Sirolimus and Pemetrexed to Treat Non-Small Cell Lung Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00923273
• Collaborator: (none)
• Enrollment: 42
• Location: 1
• Arms: 5
• Actual Duration (Months): 60.3
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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....

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: FDG-PET; Drug: Pemetrexed; Drug: Sirolimus; Dietary Supplement: Vitamin B12; Dietary Supplement: Folic acid tablets; Drug: Dexamethasone tablets	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Actual Study Start Date: Feb 29, 2008
• Actual Primary Completion Date: Mar 10, 2013
• Actual Study Completion Date: Mar 10, 2013

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

1. 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).

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. Patients must have measurable disease for the phase II portion of the study.

8. Age greater than or equal to 18 years of age.

9. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.

10. An expected survival of at least 3 months.

11. Patients must have the capacity to provide informed consent and demonstrate willingness to comply with an oral regimen.

12. 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).

1. 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:

1. Human immunodeficiency virus (HIV) positive patients.

2. Pregnant or lactating women.

3. Patients who received pemetrexed previously for Phase 1 only. Patients with prior pemetrexed are eligible for Phase 2.

4. Patients who have had prior therapy with mTOR inhibitors such as sirolimus or its analogues within six months.

5. Any concurrent therapy with chemotherapeutic agents or biologic agents or radiation therapy.

6. Subjects with brain metastases may participate if the metastases are asymptomatic. Subjects are ineligible if brain metastases are symptomatic.

7. 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.

8. 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.

9. Patients who have received live vaccines in the past 21 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Arun Rajan, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 16, 2012
• Informed Consent Form - Mar 27, 2012

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F, Kalman L, Miller V, Lee JS, Moore M, Gandara D, Karp D, Vokes E, Kris M, Kim Y, Gamza F, Hammershaimb L. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000 Jun;18(12):2354-62. Erratum in: J Clin Oncol. 2004 Jan 1;22(1):209.
• Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ. Cancer statistics, 2005. CA Cancer J Clin. 2005 Jan-Feb;55(1):10-30. Erratum in: CA Cancer J Clin. 2005 Jul-Aug;55(4):259.
• Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8.

• Responsible Party: Arun Rajan, M.D., Principal Investigator, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00923273
• Other Study ID Numbers: 080078; 08-C-0078; NCT00636532
• First Posted: Jun 18, 2009
• Last Update Posted: Nov 26, 2019
• Last Verified: Nov 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Arun Rajan, M.D., Principal Investigator, National Cancer Institute (NCI): Pemetrexed; Sirolimus; Non-Small Cell Lung Cancer; Phase I/II; mTOR Inhibitor; NSCLC; Lung Cancer
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Folic Acid; Vitamin B 12; Hydroxocobalamin; Sirolimus; Dexamethasone; Pemetrexed

Study Results

Participant Flow

Pre-assignment Detail	DL5 wasn't tolerated. We expanded DL4, had 1 DLT of gr. 3 infection that was possibly related to study drugs or his cancer and declining health. The last subject on DL4 had gr. 4 neutropenia that lasted <7days. We believe this wasn't significant and a lack of foresight to add length of neutropenia as DLT. IRB allowed DL4 with DLT stopping rule.

Arm/Group Title	Treatment Level 1: 3mg Load	Treatment Level 2: 6mg Load	Treatment Level 3: 6mg Load	Treatment Level 4: 10mg Load	Treatment Level 5: 15mg Load
Arm/Group Description	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2	Sirolimus 6mg load/2mg/day; Pemetrexed 500mg/m^2	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2	Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2
Period Title: Phase I Treatment Period
STARTED	4	3	3	7	5
COMPLETED	4	3	3	7	5
NOT COMPLETED	0	0	0	0	0
Period Title: Phase I Treatment Period
STARTED	0	0	0	27	0
COMPLETED	0	0	0	20	0
NOT COMPLETED	0	0	0	7	0

Baseline Characteristics

Arm/Group Title	Treatment Level 1: 3mg Load	Treatment Level 2: 6mg Load	Treatment Level 3: 6mg Load	Treatment Level 4: 10 mg Load	Treatment Level 5: 15mg Load	Total
Arm/Group Description	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2	Sirolimus 6mg load/2mg/day; Pemetrexed 500mg/m^2	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2	Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2	Total of all reporting groups
Overall Participants	4	3	3	27	5	42
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 50%	0 0%	1 33.3%	18 66.7%	4 80%	25 59.5%
>=65 years	2 50%	3 100%	2 66.7%	9 33.3%	1 20%	17 40.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.65 (7.84)	71.57 (3.76)	61.7 (24.74)	59.5 (11.48)	56.08 (10.75)	60.6 (11.99)
Sex: Female, Male (Count of Participants)
Female	2 50%	2 66.7%	1 33.3%	14 51.9%	2 40%	21 50%
Male	2 50%	1 33.3%	2 66.7%	13 48.1%	3 60%	21 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 33.3%	1 33.3%	2 7.4%	0 0%	4 9.5%
Not Hispanic or Latino	4 100%	2 66.7%	2 66.7%	25 92.6%	5 100%	38 90.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 33.3%	1 33.3%	4 14.8%	0 0%	6 14.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 33.3%	1 33.3%	4 14.8%	0 0%	6 14.3%
White	4 100%	0 0%	1 33.3%	18 66.7%	5 100%	28 66.7%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 33.3%	0 0%	1 3.7%	0 0%	2 4.8%
Region of Enrollment (Count of Participants)
United States	4 100%	3 100%	3 100%	27 100%	5 100%	42 100%

Outcome Measures

1. Primary Outcome

Title	Phase I: Maximum Tolerated Dose (MTD) of Pemetrexed
Description	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.
Time Frame	5 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Level 1: 3mg Load	Treatment Level 2: 6mg Load	Treatment Level 3: 6mg Load	Treatment Level 4: 10mg Load	Treatment Level 5: 15mg Load
Arm/Group Description	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2 All subjects completed the intervention and phase I outcome measure.	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2 All subjects completed the intervention and phase I outcome measure.	Sirolimus 6mg load/2mg/day; Pemetrexed 500mg/m^2 All subjects completed the intervention and phase I outcome measure.	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2 All subjects completed the intervention and phase I outcome measure.	Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2 All subjects completed the intervention and phase I outcome measure.
Measure Participants	4	3	3	7	5
Number [mg/m^2]	500	500	500	500	500

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Level 1: 3mg Load	Treatment Level 2: 6mg Load	Treatment Level 3: 6mg Load	Treatment Level 4: 10 mg Load	Treatment Level 5: 15mg Load
Arm/Group Description	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2	Sirolimus 6mg load/2mg/day; Pemetrexed 500mg/m^2	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2	Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2
Measure Participants	4	3	3	27	5
Subjects from phase I	4 100%	3 100%	3 100%	7 25.9%	5 100%
8subjects prior peme & 12 subjects peme naive	0 0%	0 0%	0 0%	20 74.1%	0 0%

3. Primary Outcome

Title	Phase II: Clinical Response Rate
Description	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.
Time Frame	21 weeks

Outcome Measure Data

Analysis Population Description

By formal criteria in the protocol, DL4 exceeds the MTD, and DL 3 would be expanded by 3 subjects to confirm it's tolerability. We believe that DL4 is safe, and that the observed DLTs at this DL are related to enrollment of a subject with a borderline performance status, and the omission of defining length of neutropenia as a DLT.

Arm/Group Title	Treatment Level 4: 10mg Load
Arm/Group Description	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2 Includes 8 subjects with prior peme; 12 subjects who were peme naive;and 7 subjects rolled over from ph I
Measure Participants	27
Complete response	0 0%
Partial response	5 125%
Stable disease	13 325%
Progressive disease	2 50%
Not evaluable	7 175%

4. Primary Outcome

Title	Phase I: Maximum Tolerated Dose (MTD) of Sirolimus
Description	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.
Time Frame	5 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment Level 1: 3mg Load	Treatment Level 2: 6mg Load	Treatment Level 3: 6mg Load	Treatment Level 4: 10mg Load	Treatment Level 5: 15mg Load
Arm/Group Description	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2 All subjects completed the intervention and phase I outcome measure.	Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2 All subjects completed the intervention and phase I outcome measure.	Sirolimus 6mg load/2mg/day; Pemetrexed 500mg/m^2 All subjects completed the intervention and phase I outcome measure.	Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2 All subjects completed the intervention and phase I outcome measure.	Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2 All subjects completed the intervention and phase I outcome measure.
Measure Participants	4	3	3	7	5
Number [mg/m^2]	10	10	10	10	10

Adverse Events

Time Frame	Date treatment consent signed to date off study, approximately 45 months.
Arm/Group Title	Treatment Level 1: 3mg Load		Treatment Level 2: 6mg Load		Treatment Level 3: 6mg Load		Treatment Level 4: 10 mg Load		Treatment Level 5: 15mg Load
Arm/Group Description	Sirolimus 3mg load/1mg/day; Pemetrexed 375mg/m^2		Sirolimus 6mg load/2mg/day; Pemetrexed 375mg/m^2		Sirolimus 6mg load/2mg/day; Pemetrexed 500mg/m^2		Sirolimus 10mg load/3mg/day; Pemetrexed 500mg/m^2		Sirolimus 15mg load/5mg/day; Pemetrexed 500mg/m^2
All Cause Mortality
	Treatment Level 1: 3mg Load		Treatment Level 2: 6mg Load		Treatment Level 3: 6mg Load		Treatment Level 4: 10 mg Load		Treatment Level 5: 15mg Load
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		00/3 (0%)		1/3 (33.3%)		0/27 (0%)		00/5 (0%)
Serious Adverse Events
	Treatment Level 1: 3mg Load		Treatment Level 2: 6mg Load		Treatment Level 3: 6mg Load		Treatment Level 4: 10 mg Load		Treatment Level 5: 15mg Load
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/4 (50%)		1/3 (33.3%)		0/3 (0%)		7/27 (25.9%)		1/5 (20%)
Blood and lymphatic system disorders
Edema: limb	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Lymphopenia	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	2
Neutrophils/granulocytes (ANC/AGC)	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
CD4 count	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Gastrointestinal disorders
Nausea	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	2	0/5 (0%)	0
Vomiting	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	4	0/5 (0%)	0
Constipation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
General disorders
Fatigue (asthenia, lethargy, malaise)	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Death not associated with CTCAE term: Disease progression NOS	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Infections and infestations
Febrile neutropenia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Infection	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils: lung (pneumonia)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Metabolism and nutrition disorders
Magnesium, serum-high (hypermagnesemia)	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
ALT, SGPT (serum glutamic pyruvic transaminase)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	1/5 (20%)	1
Cholesterol, serum-high (hypercholesteremia)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Creatinine	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Triglyceride, serum-high (hypertriglyceridemia)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Magnesium, serum-low (hypomagnesemia)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Nervous system disorders
Somnolence/depressed level of consciousness	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Pulmonary/Upper respiratory - Other (specify, pulmonary infiltrate, right lung)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Bronchospasm, wheezing	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Other (Not Including Serious) Adverse Events
	Treatment Level 1: 3mg Load		Treatment Level 2: 6mg Load		Treatment Level 3: 6mg Load		Treatment Level 4: 10 mg Load		Treatment Level 5: 15mg Load
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		3/3 (100%)		3/3 (100%)		27/27 (100%)		5/5 (100%)
Blood and lymphatic system disorders
Edema: limb	1/4 (25%)	4	1/3 (33.3%)	1	0/3 (0%)	0	4/27 (14.8%)	4	2/5 (40%)	3
Edema: trunk/genital	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Leukocytes (total WBC)	1/4 (25%)	7	2/3 (66.7%)	4	3/3 (100%)	5	9/27 (33.3%)	23	2/5 (40%)	8
Lymphopenia	3/4 (75%)	14	2/3 (66.7%)	15	3/3 (100%)	3	17/27 (63%)	49	5/5 (100%)	29
Neutrophils/granulocytes (ANC/AGC)	1/4 (25%)	4	2/3 (66.7%)	2	2/3 (66.7%)	4	10/27 (37%)	20	2/5 (40%)	7
PTT (Partial thromboplastin time)	2/4 (50%)	6	1/3 (33.3%)	2	3/3 (100%)	11	3/27 (11.1%)	7	4/5 (80%)	7
Platelets	1/4 (25%)	7	2/3 (66.7%)	5	3/3 (100%)	4	9/27 (33.3%)	17	4/5 (80%)	9
CD4 count	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	15/27 (55.6%)	37	3/5 (60%)	4
INR (International Normalized Ratio of prothrombin time)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	2	0/5 (0%)	0
Edema: head and neck	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	5/27 (18.5%)	7	0/5 (0%)	0
Cardiac disorders
Supraventricular and nodal arrhythmia: sinus tachycardia	2/4 (50%)	2	1/3 (33.3%)	1	0/3 (0%)	0	4/27 (14.8%)	4	1/5 (20%)	1
Cardiac troponin I (cTnl)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Supraventricular and nodal arrhythmia: atrial fibrillation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	1/5 (20%)	1
Hypotension	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	2/27 (7.4%)	2	0/5 (0%)	0
Cardiac arrhythmia (Other (Specify, tavhycardia)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Hypertension	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	3/27 (11.1%)	4	0/5 (0%)	0
Ear and labyrinth disorders
Auditory/Ear - Other (Specify, hearing loss right side)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Tinnitus	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Auditory/Ear - Other (Specify, congestion R/ear)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Eye disorders
Dry eye syndrome	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Watery eye (epiphora, tearing)	2/4 (50%)	2	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Ocular surface disease	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Pain: eye	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Vision-blurred vision	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	3	1/27 (3.7%)	1	0/5 (0%)	0
Uveitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	2	0/5 (0%)	0
Gastrointestinal disorders
Anorexia	1/4 (25%)	1	1/3 (33.3%)	1	0/3 (0%)	0	16/27 (59.3%)	19	4/5 (80%)	7
Constipation	1/4 (25%)	1	2/3 (66.7%)	2	0/3 (0%)	0	2/27 (7.4%)	2	1/5 (20%)	2
Diarrhea	2/4 (50%)	4	0/3 (0%)	0	0/3 (0%)	0	13/27 (48.1%)	15	2/5 (40%)	2
Distention/bloating, abdominal	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	0/5 (0%)	0
Flatulence	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	0/5 (0%)	0
Gastrointestinal - Other (Specify, bloating)	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Mucositis/stomatitis (clinical exam): oral cavity	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	6/27 (22.2%)	9	2/5 (40%)	2
Nausea	2/4 (50%)	3	0/3 (0%)	0	0/3 (0%)	0	14/27 (51.9%)	16	4/5 (80%)	5
Pain: Abdomen NOS	1/4 (25%)	1	0/3 (0%)	0	1/3 (33.3%)	1	6/27 (22.2%)	8	0/5 (0%)	0
Pain: oral cavity	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	0/5 (0%)	0
Vomiting	1/4 (25%)	2	1/3 (33.3%)	3	1/3 (33.3%)	1	9/27 (33.3%)	13	3/5 (60%)	6
Pain: rectum	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation)	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/27 (0%)	0	0/5 (0%)	0
Ascites (non-malignant)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Dry mouth/salivary gland (xerostomia)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	0/5 (0%)	0
Dysphagia (difficulty swallowing)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	5/27 (18.5%)	6	0/5 (0%)	0
Mucositis/stomatitis (functional/symptomatic): oral cavity	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	4/27 (14.8%)	4	0/5 (0%)	0
Pain: dental/teeth/periodontal	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Taste alteration (dysgeusia)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	5/27 (18.5%)	5	1/5 (20%)	1
Gastrointestinal - Other (Specify, early satiety)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Pain: Anus	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Pain: Stomach	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/27 (0%)	0	0/5 (0%)	0
Dehydration	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	3/27 (11.1%)	3	3/5 (60%)	3
Esophagitis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	2	0/5 (0%)	0
Heartburn/dyspepsia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	5/27 (18.5%)	8	1/5 (20%)	1
General disorders
Fatigue (asthenia, lethargy, malaise)	2/4 (50%)	3	1/3 (33.3%)	1	0/3 (0%)	0	18/27 (66.7%)	27	5/5 (100%)	13
Fever	2/4 (50%)	2	1/3 (33.3%)	1	1/3 (33.3%)	1	8/27 (29.6%)	9	1/5 (20%)	1
Insomnia	3/4 (75%)	4	0/3 (0%)	0	0/3 (0%)	0	3/27 (11.1%)	3	2/5 (40%)	2
Pain - Other (Specify, L rib; R costal margin; shoulder)	2/4 (50%)	3	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Rigors/chills	1/4 (25%)	1	1/3 (33.3%)	1	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Sweating (diaphoresis)	1/4 (25%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	2/27 (7.4%)	2	0/5 (0%)	0
Pain: Other (Specify)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	3/27 (11.1%)	5	0/5 (0%)	0
Weight gain	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Weight loss	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	7/27 (25.9%)	10	0/5 (0%)	0
Pain - Other (Specify, left elbow; left flank; left trunk)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	3
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	3/27 (11.1%)	3	1/5 (20%)	1
Infections and infestations
Infection - Other (Specify, pneumonia)	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Infection - Other (Specify, URI)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	0/5 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils: bladder (urinary)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils: oral cavity-gums (gingivitis)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	3	0/5 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils: sinus	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils: skin (cellulitis)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Infection (documented clinically or microbiologically) with Grade 3 or 4	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Febrile neutropenia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils: Lung (pneumonia)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils: Rectum	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Infection with unknown ANC: Lung (pneumonia)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Infection with unknown ANC: Skin (cellulitis)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Infection with unknown ANC: upper airway NOS	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	1/4 (25%)	7	2/3 (66.7%)	4	1/3 (33.3%)	1	6/27 (22.2%)	20	3/5 (60%)	13
AST/SGOT (serum glutamic oxaloacetic transaminase)	3/4 (75%)	9	2/3 (66.7%)	2	0/3 (0%)	0	5/27 (18.5%)	11	3/5 (60%)	10
Albumin, serum-low (hypoalbuminemia)	2/4 (50%)	11	3/3 (100%)	14	3/3 (100%)	8	7/27 (25.9%)	16	5/5 (100%)	13
Alkaline phosphatase	4/4 (100%)	7	2/3 (66.7%)	3	1/3 (33.3%)	2	3/27 (11.1%)	6	2/5 (40%)	5
Calcium, serum-high (hypercalcemia)	2/4 (50%)	5	1/3 (33.3%)	1	1/3 (33.3%)	2	3/27 (11.1%)	16	1/5 (20%)	1
Cholesterol, serum-high (hypercholesteremia)	1/4 (25%)	2	2/3 (66.7%)	3	1/3 (33.3%)	2	4/27 (14.8%)	10	2/5 (40%)	2
Creatinine	1/4 (25%)	8	1/3 (33.3%)	1	1/3 (33.3%)	1	3/27 (11.1%)	5	3/5 (60%)	12
GGT (gamma-Glutamyl transpeptidase)	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Glomerular filtration rate	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	2
Glucose, serum-high (hyperglycemia)	1/4 (25%)	16	2/3 (66.7%)	2	1/3 (33.3%)	1	9/27 (33.3%)	32	4/5 (80%)	14
Glucose, serum-low (hypoglycemia)	1/4 (25%)	1	1/3 (33.3%)	2	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Hemoglobin	3/4 (75%)	23	3/3 (100%)	17	3/3 (100%)	6	12/27 (44.4%)	26	5/5 (100%)	34
Magnesium, serum-high (hypermagnesemia)	2/4 (50%)	3	1/3 (33.3%)	5	0/3 (0%)	0	5/27 (18.5%)	10	2/5 (40%)	2
Magnesium, serum-low (hypomagnesemia)	2/4 (50%)	8	1/3 (33.3%)	3	1/3 (33.3%)	2	11/27 (40.7%)	22	4/5 (80%)	10
Phosphate, serum-low (hypophosphatemia)	2/4 (50%)	14	2/3 (66.7%)	5	1/3 (33.3%)	2	13/27 (48.1%)	36	3/5 (60%)	7
Potassium, serum-low (hypokalemia)	1/4 (25%)	4	1/3 (33.3%)	5	0/3 (0%)	0	2/27 (7.4%)	4	2/5 (40%)	3
Proteinuria	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	2/5 (40%)	3
Sodium, serum-high (hypernatremia)	1/4 (25%)	3	0/3 (0%)	0	1/3 (33.3%)	1	0/27 (0%)	0	0/5 (0%)	0
Sodium, serum-low (hyponatremia)	4/4 (100%)	6	2/3 (66.7%)	13	1/3 (33.3%)	2	11/27 (40.7%)	32	4/5 (80%)	11
Triglyceride, serum-high (hypertriglyceridemia)	1/4 (25%)	4	2/3 (66.7%)	2	1/3 (33.3%)	1	2/27 (7.4%)	4	1/5 (20%)	1
Uric acid, serum-high (hyperuricemia)	1/4 (25%)	2	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
CPK (creatine phosphokinase)	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/27 (7.4%)	3	0/5 (0%)	0
Bicarbonate, serum-low	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/27 (3.7%)	3	1/5 (20%)	1
Lipase	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	6	1/5 (20%)	1
Bilirubin (hyperbilirubinemia)	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Calcium, serum-low (hypocalcemia)	0/4 (0%)	0	1/3 (33.3%)	3	0/3 (0%)	0	3/27 (11.1%)	3	0/5 (0%)	0
Musculoskeletal and connective tissue disorders
Pain: Bone	1/4 (25%)	3	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Pain: extremity-limb	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Pain: back	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	3/27 (11.1%)	3	0/5 (0%)	0
Pain: joint	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	3/27 (11.1%)	4	0/5 (0%)	0
Muscle weakness, genralized or specific area (not due to neuropathy): extraocular	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Muscle weakness, genralized or specific area (not due to neuropathy): extremity-lower	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	3/27 (11.1%)	4	0/5 (0%)	0
Muscle weakness, genralized or specific area (not due to neuropathy): whole body/generalized	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	0/5 (0%)	0
Pain: chest wall	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	5/27 (18.5%)	8	1/5 (20%)	1
Pain: chest/thorax NOS	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Pain: muscle	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Nervous system disorders
Cognitive disturbance	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Confusion	1/4 (25%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	2/27 (7.4%)	2	0/5 (0%)	0
Mood alteration: anxiety	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	2/5 (40%)	2
Mood alteration: depression	1/4 (25%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/27 (0%)	0	2/5 (40%)	2
Neuropathy: sensory	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	4/27 (14.8%)	4	1/5 (20%)	1
Somnolence/depressed level of consciousness	1/4 (25%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Speech impairment (e.g., dysphagia or aphasia)	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Tremor	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Dizziness	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/27 (7.4%)	2	2/5 (40%)	2
Pain: head/headache	0/4 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	6/27 (22.2%)	6	2/5 (40%)	2
Seizure	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
CNS cerebrovascular ischemia	0/4 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/27 (0%)	0	0/5 (0%)	0
Pain: neuralgia/peripheral nerve	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Personality/behavioral	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Memory impairment	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/27 (7.4%)	3	0/5 (0%)	0
Mood alteration:agitation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	0/5 (0%)	0
Renal and urinary disorders
Renal/Genitourinary - Other (Specify, renal insufficiency)	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Urinary frequency/urgency	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	4/27 (14.8%)	4	0/5 (0%)	0
Renal/Genitourinary - Other (Specify, ARI)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Urine color change	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Renal failure	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Hemoglobinuria	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	2/5 (40%)	2
Reproductive system and breast disorders
Pain: pelvis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	2	0/5 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/4 (25%)	1	1/3 (33.3%)	1	0/3 (0%)	0	6/27 (22.2%)	6	2/5 (40%)	3
Dyspnea (shortness of breath)	1/4 (25%)	1	2/3 (66.7%)	2	0/3 (0%)	0	7/27 (25.9%)	10	3/5 (60%)	5
FEV(1)	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Hemorrhage/Bleeding - Other (Specify, nose)	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Pneumonitis/pulmonary infiltrates	1/4 (25%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	4/27 (14.8%)	4	2/5 (40%)	2
Vital capacity	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Atelectasis	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Bronchospasm, wheezing	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	2	1/5 (20%)	1
Hiccoughs (hiccups, singultus)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Pain: throat/pharynx/larynx	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	5/27 (18.5%)	7	2/5 (40%)	2
Voice changes/dysarthia (e.g., hoarseness, loss or alteration in voice, laryngitis)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	0/5 (0%)	0
Pulmonary/Upper respiratory - Other (Specify, mild drain. from podt throat)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Hemorrhage, pulmonary/upper respiratory:bronchopulmonary NOS	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Hypoxia	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	6/27 (22.2%)	6	2/5 (40%)	3
Pleural effusion (non-malignant)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	3/27 (11.1%)	5	1/5 (20%)	1
Pulmonary/Upper respiratory - Other (Specify, pulmonary infiltrates)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Hemorrhage, pulmonary/upper respiratory: nose	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	1/5 (20%)	1
Hemorrhage, pulmonary/upper respiratory: Bronchus	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Obstruction/stenosis of airway: Bronchus	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Skin and subcutaneous tissue disorders
Pruritis/itching	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	5/27 (18.5%)	5	1/5 (20%)	1
Rash/desquamation	1/4 (25%)	2	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	1/5 (20%)	1
Rash/acneiform	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	11/27 (40.7%)	12	2/5 (40%)	2
Photosensitivity	0/4 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/27 (0%)	0	0/5 (0%)	0
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Dermatology/Skin - Other (Specify, decubitus)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Nail changes	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	1/5 (20%)	1
Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	3/27 (11.1%)	3	1/5 (20%)	1
Flushing	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	1/5 (20%)	1
Hyperpigmentation	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/27 (7.4%)	2	0/5 (0%)	0
Ulceration	0/4 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0
Vascular disorders
Thrombosis/embolism (vascular access-related)	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	0/27 (0%)	0	1/5 (20%)	1
Thrombosis/thrombus/embolism	1/4 (25%)	1	0/3 (0%)	0	0/3 (0%)	0	1/27 (3.7%)	1	0/5 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.