A Phase II Trial of Pemetrexed (Alimta [Registered Trademark]) Combined With Sirolimus (Rapamycin, Rapamune [Registered Trademark]) in Subjects With Relapsed or Refractory NSCLC
- 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
- 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
- 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
- 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
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Phase I endpoints: Primary-Determine the maximum tolerated dose of combination pemetrexed and sirolimus.
Arun Rajan, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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