chemotherapy, biological, or radiation
therapy in the 21 days prior to protocol enrollment. All previous chemo and
radiation therapy induced toxicities must have resolved to grade 1 or less prior
to enrollment.

6. Because sirolimus may affect the efficacy of hormonal birth control via CYP 3A4,
study subjects of child bearing potential must be willing to use barrier birth
control while receiving sirolimus therapy and for 12 weeks after discontinuation
of sirolimus.

7. Patients must have measurable disease for the phase II portion of the study.

8. Age greater than or equal to 18 years of age.

9. ECOG performance score of 0-2.

10. An expected survival of at least 3 months.

11. Patients must have the capacity to provide informed consent and demonstrate
willingness to comply with an oral regimen.

12. Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count greater than or equal to 1,500/mL.

- Platelets greater than or equal 100,000/mL.

- Total bilirubin less than 1.5 times upper limit of institutional normal.

- AST(SGOT) less than 2.5 times upper limit of institutional normal.

- ALT(SGPT) less than 2.5 times upper limit of institutional normal.

- Creatinine Estimated creatinine clearance as calculated using the MDRD equation must
be greater than or equal to 60ml/min/1.73m(2). The formula to be used is MDRD: 186
times (Scr)(-1.154) times (Age)(0.203) times (0.742 if female) times (1.212 if
African American)

- Serum triglycerides less than or equal to 2.5 times upper limit of normal; serum
cholesterol less than or equal 300 mg/dl (includes subjects with familial and
acquired hyperlipidemia).

13. Subjects on steroids must be on a stable or tapering dose of less than or equal
20 mg/day of prednisone (or equivalent dose of another glucocorticoid) for at least
one week prior to study entry.

EXCLUSION CRITERIA:

1. HIV positive patients.

2. Pregnant or lactating women.

3. Patients who received pemetrexed previously for Phase 1 only. Patients with prior
pemetrexed are eligible for Phase 2.

4. Patients who have had prior therapy with mTOR inhibitors such as sirolimus or its
analogues within six months.

5. Any concurrent therapy with chemotherapeutic agents or biologic agents or radiation
therapy.

6. Subjects with brain metastases may participate if the metastases are asymptomatic.
Subjects are ineligible if brain metastases are symptomatic.

7. Patients who are on the following drugs that modulate CYP3A4 and cannot replace these
medications with other equivalent medications for the period of the study:
amprenavir, atazanavir, bromocriptine, cimetidine, clarithromycin, clotrimazole,
cyclosporine, danazol, diltiazem, erythromycin, fluconazole, fosamprenavir, other HIV
protease inhibitors, indinavir, itraconazole, ketoconazole, metoclopramide,
nefazodone, nelfinavir, nicardipine, nifedipine, ritonavir, saquinavir,
telithromycin, troleandomycin (TAO), verapamil, voriconazole, nevirapine, rifampicin,
rifampin, rifabutin, rifapentin, phenytoin, carbamazepine, phenobarbital, and St.
John's Wort.

8. Subjects taking non steroidal anti-inflammatory agents who are unable to stop or
replace the agents for the 5 days prior to and the 2 days after pemetrexed will not
be eligible.

9. Patients who have received live vaccines in the past 21 days.