Sirolimus and Pemetrexed to Treat Non-Small Cell Lung Cancer

Phase 1

Terminated

Conditions: Carcinoma, Non-Small-Cell Lung

Interventions: Drug: FDG-PET
Drug: Pemetrexed
Drug: Sirolimus
Dietary Supplement: Vitamin B12
Dietary Supplement: Folic acid tablets
Drug: Dexamethasone tablets

Registration Number: NCT00923273

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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....

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 42

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment level 3 - 6mg load	Dexamethasone tablets	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 1 - 3mg load	FDG-PET	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m\^2
Treatment level 1 - 3mg load	Vitamin B12	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m\^2
Treatment level 3 - 6mg load	Vitamin B12	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 4 - 10 mg load	Vitamin B12	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m\^2
Treatment level 1 - 3mg load	Folic acid tablets	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m\^2
Treatment level 1 - 3mg load	Dexamethasone tablets	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m\^2
Treatment level 2 - 6 mg load	FDG-PET	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 2 - 6 mg load	Dexamethasone tablets	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 1 - 3mg load	Sirolimus	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m\^2
Treatment level 2 - 6 mg load	Vitamin B12	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 2 - 6 mg load	Folic acid tablets	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 3 - 6mg load	FDG-PET	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 3 - 6mg load	Folic acid tablets	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 5 - 15 mg load	Vitamin B12	Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m\^2
Treatment level 5 - 15 mg load	FDG-PET	Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m\^2
Treatment level 5 - 15 mg load	Pemetrexed	Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m\^2
Treatment level 5 - 15 mg load	Dexamethasone tablets	Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m\^2
Treatment level 4 - 10 mg load	Dexamethasone tablets	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m\^2
Treatment level 5 - 15 mg load	Folic acid tablets	Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m\^2
Treatment level 4 - 10 mg load	FDG-PET	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m\^2
Treatment level 4 - 10 mg load	Folic acid tablets	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m\^2
Treatment level 2 - 6 mg load	Pemetrexed	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 1 - 3mg load	Pemetrexed	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m\^2
Treatment level 2 - 6 mg load	Sirolimus	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 3 - 6mg load	Pemetrexed	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 3 - 6mg load	Sirolimus	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m\^2
Treatment level 4 - 10 mg load	Sirolimus	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m\^2
Treatment level 4 - 10 mg load	Pemetrexed	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m\^2
Treatment level 5 - 15 mg load	Sirolimus	Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m\^2

Primary Outcome Measures

Name	Time	Method
Phase II: Clinical Response Rate	21 weeks	Clinical response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is disappearance of all target lesions. Partial response (PR) at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. Progressive disease (PD) is at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Phase I: Maximum Tolerated Dose (MTD) of Pemetrexed	5 weeks	The phase I component of the study are to determine the safety and tolerability of pemetrexed in human subjects with non small cell lung cancer (NSCLC), and to determine the maximum tolerated dose.
Phase I: Maximum Tolerated Dose (MTD) of Sirolimus	5 weeks	The phase I component of the study are to determine the safety and tolerability of sirolimus in human subjects with non small cell lung cancer (NSCLC), and to determine the maximum tolerated dose.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Serious and Non-Serious Adverse Events	Date treatment consent signed to date off study, approximately 45 months	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.