Sirolimus and Pemetrexed to Treat Non-Small Cell Lung Cancer
The drug pemetrexed is used to treat non-small cell lung cancer (NSCLC) that does not respond to standard therapy or that has recurred after standard therapy; however, only 9 in 100 patients respond to pemetrexed.
Sirolimus is a drug that blocks a protein in cells called mTOR. In cancer cells, mTOR is active when it should not be, allowing the cells to grow uncontrollably. This protein is unusually active in many cases of NSCLC. By blocking the activity of mTOR, sirolimus may make the cancer cells more responsive to treatment with pemetrexed.
To determine if sirolimus in combination with pemetrexed is safe and well tolerated in patients with NSCLC.
To determine the highest safe dose of pemetrexed combined with sirolimus.
To look at the ability of sirolimus and pemetrexed to fight NSCLC.
To learn how the body eliminates sirolimus and pemetrexed.
Patients 18 years of age and older with NSCLC whose disease does not respond to standard therapy or has recurred after treatment with standard therapy.
Biopsy before treatment starts, if the tumor is easy to reach by bronchoscopy or can be done by needle biopsy. This procedure is optional.
Drug treatment, as follows:
- Day 1: Intravenous (through a vein) infusions of pemetrexed. Small groups (3 to 6) of patients are given pemetrexed at a certain dose level. If the first group experiences no significant side effects, the next group receives a higher dose. This continues in succeeding groups for up to five dose levels until the maximum tolerated study dose (highest dose that patients can be given safely) is determined.
- To lessen the side effects of pemetrexed, patients also receive a Vitamin B12 injection every 21 days, folic acid tablets daily, and dexamethasone tablets twice a day the day before, the day of, and the day after pemetrexed infusions.
- Days 1-21: Sirolimus tablets by mouth.
Evaluations during the treatment period:
- History and physical examinations, blood and urine tests, electrocardiogram.
- Disease evaluation with CT, PET or MRI scans....
Carcinoma, Non-Small-Cell Lung
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Trial of Pemetrexed (Alimta [Registered Trademark]) Combined With Sirolimus (Rapamycin, Rapamune [Registered Trademark]) in Subjects With Relapsed or Refractory NSCLC|
- Phase I endpoints: Primary-Determine the maximum tolerated dose of combination pemetrexed and sirolimus.
- Phase I: Measure pharmacokinetics; define effects on mTOR pathway activation; observe any early evidence of tumor regression via CT or MRI; observe metabolic changes in tumor via PET/CT.
|Study Start Date:||February 2008|
|Study Completion Date:||March 2013|
|Primary Completion Date:||March 2013 (Final data collection date for primary outcome measure)|
- Lung cancer is the most deadly cancer due to late stage of diagnosis and intrinsic resistance to chemotherapy.
- Pemetrexed is a well tolerated 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 PI3K/Akt/mTOR pathway may increase response to chemotherapy.
- Combining sirolimus, an mTOR inhibitor, with pemetrexed could improve patient outcomes.
- Determine the safety, tolerability, PKs, and 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 PBMCs and/or tumor tissues, to determine metabolic changes using PET scans, and measure PKs.
- Adults with refractory or relapsed NSCLC regardless of mTOR pathway activation are permitted to enroll in the trial.
- 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.
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Arun Rajan, M.D.||National Cancer Institute (NCI)|