Phase II Study Alimta and Gemzar + Avastin as First Line Chemotherapy for Elderly Patients With Stage IIIB/IV NSCLC

• Sponsor: Accelerated Community Oncology Research Network (Other)
• Overall Status: Completed
• CT.gov ID: NCT00517595
• Collaborator: Eli Lilly and Company (Industry), Genentech, Inc. (Industry)
• Enrollment: 48
• Locations: 10
• Duration (Months): 44
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective is to determine the progression free survival with pemetrexed, and gemcitabine plus bevacizumab as first-line chemotherapy in elderly patients with Stage IIIB/IV non-small cell lung cancer (NSCLC).

The secondary objectives are to determine the overall response rate; overall survival; chemotherapy induced toxicity profile of this combination; time to progression; and patient reported symptom burden.

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer	Drug: Pemetrexed and Gemcitabine plus Bevacizumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Pemetrexed and Gemcitabine Plus Bevacizumab as First Line Chemotherapy for Elderly Patients With Stage IIIB/IV Non-Small Cell Lung Cancer
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Apr 1, 2011

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first, assessed up to 15 months.]

   PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. Progression is defined per RECIST criteria v1.0 as a measurable increase in the smallest diameter of any target lesion, progression of existing non-target lesions, or the appearance of 1 or more new lesions. The median progression free survival is the parameter used to describe PFS.

Secondary Outcome Measures

1. Time to Progression (TTP) [TTP was measured from day 1 of treatment until time of progression (assessed every 8 weeks), assessed up to 15 months.]

   Time to progression is defined as the time from treatment start until objective tumor progression. Progression is defined per RECIST criteria v1.0 as a measurable increase in the smallest diameter of any target lesion, progression of existing non-target lesions, or the appearance of 1 or more new lesions. The median time to progression is the parameter used to describe TTP.

2. Overall Survival (OS) [OS was measured from day 1 of treatment until time of death, assessed up to 20 months.]

   Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS.

3. Overall Response [Response to treatment was assessed after every 8 weeks of treatment, up to 50 weeks.]

   Response was evaluated via changes from baseline in radiological tumor measurements performed after every 4th treatment cycle and at the end of treatment or time of progression. Response was evaluated using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of >=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions.

Other Outcome Measures

1. Progression Free Survival (PFS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status [PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first, assessed up to 15 months.]

   PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. The median progression free survival is the parameter used to describe PFS. ECOG performance status describes how daily living activities of the patient are affected by disease. ECOG of 0 means the patient is fully active without restriction. ECOG of 1 means the patient is restricted in physically strenuous activity but is able to carry out light work. The investigator assigned the ECOG score at baseline (i.e., before the patient started study treatment).

2. Overall Survival (OS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status [OS was measured from day 1 of treatment until time of death, assessed up to 20 months.]

   Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS. ECOG performance status describes how daily living activities of the patient are affected by disease. ECOG of 0 means the patient is fully active without restriction. ECOG of 1 means the patient is restricted in physically strenuous activity but is able to carry out light work. The investigator assigned the ECOG score at baseline (i.e., before the patient started study treatment).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patient provides voluntary written informed consent before performance of any study-related procedure not part of normal medical care.

• Patient ≥ 65 years of age with ECOG of 0 to 1

• Patient must have histologically/cytologically confirmed Stage IIIB/IV NSCLC.

• Patient has measurable disease defined as at least 1 lesion that can be accurately measured in at least 1 dimension (by CT or MRI) & used to assess response as defined by RECIST criteria. Tumors within a previously irradiated field will be designated nontarget lesions.

• Patient has not received radiotherapy within 2 weeks(4 weeks required for brain metastases radiotherapy)of initial chemotherapy dosing for this study, and all acute toxicities due to prior radiotherapy have resolved prior to initial chemotherapy dosing.

• Patient has a negative serum pregnancy test or has undergone hysterectomy at time of enrollment.

• Greater than 12 weeks life expectancy.

• Patient has recovered from any recent surgery for at least 30 days & is free of active infection requiring antibiotics.

• Patient must be willing/able to discontinue use of NSAIDS prior to study drug dosing.

• Patient must be able to take folic acid, Vitamin B12, & dexamethasone per protocol.

• Patient must exhibit no greater than Grade 1 peripheral neuropathy.

Exclusion Criteria:

• Prior systemic or other concurrent chemo for metastatic NSCLC(Prior Tarceva is not allowed).Prior adjuvant chemo acceptable as long as > 12 months since completion and no prior pemetrexed, gemcitabine or bevacizumab.

• Lung carcinoma of squamous cell histology(mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is ineligible; sputum cytology alone is acceptable.Patients with extrathoracic-only squamous cell NSCLC are eligible.Patients with only peripheral lung lesions (of any NSCLC histology) will also be eligible(a peripheral lesion is defined as a lesion in which the epicenter of the tumor is ≤ 2 cm from the costal or diaphragmatic pleura in a three-dimensional orientation based on each lobe of the lung and is > 2 cm from the trachea, main, and lobar bronchi).

• Hemoptysis within 1 month prior to study enrollment

• Ongoing treatment with full-dose warfarin or its equivalent i.e., unfractionated and/or low molecular weight heparin.(Low dose warfarin 1 mg given for prophylaxis is allowed).

• Hypersensitivity to any component of Alimta, gemcitabine &/or bevacizumab, &/or cannot tolerate folic acid, corticosteroids or Vitamin B12 supplements.

• Currently/have recently taken long-acting NSAID (Ibuprofen ≤ 400 mg QID acceptable) or aspirin (>325mg/day) within 5 days of initial pemetrexed administration.

• Clinically significant pericardial/pleural effusion or ascites unless able to be drained before study entry.

• Presence of third space fluid which cannot be controlled by drainage.

• Core biopsy/other minor surgical procedure(excluding placement of a vascular access device)within 7 days prior to study enrollment.

• Active infection or fever ≥ 38.5°C within 3 days of first scheduled day of protocol treatment.

• Serious, non-healing wound, ulcer, or untreated bone fracture.

• NYHA Grade II or greater CHF

• Inadequately controlled hypertension (defined as systolic blood pressure > 150 &/or diastolic blood pressure > 100mmHg on antihypertensive meds)

• Any prior history of hypertensive crisis or hypertensive encephalopathy.

• History of MI, CVA, TIA, or unstable angina within 6 months of study enrollment.

• Significant vascular disease (aortic aneurysm, aortic dissection or recent peripheral arterial thrombosis.)

• Symptomatic peripheral vascular disease

• Known bleeding diathesis or coagulopathy

• Presence of CNS(central nervous system) except for treated brain metastases. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging(MRI or CT)during the screening period.Anticonvulsants(stable dose)are allowed.Treatment for brain metastases may include whole brain radiotherapy(WBRT),radiosurgery(RS;Gamma Knife,LINAC,or equivalent)or a combination as deemed appropriate by the treating physician.Radiotherapy must be completed at least 4 weeks prior to study enrollment and all acute radiotherapy toxicities resolved.Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded.

• A major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study.

• Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to enrollment.

• History of prior malignancy within the past 5 years except for curatively treated basal cell carcinoma of the skin, cervical intra-epithelial neoplasia, or localized prostate cancer with a current prostate specific antigen of < 1.0 mg/dL on 2 successive evaluations, at least 3 months apart, with the most recent evaluation no more than 4 weeks prior to entry.

• Have received radiotherapy to more than 25% of their bone marrow.

• Receiving concurrent investigational therapy or has received investigational therapy within 30 days of the first scheduled day of protocol treatment

• Pregnant/lactating.

• Any other medical condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate/participate in the study, or interfere with interpretation of the results.

• History of allogeneic transplant.

• Known HIV infection or Hepatitis B or C.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical Oncology & Hematology	Waterbury	Connecticut	United States	06708
2	Augusta Oncology Associates	Augusta	Georgia	United States	30901
3	Central Georgia Cancer Care	Macon	Georgia	United States	31201
4	Northwest Georgia Oncology Center	Marietta	Georgia	United States	30060
5	Hematology Oncology Centers of the Northern Rockies	Billings	Montana	United States	59101
6	Tri-County Oncology Hematology Associates	Canton	Ohio	United States	44718
7	Pacific Oncology, PC	Portland	Oregon	United States	97225
8	Pennsylvania Oncology Hematology Associates	Philadelphia	Pennsylvania	United States	19106
9	The West Clinic	Memphis	Tennessee	United States	38120
10	Cancer Specialists of Tidewater	Chesapeake	Virginia	United States	23320

Sponsors and Collaborators

• Accelerated Community Oncology Research Network
• Eli Lilly and Company
• Genentech, Inc.

Investigators

• Principal Investigator: Johnetta L Blakely, MD, Accelerated Community Oncology Research Network

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Accelerated Community Oncology Research Network
• ClinicalTrials.gov Identifier: NCT00517595
• Other Study ID Numbers: ALJBNSCLC0602
• First Posted: Aug 17, 2007
• Last Update Posted: Mar 12, 2012
• Last Verified: Mar 1, 2012

• Keywords provided by Accelerated Community Oncology Research Network: Non-Small Cell Lung Cancer
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Gemcitabine; Bevacizumab; Pemetrexed

Study Results

Participant Flow

Recruitment Details	9 community oncology research sites across the US within the ACORN network participated in this study. Enrollment started in August 2007 and was completed in September 2009.
Pre-assignment Detail	Informed consent was obtained from all subjects. All subjects underwent screening procedures to verify eligibility.

Arm/Group Title	Pemetrexed, Gemcitabine, and Bevacizumab
Arm/Group Description	All subjects received treatment with pemetrexed 500 mg/m^2, gemcitabine 1500 mg/m^2, and bevacizumab 10 mg/kg every 2 weeks.
Period Title: Overall Study
STARTED	48
COMPLETED	48
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Pemetrexed, Gemcitabine, and Bevacizumab
Arm/Group Description	All subjects received treatment with pemetrexed 500 mg/m^2, gemcitabine 1500 mg/m^2, and bevacizumab 10 mg/kg every 2 weeks.
Overall Participants	48
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	0 0%
>=65 years	48 100%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72.60 (5.20)
Sex: Female, Male (Count of Participants)
Female	21 43.8%
Male	27 56.3%
Region of Enrollment (participants) [Number]
United States	48 100%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. Progression is defined per RECIST criteria v1.0 as a measurable increase in the smallest diameter of any target lesion, progression of existing non-target lesions, or the appearance of 1 or more new lesions. The median progression free survival is the parameter used to describe PFS.
Time Frame	PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first, assessed up to 15 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pemetrexed, Gemcitabine, and Bevacizumab
Arm/Group Description	All subjects received treatment with pemetrexed 500 mg/m^2, gemcitabine 1500 mg/m^2, and bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	48
Median (95% Confidence Interval) [Months]	4.90

2. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time to progression is defined as the time from treatment start until objective tumor progression. Progression is defined per RECIST criteria v1.0 as a measurable increase in the smallest diameter of any target lesion, progression of existing non-target lesions, or the appearance of 1 or more new lesions. The median time to progression is the parameter used to describe TTP.
Time Frame	TTP was measured from day 1 of treatment until time of progression (assessed every 8 weeks), assessed up to 15 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pemetrexed, Gemcitabine, and Bevacizumab
Arm/Group Description	All subjects received treatment with pemetrexed 500 mg/m^2, gemcitabine 1500 mg/m^2, and bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	48
Median (95% Confidence Interval) [Months]	5.56

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS.
Time Frame	OS was measured from day 1 of treatment until time of death, assessed up to 20 months.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pemetrexed, Gemcitabine, and Bevacizumab
Arm/Group Description	All subjects received treatment with pemetrexed 500 mg/m^2, gemcitabine 1500 mg/m^2, and bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	48
Median (95% Confidence Interval) [Months]	8.78

4. Secondary Outcome

Title	Overall Response
Description	Response was evaluated via changes from baseline in radiological tumor measurements performed after every 4th treatment cycle and at the end of treatment or time of progression. Response was evaluated using RECIST version 1.0 guidelines, where complete response (CR) is the disappearance of all target lesions; partial response (PR) is >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD) is neither sufficient shrinkage in sum of LD of target lesions to be PR nor increase of >=20%; Progressive Disease (PD) is the increase in existing lesions or new lesions.
Time Frame	Response to treatment was assessed after every 8 weeks of treatment, up to 50 weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pemetrexed, Gemcitabine, and Bevacizumab
Arm/Group Description	All subjects received treatment with pemetrexed 500 mg/m^2, gemcitabine 1500 mg/m^2, and bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	48
Complete response (CR)	0 0%
Partial response (PR)	17 35.4%
Stable disease (SD)	21 43.8%
Progressive disease (PD)	6 12.5%
Not evaluable (NE)	4 8.3%

5. Other Pre-specified Outcome

Title	Progression Free Survival (PFS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status
Description	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. The median progression free survival is the parameter used to describe PFS. ECOG performance status describes how daily living activities of the patient are affected by disease. ECOG of 0 means the patient is fully active without restriction. ECOG of 1 means the patient is restricted in physically strenuous activity but is able to carry out light work. The investigator assigned the ECOG score at baseline (i.e., before the patient started study treatment).
Time Frame	PFS was measured from day 1 of treatment until time of progression (assessed every 8 weeks) or death, whichever came first, assessed up to 15 months.

Outcome Measure Data

Analysis Population Description

Note that N=18 patients for the Baseline ECOG performance status 0 group, and N=30 patients for the Baseline ECOG performance status 1 group.

Arm/Group Title	Pemetrexed, Gemcitabine, and Bevacizumab
Arm/Group Description	All subjects received treatment with pemetrexed 500 mg/m^2, gemcitabine 1500 mg/m^2, and bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	48
Baseline ECOG performance status 0 (N=18)	7.57
Baseline ECOG performance status 1 (N=30)	4.67

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pemetrexed, Gemcitabine, and Bevacizumab
	Comments	Within Group 1 (N=48), patients with an ECOG of 0 at baseline (N=18) were compared to patients with an ECOG of 1 at baseline (N=30).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Log Rank
	Comments

6. Other Pre-specified Outcome

Title	Overall Survival (OS) by Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status
Description	Overall survival is defined as the time from treatment start until death from any cause. The median overall survival time is used to measure OS. ECOG performance status describes how daily living activities of the patient are affected by disease. ECOG of 0 means the patient is fully active without restriction. ECOG of 1 means the patient is restricted in physically strenuous activity but is able to carry out light work. The investigator assigned the ECOG score at baseline (i.e., before the patient started study treatment).
Time Frame	OS was measured from day 1 of treatment until time of death, assessed up to 20 months.

Outcome Measure Data

Analysis Population Description

Note that N=18 patients for the Baseline ECOG performance status 0 group, and N=30 patients for the Baseline ECOG performance status 1 group.

Arm/Group Title	Pemetrexed, Gemcitabine, and Bevacizumab
Arm/Group Description	All subjects received treatment with pemetrexed 500 mg/m^2, gemcitabine 1500 mg/m^2, and bevacizumab 10 mg/kg every 2 weeks.
Measure Participants	48
Baseline ECOG performance status 0 (N=18)	19.87
Baseline ECOG performance status 1 (N=30)	6.71

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pemetrexed, Gemcitabine, and Bevacizumab
	Comments	Within Group 1 (N=48), patients with an ECOG of 0 at baseline (N=18) were compared to patients with an ECOG of 1 at baseline (N=30).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0041
	Comments
	Method	Log Rank
	Comments

Adverse Events

Time Frame	Adverse events were collected beginning on day 1 of study treatment until one month after the end of study treatment, up to 54 weeks.
Arm/Group Title	Pemetrexed, Gemcitabine, and Bevacizumab
Arm/Group Description	All subjects received treatment with pemetrexed 500 mg/m^2, gemcitabine 1500 mg/m^2, and bevacizumab 10 mg/kg every 2 weeks.
All Cause Mortality
	Pemetrexed, Gemcitabine, and Bevacizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Pemetrexed, Gemcitabine, and Bevacizumab
	Affected / at Risk (%)	# Events
Total	26/48 (54.2%)
Blood and lymphatic system disorders
Anemia	1/48 (2.1%)
Febrile neutropenia	1/48 (2.1%)
Neutropenia	3/48 (6.3%)
Thrombocytopenia	1/48 (2.1%)
Cardiac disorders
Atrial fibrillation	1/48 (2.1%)
Cardiac failure congestive	1/48 (2.1%)
Sinus arrhythmia	1/48 (2.1%)
Eye disorders
Visual impairment	1/48 (2.1%)
Gastrointestinal disorders
Abdominal pain	1/48 (2.1%)
Constipation	2/48 (4.2%)
Gastrointestinal hemorrhage	1/48 (2.1%)
Intestinal obstruction	1/48 (2.1%)
Nausea	1/48 (2.1%)
Vomiting	2/48 (4.2%)
General disorders
Adverse drug reaction	1/48 (2.1%)
Asthenia	2/48 (4.2%)
Chest pain	1/48 (2.1%)
Fatigue	2/48 (4.2%)
Edema peripheral	1/48 (2.1%)
Pain	1/48 (2.1%)
Pyrexia	1/48 (2.1%)
Infections and infestations
Cellulitis	1/48 (2.1%)
Gastroenteritis	1/48 (2.1%)
Pneumonia	4/48 (8.3%)
Injury, poisoning and procedural complications
Hip fracture	1/48 (2.1%)
Metabolism and nutrition disorders
Decreased appetite	1/48 (2.1%)
Dehydration	3/48 (6.3%)
Hypoglycemia	1/48 (2.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/48 (2.1%)
Back pain	2/48 (4.2%)
Fistula	1/48 (2.1%)
Musculoskeletal pain	2/48 (4.2%)
Nervous system disorders
Cerebrovascular accident	1/48 (2.1%)
Convulsion	1/48 (2.1%)
Dizziness	2/48 (4.2%)
Psychiatric disorders
Confusional state	1/48 (2.1%)
Hallucination	1/48 (2.1%)
Mental status changes	2/48 (4.2%)
Renal and urinary disorders
Renal failure	1/48 (2.1%)
Urinary incontinence	1/48 (2.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/48 (2.1%)
Hemoptysis	1/48 (2.1%)
Hypoxia	3/48 (6.3%)
Pleural effusion	1/48 (2.1%)
Pulmonary edema	1/48 (2.1%)
Respiratory arrest	1/48 (2.1%)
Respiratory failure	1/48 (2.1%)
Vascular disorders
Deep vein thrombosis	1/48 (2.1%)
Thrombophlebitis superficial	1/48 (2.1%)
Other (Not Including Serious) Adverse Events
	Pemetrexed, Gemcitabine, and Bevacizumab
	Affected / at Risk (%)	# Events
Total	46/48 (95.8%)
Blood and lymphatic system disorders
Anemia	16/48 (33.3%)
Febrile neutropenia	1/48 (2.1%)
Leukopenia	1/48 (2.1%)
Neutropenia	15/48 (31.3%)
Thrombocytopenia	9/48 (18.8%)
Endocrine disorders
Hypothyroidism	1/48 (2.1%)
Eye disorders
Eye irritation	1/48 (2.1%)
Eye swelling	1/48 (2.1%)
Lacrimation increased	5/48 (10.4%)
Periorbital edema	1/48 (2.1%)
Vision blurred	2/48 (4.2%)
Visual impairment	1/48 (2.1%)
Vitreous hemorrhage	1/48 (2.1%)
Gastrointestinal disorders
Abdominal pain	4/48 (8.3%)
Cheilitis	1/48 (2.1%)
Constipation	9/48 (18.8%)
Diarrhea	15/48 (31.3%)
Dry mouth	1/48 (2.1%)
Dyspepsia	5/48 (10.4%)
Dysphagia	3/48 (6.3%)
Gastroesophageal reflux disease	2/48 (4.2%)
Hemorrhoids	2/48 (4.2%)
Nausea	18/48 (37.5%)
Esophagitis	1/48 (2.1%)
Oral discomfort	1/48 (2.1%)
Oral pain	3/48 (6.3%)
Stomatitis	13/48 (27.1%)
Vomiting	6/48 (12.5%)
General disorders
Asthenia	7/48 (14.6%)
Catheter site erosion	1/48 (2.1%)
Catheter site pain	1/48 (2.1%)
Chest pain	1/48 (2.1%)
Chills	3/48 (6.3%)
Device occlusion	1/48 (2.1%)
Face edema	1/48 (2.1%)
Fatigue	30/48 (62.5%)
Gait disturbance	1/48 (2.1%)
Irritability	1/48 (2.1%)
Malaise	3/48 (6.3%)
Mucosal inflammation	5/48 (10.4%)
Edema	3/48 (6.3%)
Edema peripheral	9/48 (18.8%)
Pain	1/48 (2.1%)
Pyrexia	8/48 (16.7%)
Swelling	1/48 (2.1%)
Thirst	1/48 (2.1%)
Immune system disorders
Seasonal allergy	2/48 (4.2%)
Infections and infestations
Anal abscess	1/48 (2.1%)
Cellulitis	1/48 (2.1%)
Clostridial infection	1/48 (2.1%)
Cystitis	3/48 (6.3%)
Fungal infection	1/48 (2.1%)
Influenza	1/48 (2.1%)
Localized infection	2/48 (4.2%)
Lower respiratory infection	1/48 (2.1%)
Nasopharyngitis	1/48 (2.1%)
Oral candidiasis	2/48 (4.2%)
Oral herpes	1/48 (2.1%)
Perirectal abscess	1/48 (2.1%)
Pneumonia	1/48 (2.1%)
Rhinitis	1/48 (2.1%)
Sinusitis	5/48 (10.4%)
Skin infection	1/48 (2.1%)
Staphylococcal infection	2/48 (4.2%)
Urinary tract infection	6/48 (12.5%)
Vulvovaginal mycotic infection	1/48 (2.1%)
Injury, poisoning and procedural complications
Contusion	3/48 (6.3%)
Excoriation	1/48 (2.1%)
Fall	2/48 (4.2%)
Laceration	1/48 (2.1%)
Periorbital hematoma	1/48 (2.1%)
Investigations
Alanine aminotransferase	3/48 (6.3%)
Alanine aminotransferase increased	3/48 (6.3%)
Aspartate aminotransferase	2/48 (4.2%)
Aspartate aminotransferase increased	2/48 (4.2%)
Blood alkaline phosphatase increased	2/48 (4.2%)
Blood creatinine	1/48 (2.1%)
Blood creatinine increased	2/48 (4.2%)
Glomerular filtration rate	1/48 (2.1%)
Neutrophil count	2/48 (4.2%)
Neutrophil count increased	1/48 (2.1%)
Occult blood positive	1/48 (2.1%)
Weight decreased	4/48 (8.3%)
Metabolism and nutrition disorders
Decreased appetite	12/48 (25%)
Dehydration	7/48 (14.6%)
Fluid retention	1/48 (2.1%)
Hyperglycemia	4/48 (8.3%)
Hyperkalemia	3/48 (6.3%)
Hypermagnesemia	1/48 (2.1%)
Hypoalbuminemia	3/48 (6.3%)
Hypocalcemia	1/48 (2.1%)
Hypoglycemia	1/48 (2.1%)
Hypokalemia	3/48 (6.3%)
Hypomagnesemia	3/48 (6.3%)
Hyponatremia	1/48 (2.1%)
Hypophagia	2/48 (4.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/48 (4.2%)
Back pain	7/48 (14.6%)
Muscular weakness	2/48 (4.2%)
Musculoskeletal chest pain	1/48 (2.1%)
Musculoskeletal pain	1/48 (2.1%)
Myalgia	3/48 (6.3%)
Pain in extremity	1/48 (2.1%)
Pain in jaw	1/48 (2.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/48 (2.1%)
Nervous system disorders
Ataxia	1/48 (2.1%)
Cerebral atrophy	1/48 (2.1%)
Dizziness	8/48 (16.7%)
Dysgeusia	9/48 (18.8%)
Headache	4/48 (8.3%)
Hypoesthesia	1/48 (2.1%)
Lethargy	1/48 (2.1%)
Memory impairment	2/48 (4.2%)
Tremor	2/48 (4.2%)
Psychiatric disorders
Anxiety	2/48 (4.2%)
Confusional state	1/48 (2.1%)
Depressed mood	1/48 (2.1%)
Depression	2/48 (4.2%)
Disorientation	1/48 (2.1%)
Insomnia	9/48 (18.8%)
Mood altered	1/48 (2.1%)
Psychotic disorder	1/48 (2.1%)
Renal and urinary disorders
Bladder pain	1/48 (2.1%)
Dysuria	2/48 (4.2%)
Incontinence	1/48 (2.1%)
Nocturia	1/48 (2.1%)
Pollakiuria	2/48 (4.2%)
Proteinuria	6/48 (12.5%)
Renal pain	1/48 (2.1%)
Urinary bladder hemorrhage	1/48 (2.1%)
Urinary retention	2/48 (4.2%)
Urogenital hemorrhage	1/48 (2.1%)
Respiratory, thoracic and mediastinal disorders
Cough	10/48 (20.8%)
Dysphonia	3/48 (6.3%)
Dyspnea	13/48 (27.1%)
Dyspnea exertional	1/48 (2.1%)
Epistaxis	7/48 (14.6%)
Hemoptysis	2/48 (4.2%)
Hiccups	3/48 (6.3%)
Hypoxia	1/48 (2.1%)
Oropharyngeal pain	3/48 (6.3%)
Productive cough	1/48 (2.1%)
Pulmonary hemorrhage	1/48 (2.1%)
Rales	1/48 (2.1%)
Respiratory disorder	1/48 (2.1%)
Rhinorrhea	2/48 (4.2%)
Rhonchi	1/48 (2.1%)
Sinus congestion	1/48 (2.1%)
Skin and subcutaneous tissue disorders
Alopecia	4/48 (8.3%)
Decubitus ulcer	2/48 (4.2%)
Dry skin	2/48 (4.2%)
Exfoliative rash	1/48 (2.1%)
Hyperhidrosis	3/48 (6.3%)
Pruritus	2/48 (4.2%)
Rash	7/48 (14.6%)
Rash macular	1/48 (2.1%)
Rash pruritic	1/48 (2.1%)
Swelling face	1/48 (2.1%)
Surgical and medical procedures
Catheter placement	1/48 (2.1%)
Vascular disorders
Embolism venous	2/48 (4.2%)
Flushing	1/48 (2.1%)
Hematoma	1/48 (2.1%)
Hypertension	4/48 (8.3%)
Hypotension	3/48 (6.3%)
Orthostatic hypotension	1/48 (2.1%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

A copy of the proposed publication or presentation must be submitted to the funders for review and comment two months prior to the presentation or submission for publication. An additional 60 day delay of presentation or publication may be requested by the funder.