Sirolimus and Pemetrexed to Treat Non-Small Cell Lung Cancer

Background:

- Lung cancer is the most deadly cancer due to late stage of diagnosis and intrinsic
resistance to chemotherapy.

- Pemetrexed is a well tolerated Food and Drug Administration (FDA)-approved second line
chemotherapeutic agent with a 9% response rate.

- Increasing the efficacy of pemetrexed could provide clinical benefit for patients with
refractory NSCLC.

- Inhibition of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mTOR pathway
may increase response to chemotherapy.

- Combining sirolimus, an mTOR inhibitor, with pemetrexed could improve patient outcomes.

Objectives:

- Determine the safety, tolerability, pharmacokinetics (PKs), and maximum tolerated dose
(MTD) of the combination of sirolimus with pemetrexed in subjects with NSCLC subjects
with activation of the Akt/mTOR pathway.

- Determine the clinical response rate at the MTD of sirolimus plus pemetrexed in NSCLC
subjects.

- Determine effects of sirolimus on activation of the PI3K/Akt/mTOR pathway in peripheral
blood mononuclear cells (PBMCs) and/or tumor tissues, to determine metabolic changes
using PET scans, and measure PKs.

Eligibility:

- Adults with refractory or relapsed NSCLC regardless of mTOR pathway activation are
permitted to enroll in the trial.

Design:

- Phase I followed by Phase II study

- For phase I/II subjects, documentation of mTOR pathway activation is not mandatory. If
accessible, tissue will be obtained at baseline and following two cycles of therapy or
at time of progression, whichever occurs first. Tumor tissue will be obtained at
baseline and after two cycles of therapy or at time of progression, whichever occurs
first. All subjects will have pathway analysis using PBMCs at baseline, day 8 and every
two cycles of therapy or at time of progression, whichever occurs first. Cycle 1 is 28
days in length and all others 21 days.

- Each dose level incorporates a lead-in period of sirolimus alone that will allow for
correlations of dose level, pharmacokinetics, and biologic effects.

- The phase I portion of the study has 5 dose cohorts beginning below the FDA approved
doses for both agents. There are 3 dose escalations for sirolimus and 2 for pemetrexed.
Up to 30 subjects may enroll in the phase I study.

- The Phase II portion will utilize the MTD from the Phase I and enroll up to 60
subjects.

- Sirolimus will be administered by mouth daily, and pemetrexed will be administered
intravenously every 21 days until unacceptable toxicity or disease progression.

- Clinical imaging (CT or MRI) and a PET CT will be obtained at baseline and after two
cycles of treatment. Clinical imaging will be performed every two cycles until disease
progression.

- INCLUSION CRITERIA:

1. Histologically documented non small cell lung cancer (NSCLC) that is confirmed
by the Laboratory of Pathology at the Clinical Center/National Institutes of
Health (NIH) or the Laboratory of Pathology at National Naval Medical Center
(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 mammalian target of rapamycin
(mTOR) activation as assessed by immunohistochemistry in a fresh biopsy. mTOR
activation will be defined using distribution and intensity of staining for
phosphorylation of mTOR, or its downstream substrates S6 kinase (S6K), and S6.
Standard operating procedures (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, factor 4E binding protein 1 (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 computed
tomography (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
cytochrome P450 3A4 (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. Eastern Cooperative Oncology Group (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.

- Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) less
than 2.5 times upper limit of institutional normal.

- Alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) less than
2.5 times upper limit of institutional normal.

- Creatinine Estimated creatinine clearance as calculated using the modification of
diet in renal disease (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. Human immunodeficiency virus (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, rifapentine, 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.