Carcinoma, Non-Small-Cell Lung Clinical Trial
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
Background:
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 mammalian target of rapamycin
(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.
Objectives:
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.
Eligibility:
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.
Design:
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 computed tomography (CT), positron emission tomography (PET) or
magnetic resonance scans (MRI) scans....
Background:
- Lung cancer is the most deadly cancer due to late stage of diagnosis and intrinsic
resistance to chemotherapy.
- Pemetrexed is a well tolerated Food and Drug Administration (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 phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mTOR pathway
may increase response to chemotherapy.
- Combining sirolimus, an mTOR inhibitor, with pemetrexed could improve patient outcomes.
Objectives:
- Determine the safety, tolerability, pharmacokinetics (PKs), and maximum tolerated dose
(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 peripheral
blood mononuclear cells (PBMCs) and/or tumor tissues, to determine metabolic changes
using PET scans, and measure PKs.
Eligibility:
- Adults with refractory or relapsed NSCLC regardless of mTOR pathway activation are
permitted to enroll in the trial.
Design:
- 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.
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