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Investigator(s):
Phillip A. Dennis, M.D., Ph.D. Principal Investigator Phone: 301-496-0929 pdennis@nih.gov	Wendy Bernstein, M.D. Protocol Chair Phone: 301-827-1593 bernsteinw@mail.nih.gov
Referral Contact(s):
Hyejeong Root, R.N., M.S.N. Research Nurse Phone: 301-402-0998 Fax: 301-480-2590 roothy@mail.nih.gov

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Primary Eligibility:

• Histologically documented non-small cell lung cancer that is confirmed by the NCI Laboratory of Pathology
• Relapsed disease must have been treated with at least one chemotherapy
• Measurable disease for the Phase II portion only
• No prior treatment with pemetrexed
• No prior treatment with mTOR inhibitors such as sirolimus or its analogues
• Must have recovered from all prior therapy
• No symptomatic brain metastasis
• ≥ 18 years of age
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0–2
• Expected survival ≥ 3 months
• Absolute neutrophil count ≥ 1,500/mL
• Platelets ≥ 100,000/mL
• Total bilirubin < 1.0 x upper limit of institutional normal (ULN)
• AST (SGOT) < 2.5 x ULN
• ALT (SGPT) < 2.5 x ULN
• Creatinine clearance > 60 cc/min
• Urine protein ≤ 1+ OR 24 hour urine < 200 mg/24 hours
• Serum triglycerides ≤ 2.5 x ULN; serum cholesterol ≤ 300 mg/dL (includes subjects with familial and acquired hyperlipidemia)
• No pregnant or nursing; fertile patients must use effective contraception while receiving sirolimus therapy and for 12 weeks after discontinuation of sirolimus
• No HIV
• Patients must discontinue the use of any medications that are metabolized by the CYP3A4 pathway OR switch to an alternative agent for the duration of the study

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Treatment Plan:

This is a Phase I followed by a Phase II study.

• Tumor tissue will be obtained at baseline and after two cycles of therapy or at time of progression, whichever occurs first:
• For the Phase I portion, patients can provide fixed tissue from any time point for baseline, and subsequent biopsies are optional
• For the Phase II portion, fixed tissue for baseline must be from a time point after the most recent chemotherapy
• All patients will have pathway analysis using peripheral blood mononuclear cells at baseline; at Day 8; and at every two cycles of therapy or at time of progression, whichever occurs first
• Patients will receive sirolimus for 7 days prior to the initiation of pemetrexed
• Patients receive a daily dose of folic acid orally and B12 subcutaneously/intramuscularly every 21 days starting 5 to 7 days before the first dose of pemetrexed
• Patients receive a 21-day cycle of intravenous (IV) pemetrexed starting on Day 8
• Patients receive oral dexamethasone twice daily (the day before, the day of, and the day after the administration of pemetrexed)

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Additional Information:

• This trial will be conducted at the NIH Clinical Center in Bethesda, MD. It is open to patients who meet the eligibility requirements, regardless of where they live in the United States.
• There is no charge for medical care received at NIH Clinical Center.
• FAQs about this study - provides information for patients about the trial such as frequency and duration of visits, costs, how to enroll, treatment plan.
• PDQ (Physicians Data Query) - provides additional details about this study for health care providers.

Reviewed: 6/12/08
Updated: 10/22/08