A Phase I/II Trial of Pemetrexed (Alimta®) Combined With Sirolimus (Rapamycin, Rapamune®) in Subjects With Relapsed or Refractory NSCLC Whose Tumors Bear Activation of mTOR
Protocol # 08-C-0078
- Why is this trial important?
- Who is eligible for this trial?
- What types of drugs or therapies are being used?
- What is the study outline?
- What is the frequency and duration of the visits?
- What are the costs?
- Who is the Principal Investigator?
- Where is this trial taking place?
- Who are the contacts for this trial?
- Where can additional information be found?
Why is this trial important?
Lung cancer is a leading cause of cancer mortality because it is often diagnosed late, and is associated with resistance to chemotherapy. The mTOR pathway, responsible for cell proliferation and survival, is often activated in lung cancer and may contribute to drug resistance. Sirolimus is an FDA-approved drug for preventing transplant rejection that is known to block the mTOR pathway. Pemetrexed is an FDA-approved drug with a 9% response rate in relapsed lung cancer. By combining sirolimus with pemetrexed, we might be able to obtain an improvement in the response rate and offer people with relapsed lung cancer a better chance of response to chemotherapy.
Who is eligible for this trial? (PDQ)
- 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
- 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
What types of drugs or therapies are being used?
We are testing a combination of pemetrexed (an FDA-approved drug used to treat lung cancer) and sirolimus (an FDA-approved drug used to prevent rejection in organ transplant patients). Sirolimus inhibits a cellular pathway called mTOR, which may make the pemetrexed more effective.
What is the study outline? (PDQ)
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)
What is the frequency and duration of the visits?
The first cycle is 28 days long. Each cycle after that is 21 days long. On the first day of the first cycle, patients start taking sirolimus (a pill) by mouth daily. There is pharmacokinetic testing that requires a 12-hour stay on the first day, with a final blood draw done early the next day. On Day 8, the first dose of pemetrexed is given by vein, and the 12-hour stay for pharmacokinetic testing, with a final blood draw early the next day, is repeated. Another 12-hour stay for pharmacokinetics takes place 3 weeks later, when the second dose of pemetrexed is given, followed by a final blood draw early the next day. Patients will be seen in clinic at the beginning of each cycle. Scans will be done every other cycle.
What are the costs?
There is no charge for medical care received at the National Institutes of Health (NIH) Clinical Center. Patients will be responsible for travel costs for their initial screening visits. In most cases, once patients are enrolled in a trial, the National Cancer Institute (NCI) will pay the transportation costs for all subsequent trial-related visits for patients who do not live in the local area. In addition, these patients will receive a small per diem to help offset the costs of meals and lodging if they are being treated as outpatients.
It will be important to maintain your current insurance plan to cover all medical care that is provided away from the NIH Clinical Center.
No U.S. citizen or permanent U.S. resident residing in the U.S. who otherwise meets the eligibility requirements will be denied enrollment in clinical research protocols because of their inability to pay the costs of travel and subsistence.
Who is the Principal Investigator?
Dr. Phillip A. Dennis received his B.A. in 1984 as an Echols Scholar from the University of Virginia, and his Ph.D. and M.D. degrees in 1991 and 1992 respectively, from the New York University School of Medicine as part of the Medical Scientist Training Program. He completed his internal medicine training on the Osler Medical Service at Johns Hopkins Hospital. Following his residency, he completed a fellowship in medical oncology at the Johns Hopkins Oncology Center. Dr. Dennis joined NCI in 1999 as a tenure track investigator. In 2005, he became clinical service director at NCI/Navy Medical Oncology, and in 2006 became a senior investigator in the Medical Oncology Branch.
Where is this trial taking place?
NIH Clinical Center
National Institutes of Health
NCI Medical Oncology Branch and Affiliates
10 Center Drive
Bethesda, Maryland 20892
Who are the contacts for this trial?
Phillip A. Dennis, M.D., Ph.D.
Principal Investigator
Phone: 301-496-0929
pdennis@nih.gov
Referrals:
Hyejeong Root, R.N., M.S.N.
Research Nurse
Phone: 301-402-0998
Fax: 301-480-2590
roothy@mail.nih.gov
Where can additional information be found?
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