Sirolimus and Pemetrexed to Treat Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase II Trial of Pemetrexed (Alimta [Registered Trademark]) Combined With Sirolimus (Rapamycin, Rapamune [Registered Trademark]) in Subjects With Relapsed or Refractory NSCLC

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: FDG-PET
* Drug: Pemetrexed
* Drug: Sirolimus
* Dietary Supplement: Vitamin B12
* Dietary Supplement: Folic acid tablets
* Drug: Dexamethasone tablets


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Histologically documented non small cell lung cancer (NSCLC) that is confirmed by the Laboratory of Pathology at the Clinical Center/National Institutes of Health (NIH) or the Laboratory of Pathology at National Naval Medical Center (NNMC). Tumor biopsy will be requested from all study subjects unless the procedure poses too great a risk. If the subject declines, he or she may still participate in the study. We will ask subjects not undergoing biopsy to provide 6 unstained slides or a tissue block of archived tissue for immunohistochemistry (IHC) evaluation. Tumors from subjects enrolling in the phase II portion of the study will be analyzed retrospectively to demonstrate mammalian target of rapamycin (mTOR) activation as assessed by immunohistochemistry in a fresh biopsy. mTOR activation will be defined using distribution and intensity of staining for phosphorylation of mTOR, or its downstream substrates S6 kinase (S6K), and S6. Standard operating procedures (SOPs) describing the acquisition and handling of PBMCs and tissues are outlined in appendix 10.3 and 10.4. At a minimum, a total score (sum of intensity and distribution scores) of 2 for phospho-S6 or phospho-mTOR (S2448) mTOR will be required to determine that mTOR is active. Either measurement will be sufficient to ascertain that mTOR is active. Measurement of phosphorylation of Akt, factor 4E binding protein 1 (4E-BP1), and total levels of thymidylate synthase (TS) will also be measured, but are not part of the eligibility requirements. In the event of limited tissue availability, the stains will be prioritized as follows: S6, mTOR, S6K, Akt (S473), Akt (T308), and TS. Phosphorylation of S6 correlates most closely with mTOR activity, while phosphorylation of mTOR at S2448 best predicts response to sirolimus. Tissue from the time of original diagnosis will be adequate for enrollment on study. Optional fresh tissue biopsy must be obtained AFTER their most recent chemotherapy (including small molecule or targeted therapy) or radiation therapy. Tumors that can be biopsied percutaneously (with or without computed tomography (CT)/ultrasound guidance) or via bronchoscopy will be considered accessible if there are no other competing risk factors such as coagulopathy, hypoxemia, unstable cardiovascular disease, uncontrolled pain, or inability to give informed consent. Individuals with relapsed NSCLC who have received at least one standard chemotherapeutic regimen are eligible. Patients who received adjuvant chemotherapy and then relapse or recur less than or equal to 12 months after completion of chemotherapy will be eligible. Patients who received adjuvant chemotherapy and relapse greater than 12 months after completion of chemotherapy should receive frontline therapy for metastatic disease before enrollment, as should individuals who initially present with incurable disease that is chemotherapy naive. Individuals unwilling to receive standard front line therapy for metastatic lung cancer may enroll. Patients must have not received any chemotherapy, biological, or radiation therapy in the 21 days prior to protocol enrollment. All previous chemo and radiation therapy induced toxicities must have resolved to grade 1 or less prior to enrollment. Because sirolimus may affect the efficacy of hormonal birth control via cytochrome P450 3A4 (CYP 3A4), study subjects of child bearing potential must be willing to use barrier birth control while receiving sirolimus therapy and for 12 weeks after discontinuation of sirolimus. Patients must have measurable disease for the phase II portion of the study. Age greater than or equal to 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2. An expected survival of at least 3 months. Patients must have the capacity to provide informed consent and demonstrate willingness to comply with an oral regimen. Patients must have normal organ and marrow function as defined below: Absolute neutrophil count greater than or equal to 1,500/mL. Platelets greater than or equal 100,000/mL. Total bilirubin less than 1.5 times upper limit of institutional normal. Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT) less than 2.5 times upper limit of institutional normal. Alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) less than 2.5 times upper limit of institutional normal. Creatinine Estimated creatinine clearance as calculated using the modification of diet in renal disease (MDRD) equation must be greater than or equal to 60ml/min/1.73m^2. The formula to be used is MDRD: 186 times (Scr)(-1.154) times (Age)(0.203) times (0.742 if female) times (1.212 if African American) Serum triglycerides less than or equal to 2.5 times upper limit of normal; serum cholesterol less than or equal 300 mg/dl (includes subjects with familial and acquired hyperlipidemia). 13. Subjects on steroids must be on a stable or tapering dose of less than or equal 20 mg/day of prednisone (or equivalent dose of another glucocorticoid) for at least one week prior to study entry. EXCLUSION CRITERIA: Human immunodeficiency virus (HIV) positive patients. Pregnant or lactating women. Patients who received pemetrexed previously for Phase 1 only. Patients with prior pemetrexed are eligible for Phase 2. Patients who have had prior therapy with mTOR inhibitors such as sirolimus or its analogues within six months. Any concurrent therapy with chemotherapeutic agents or biologic agents or radiation therapy. Subjects with brain metastases may participate if the metastases are asymptomatic. Subjects are ineligible if brain metastases are symptomatic. Patients who are on the following drugs that modulate CYP3A4 and cannot replace these medications with other equivalent medications for the period of the study: amprenavir, atazanavir, bromocriptine, cimetidine, clarithromycin, clotrimazole, cyclosporine, danazol, diltiazem, erythromycin, fluconazole, fosamprenavir, other HIV protease inhibitors, indinavir, itraconazole, ketoconazole, metoclopramide, nefazodone, nelfinavir, nicardipine, nifedipine, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), verapamil, voriconazole, nevirapine, rifampicin, rifampin, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital, and St. John's Wort. Subjects taking non steroidal anti-inflammatory agents who are unable to stop or replace the agents for the 5 days prior to and the 2 days after pemetrexed will not be eligible. Patients who have received live vaccines in the past 21 days.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment level 1 - 3mg load<br>Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2 | Drug: FDG-PET<br>* PET CT will be performed at baseline and after two cycles of treatment.<br>* Other names: fluorodeoxyglucose positron emission tomography;Drug: Pemetrexed<br> <br> Drug: Sirolimus<br> <br> Dietary Supplement: Vitamin B12<br>* 1000 micrograms intramuscularly every 63 days administered the preceding first dose of pemetrexed<br>* Other names: Cobalamin;Dietary Supplement: Folic acid tablets<br>* 1 mg dose every 63 days administered during the week preceding first dose of pemetrexed and will be continued for 21 days following last dose of pemetrexed.<br>* Other names: Folate;Drug: Dexamethasone tablets<br>* 4 mg dose twice daily the day before, the day of, and the day after pemetrexed.<br>* Other names: Decadron;|
| Experimental: Treatment level 2 - 6 mg load<br>Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2 | Drug: FDG-PET<br>* PET CT will be performed at baseline and after two cycles of treatment.<br>* Other names: fluorodeoxyglucose positron emission tomography;Drug: Pemetrexed<br> <br> Drug: Sirolimus<br> <br> Dietary Supplement: Vitamin B12<br>* 1000 micrograms intramuscularly every 63 days administered the preceding first dose of pemetrexed<br>* Other names: Cobalamin;Dietary Supplement: Folic acid tablets<br>* 1 mg dose every 63 days administered during the week preceding first dose of pemetrexed and will be continued for 21 days following last dose of pemetrexed.<br>* Other names: Folate;Drug: Dexamethasone tablets<br>* 4 mg dose twice daily the day before, the day of, and the day after pemetrexed.<br>* Other names: Decadron;|
| Experimental: Treatment level 3 - 6mg load<br>Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2 | Drug: FDG-PET<br>* PET CT will be performed at baseline and after two cycles of treatment.<br>* Other names: fluorodeoxyglucose positron emission tomography;Drug: Pemetrexed<br> <br> Drug: Sirolimus<br> <br> Dietary Supplement: Vitamin B12<br>* 1000 micrograms intramuscularly every 63 days administered the preceding first dose of pemetrexed<br>* Other names: Cobalamin;Dietary Supplement: Folic acid tablets<br>* 1 mg dose every 63 days administered during the week preceding first dose of pemetrexed and will be continued for 21 days following last dose of pemetrexed.<br>* Other names: Folate;Drug: Dexamethasone tablets<br>* 4 mg dose twice daily the day before, the day of, and the day after pemetrexed.<br>* Other names: Decadron;|
| Experimental: Treatment level 4 - 10 mg load<br>Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2 | Drug: FDG-PET<br>* PET CT will be performed at baseline and after two cycles of treatment.<br>* Other names: fluorodeoxyglucose positron emission tomography;Drug: Pemetrexed<br> <br> Drug: Sirolimus<br> <br> Dietary Supplement: Vitamin B12<br>* 1000 micrograms intramuscularly every 63 days administered the preceding first dose of pemetrexed<br>* Other names: Cobalamin;Dietary Supplement: Folic acid tablets<br>* 1 mg dose every 63 days administered during the week preceding first dose of pemetrexed and will be continued for 21 days following last dose of pemetrexed.<br>* Other names: Folate;Drug: Dexamethasone tablets<br>* 4 mg dose twice daily the day before, the day of, and the day after pemetrexed.<br>* Other names: Decadron;|
| Experimental: Treatment level 5 - 15 mg load<br>Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2 | Drug: FDG-PET<br>* PET CT will be performed at baseline and after two cycles of treatment.<br>* Other names: fluorodeoxyglucose positron emission tomography;Drug: Pemetrexed<br> <br> Drug: Sirolimus<br> <br> Dietary Supplement: Vitamin B12<br>* 1000 micrograms intramuscularly every 63 days administered the preceding first dose of pemetrexed<br>* Other names: Cobalamin;Dietary Supplement: Folic acid tablets<br>* 1 mg dose every 63 days administered during the week preceding first dose of pemetrexed and will be continued for 21 days following last dose of pemetrexed.<br>* Other names: Folate;Drug: Dexamethasone tablets<br>* 4 mg dose twice daily the day before, the day of, and the day after pemetrexed.<br>* Other names: Decadron;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Tolerated Dose (MTD) of Pemetrexed | 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. | 5 weeks | 
| Phase II: Clinical Response Rate | 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. | 21 weeks | 
| Phase I: Maximum Tolerated Dose (MTD) of Sirolimus | 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. | 5 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious and Non-Serious Adverse Events | 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. | Date treatment consent signed to date off study, approximately 45 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pemetrexed, Sirolimus, Non-Small Cell Lung Cancer, Phase I/II, mTOR Inhibitor, NSCLC, Lung Cancer