Study of Everolimus, Pemetrexed, Carboplatin, and Bevacizumab to Treat Stage IV Lung Cancer

Advanced lung cancer remains an incurable disease although new agents and new treatment
strategies have resulted in improved survival outcomes for patients. Most recently there
has been interest in augmenting tumor response to chemotherapy by the addition of drugs
which inhibit tumor cell growth and proliferation. Everolimus is a new cancer drug which
works as an inhibitor of mammalian target of rapamycin (or mTOR), mTOR is a protein that is
part of a signaling pathway which can cause cancer cells to divide. Everolimus when used
alone as a single agent has produced some response as well as prolonged stable disease in
both chemo-naïve and pre-treated non-small cell lung cancer. The goal of this study is to
evaluate the safety of everolimus with combined other cancer drugs called pemetrexed,
carboplatin, and bevacizumab. Pemetrexed and carboplatin are both chemotherapy drugs and
bevacizumab inhibits the growth of new blood vessels.

Patients will be entered onto dosing cohorts of 3 patients according to the following dose
escalation scheme. The first cohort will begin at dose level 1. At least three patients on
each dose level must have completed cycle one before the study leadership (principal
investigators, study statisticians) will allow patients to be enrolled onto the successive
dose level.

Dose Levels: 1, 2, 3

Pemetrexed (mg/m²): 500, 500, 500

Carboplatin (AUC): 5, 6, 6

Bevacizumab (mg/kg): 15, 15, 15

Everolimus (mg/day): 2.5, 2.5, 5.0

The purpose of this study is to determine the maximum tolerated dose, or MTD, for the
combination of everolimus with pemetrexed, carboplatin, and bevacizumab in patients with
Stage IV non-squamous, non small cell lung cancer.

1. Inclusion Criteria:

1. Signed informed consent

2. Confirmed diagnosis of Stage IV non-squamous non-small cell lung cancer

3. CT of the chest, abdomen, and pelvis which shows metastatic disease. If the
patient has had previous radiation to the marker lesion(s), there must be
evidence of progression since the radiation.

4. At least one measurable site of disease according to RECIST criteria that has
not been previously irradiated. If the patient has had previous radiation to the
marker lesion(s), there must be evidence of progression since the radiation.

5. Age ≥ 18 years

6. Normal blood function levels as evidenced by laboratory tests.

7. Adequate liver, kidney and blood chemistry function.

8. Adequate blood clotting levels

9. Urine dipstick levels of protein must be between 0-1+.

10. Fasting serum cholesterol ≤ 300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides
≤ 2.5 x IULN. Testing must be performed within 14 days prior to enrollment.

11. The ability to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs),
the day of, and 2 days following administration of pemetrexed.

12. No prior treatment with everolimus. Prior treatment with pemetrexed or
carboplatin is allowed, provided no disease progression with prior exposure to
drugs. Prior treatment with bevacizumab allowed.

2. Exclusion Criteria:

1. Evidence of severe or uncontrolled systemic disease or any concurrent condition
which in the Investigator's opinion makes it undesirable for the patient to
participate in the trial or which would jeopardize compliance with the protocol

2. Clinically significant cardiac event such as Myocardial infarction

3. Inadequately controlled high blood pressure

4. Active gastrointestinal disease resulting in an inability to take oral or
enteral medication via a feeding tube or a requirement for IVplacement; prior
surgical procedures affecting absorption; or active peptic ulcer disease

5. Presence of fluid accumulation which cannot be controlled by drainage

6. Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to enrollment

7. History of stroke within 6 months prior to enrollment

8. History of significant vascular disease within 6 months prior to
enrollment(i.e., aortic aneurysm)

9. No unusual bleeding or inability to clot (assuming not on anti-coagulation);
patients with a history of DVT and/pr pulmonary embolism are excluded

10. Serious non-healing wound, ulcer, or bone fracture

11. Major surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to enrollment, or anticipation of need for major surgical procedure
during the course of the study. Core biopsy or other minor surgical procedure,
excluding placement of a vascular access device, within 7 days prior to Day 1.

12. Untreated brain metastases Radiation treatment than 28 days prior to
registration. Side effects due to radiation therapy must have resolved.

13. Coughing up of blood

14. Excessive protein in your urine

15. Abnormal levels of lipids in your blood

16. Previous or current malignancies within the last 3 years, with the exception of
cervical cancer and adequately treated basal cell or squamous cell carcinoma of
the skin

17. Prior treatment with any investigational drug within the preceding 4 weeks prior
to enrollment

18. Patients receiving chronic, systemic treatment with corticosteroids or another
immunotherapy. Topical or inhaled corticosteroids are allowed.

19. Patients must not receive immunization with attenuated live vaccines within one
week prior to study enrollment or during study period.

20. Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation.

21. HIV positive

22. Impairment of stomach or intestinal function or stomach or intestinal disease
that may significantly alter the absorption of everolimus (e.g., ulcerative
disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or
small bowel resection)

23. Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. Women of
childbearing potential must have a negative urine or serum pregnancy test within
7 days prior to administration of everolimus.

24. Patients who have received prior treatment with an mTOR inhibitor (sirolimus,
temsirolimus, everolimus)

25. Patients with a known hypersensitivity to everolimus or other rapamycins
(sirolimus, temsirolimus) or to its excipients