Bortezomib and Lenalidomide in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00553644
• Collaborator: (none)
• Enrollment: 53
• Locations: 82
• Arm: 1
• Actual Duration (Months): 74.2
• Patients Per Site: 0.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This phase II trial studies how well bortezomib and lenalidomide work in treating patients with mantle cell lymphoma that has come back after a period of improvement (refractory) or is not responding to treatment (refractory). Bortezomib may also stop the growth of cancer cells by blocking some proteins needed for cell growth. Lenalidomide may stimulate the immune system to kill cancer cells and may also block the growth of new blood vessels necessary for cell growth. Giving bortezomib with lenalidomide may be an effective treatment for relapsed or refractory mantle cell lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Mantle Cell Lymphoma	Drug: Bortezomib; Other: Laboratory Biomarker Analysis; Drug: Lenalidomide	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the overall response (complete response [CR] and partial response [PR]) rate and the complete response (CR) rate to bortezomib + lenalidomide therapy in patients with relapsed or refractory mantle cell lymphoma.

SECONDARY OBJECTIVES:

1. To determine the time to progression after therapy with bortezomib + lenalidomide in patients with relapsed or refractory mantle cell lymphoma.

2. To determine the disease-free survival and overall survival after therapy with bortezomib

• lenalidomide in patients with relapsed or refractory mantle cell lymphoma.

OUTLINE:

Patients receive induction therapy comprising bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11 and lenalidomide orally (PO) once daily (QD) on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete or partial response as best response after completion of induction therapy receive maintenance therapy comprising bortezomib IV on days 1 and 8 and lenalidomide PO QD on days 1-14. Treatment repeats every 21 days for up to 6 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 2 years, and then annually for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Bortezomib (NSC #681239) + Lenalidomide (Revlimid™, CC-5013) (NSC #703813) for Relapsed/Refractory Mantle Cell Lymphoma
• Actual Study Start Date: Nov 15, 2007
• Actual Primary Completion Date: Dec 31, 2012
• Actual Study Completion Date: Jan 21, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (bortezomib, lenalidomide) Patients receive induction therapy comprising bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and lenalidomide PO QD on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete or partial response as best response after completion of induction therapy receive maintenance therapy comprising bortezomib IV on days 1 and 8 and lenalidomide PO QD on days 1-14. Treatment repeats every 21 days for up to 6 years in the absence of disease progression or unacceptable toxicity.

Drug: Bortezomib; Given IV; Other Names: [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid LDP 341 MLN341 PS-341 PS341 Velcade ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Lenalidomide; Given PO; Other Names: CC-5013 CC5013 CDC 501 Revlimid

Outcome Measures

Primary Outcome Measures

1. Number of Participants With an Overall Response Defined as Complete Response and Partial Response [Duration of treatment (assessed up to 6 years)]

   Response is assessed by investigator according to International Working Group (IWG) criteria. A complete response requires disappearance of all evidence of disease. A partial response is a >/= 50% decrease in the sum of products of 6 largest dominant nodes or nodal masses as well as for splenic and hepatic nodules. No increase in size of nodes, liver or spleen and no new sites of disease.

Secondary Outcome Measures

1. Incidence of Adverse Events [Duration of Treatment (up to 6 years)]

   Number of participants who experienced a maximum grade 3, 4 or 5 adverse event. The grading scales found in the revised NCI CTCAE version 4.0 was utilized for adverse event reporting

2. Time to Progression [Assessed up to 6 years]

   Time to progression (TTP) is defined as the time from study entry until progression or death due to any cause. The median TTP with 95% CI was estimated using the Kaplan-Meier method.

3. Overall Survival [Assessed up to 6 years]

   Overall survival (OS) is defined as the time from study entry until death. The median OS with 95% CI was estimated using the Kaplan-Meier method..

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically documented mantle cell lymphoma, with the following immunophenotypic characteristics: cluster of differentiation (CD)5+, CD23-, cyclin D1+; this may be from an initial diagnostic biopsy, or one obtained at time of relapse

• Bone marrow biopsies as the sole means of diagnosis are not acceptable, but they may be submitted in conjunction with nodal biopsies; fine needle aspirates are not acceptable

• Failure to submit pathology specimens within 60 days of patient registration will be considered a major protocol violation

• Institutional flow cytometry or immunohistochemistry must confirm CD5 antigen expression, lack of CD23 antigen expression, and expression of cyclin D1

• Prior therapy with at least one regimen, which may have been single agent or multi-agent, and consisted of traditional cytotoxic agents and/or biologic agents; patient may not have received prior bortezomib or lenalidomide therapy; patient must have progressive disease or refractory disease following that initial regimen(s); refractory disease will be defined as stable disease (SD) or progressive disease (PD) as best response to prior therapy, or CR or PR as initial response followed by disease progression within 6 months

• Prior autologous, but not allogeneic, stem cell transplant is allowed

• No corticosteroids within two weeks prior to study, except for maintenance therapy for a non-malignant disease; maintenance therapy dose may not exceed 20 mg/day prednisone or equivalent

• No prior radioimmunotherapy within 12 months of study entry

• No >= grade 3 peripheral neuropathy within a month prior to study entry

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable; any tumor mass > 1 cm by physical exam, computed tomography (CT), magnetic resonance imaging (MRI), or conventional radiograph is acceptable; lesions that are considered non-measurable include the following:

• Bone lesions (lesions, if present, should be noted)

• Ascites

• Pleural/pericardial effusion

• Lymphangitis cutis or pulmonis

• Bone marrow (involvement by non-Hodgkin lymphoma should be noted)

• No known central nervous system (CNS) involvement by lymphoma

• Patients with human immunodeficiency virus (HIV) infection are eligible, provided they meet the following: CD4+ cell count > 350/mm^{3; treatment sensitive HIV and, if on anti-HIV therapy, HIV viral load < 50 copies/mm}3; no history of acquired immunodeficiency syndrome (AIDS)-defining conditions or other HIV-related illnesses; no concurrent zidovudine or stavudine

• Non-pregnant and non-nursing; females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to registration; further, they must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP, even if they have had a successful vasectomy; a FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months); all patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure; documentation of counseling is required on Cancer and Leukemia Group B (CALGB) form S-041

• Patients with a recent history (within 3 months of study entry) of deep vein thrombosis (DVT)/pulmonary embolism (PE) are not eligible; patients with a distant history (greater than 3 months before study entry) of DVT/PE are eligible, but must receive either prophylactic aspirin or low molecular weight heparin, unless contraindicated

• Left ventricular ejection fraction (LVEF) >= 45% by multigated acquisition (MUGA) scan or echocardiogram

• No New York Heart Association class III or class IV congestive heart failure at study entry

• No myocardial infarction within the past 6 months of study entry

• No known positivity for hepatitis A, B, or C

• Absolute neutrophil count (ANC) >= 1,000/uL (>= 500/uL if marrow involvement)

• Platelets >= 75,000/uL

• Creatinine =< 1.5 x upper limit of normal (ULN) (unless attributable to non-Hodgkin's lymphoma) and estimated creatinine clearance >= 30 mL/min (patients on dialysis are not eligible)

• Total bilirubin =< 2 x ULN (unless attributable to non-Hodgkin's lymphoma and Gilbert's disease)

• Urine (U)-human chorionic gonadotropin (HCG) or serum HCG negative

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kaiser Permanente-Anaheim	Anaheim	California	United States	92806
2	Kaiser Permanente-Baldwin Park	Baldwin Park	California	United States	91706
3	Kaiser Permanente-Bellflower	Bellflower	California	United States	90706
4	Kaiser Permanente-Fontana	Fontana	California	United States	92335
5	Kaiser Permanente - Harbor City	Harbor City	California	United States	90710
6	Kaiser Permanente-Irvine	Irvine	California	United States	92618
7	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California	United States	90027
8	Kaiser Permanente-Cadillac	Los Angeles	California	United States	90034
9	Kaiser Permanente - Panorama City	Panorama City	California	United States	91402
10	Kaiser Permanente-Riverside	Riverside	California	United States	92505
11	Kaiser Permanente-San Diego Mission	San Diego	California	United States	92108
12	Kaiser Permanente-San Diego Zion	San Diego	California	United States	92120
13	Kaiser Permanente-San Marcos	San Marcos	California	United States	92078
14	Kaiser Permanente-Woodland Hills	Woodland Hills	California	United States	91367
15	Hartford Hospital	Hartford	Connecticut	United States	06102
16	Beebe Medical Center	Lewes	Delaware	United States	19958
17	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
18	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
19	Graham Hospital Association	Canton	Illinois	United States	61520
20	Memorial Hospital	Carthage	Illinois	United States	62321
21	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
22	Heartland Cancer Research NCORP	Decatur	Illinois	United States	62526
23	Eureka Hospital	Eureka	Illinois	United States	61530
24	Galesburg Cottage Hospital	Galesburg	Illinois	United States	61401
25	Illinois CancerCare-Galesburg	Galesburg	Illinois	United States	61401
26	Western Illinois Cancer Treatment Center	Galesburg	Illinois	United States	61401
27	Mason District Hospital	Havana	Illinois	United States	62644
28	Hopedale Medical Complex - Hospital	Hopedale	Illinois	United States	61747
29	Mcdonough District Hospital	Macomb	Illinois	United States	61455
30	Bromenn Regional Medical Center	Normal	Illinois	United States	61761
31	Community Cancer Center Foundation	Normal	Illinois	United States	61761
32	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
33	Ottawa Regional Hospital and Healthcare Center	Ottawa	Illinois	United States	61350
34	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois	United States	61554
35	Pekin Hospital	Pekin	Illinois	United States	61554
36	Proctor Hospital	Peoria	Illinois	United States	61614
37	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
38	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
39	Illinois Valley Hospital	Peru	Illinois	United States	61354
40	Valley Radiation Oncology	Peru	Illinois	United States	61354
41	Perry Memorial Hospital	Princeton	Illinois	United States	61356
42	Saint Margaret's Hospital	Spring Valley	Illinois	United States	61362
43	Fort Wayne Medical Oncology and Hematology Inc-Parkview	Fort Wayne	Indiana	United States	46845
44	University of Iowa Healthcare Cancer Services Quad Cities	Bettendorf	Iowa	United States	52722
45	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
46	Harold Alfond Center for Cancer Care	Augusta	Maine	United States	04330
47	Eastern Maine Medical Center	Bangor	Maine	United States	04401
48	Union Hospital of Cecil County	Elkton	Maryland	United States	21921
49	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
50	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
51	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
52	Newton-Wellesley Hospital	Newton	Massachusetts	United States	02462
53	Bronson Battle Creek	Battle Creek	Michigan	United States	49017
54	Spectrum Health Big Rapids Hospital	Big Rapids	Michigan	United States	49307
55	Cancer Research Consortium of West Michigan NCORP	Grand Rapids	Michigan	United States	49503
56	Mercy Health Saint Mary's	Grand Rapids	Michigan	United States	49503
57	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
58	Mercy Health Mercy Campus	Muskegon	Michigan	United States	49444
59	Munson Medical Center	Traverse City	Michigan	United States	49684
60	Metro Health Hospital	Wyoming	Michigan	United States	49519
61	Minneapolis Veterans Medical Center	Minneapolis	Minnesota	United States	55417
62	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
63	Veterans Administration	Columbia	Missouri	United States	65201
64	University of Missouri - Ellis Fischel	Columbia	Missouri	United States	65212
65	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
66	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
67	Cooper Hospital University Medical Center	Camden	New Jersey	United States	08103
68	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
69	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York	United States	13057
70	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
71	Mission Hospital Inc-Memorial Campus	Asheville	North Carolina	United States	28801
72	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
73	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
74	Wayne Memorial Hospital	Goldsboro	North Carolina	United States	27534
75	Vidant Oncology-Kinston	Kinston	North Carolina	United States	28501
76	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
77	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
78	McLeod Regional Medical Center	Florence	South Carolina	United States	29506
79	Central Vermont Medical Center/National Life Cancer Treatment	Berlin	Vermont	United States	05602
80	University of Vermont College of Medicine	Burlington	Vermont	United States	05405
81	Danville Regional Medical Center	Danville	Virginia	United States	24541
82	Sovah Health Martinsville	Martinsville	Virginia	United States	24115

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Vicki Morrison, Alliance for Clinical Trials in Oncology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00553644
• Other Study ID Numbers: NCI-2009-00483; NCI-2009-00483; CDR0000573827; CALGB 50501; CALGB-50501; U10CA180821; U10CA031946
• First Posted: Nov 4, 2007
• Last Update Posted: Oct 30, 2018
• Last Verified: Oct 1, 2018

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Lenalidomide; Bortezomib

Study Results

Participant Flow

Recruitment Details	Between November 2007 and July 2011, 54 participants were recruited to this study.
Pre-assignment Detail	One participant was deemed ineligible and removed for all analyses; therefore, 53 participants were analyzed.

Arm/Group Title	Treatment (Antiangiogenesis Therapy, Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive induction therapy comprising bortezomib 1.3mg/m^2 IV over 3-5 seconds on days 1, 4, 8, and 11 and lenalidomide 20 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete or partial response as best response after completion of induction therapy receive maintenance therapy comprising bortezomib 1.3 mg/m^2 IV on days 1 and 8 and lenalidomide 15 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 6 years in the absence of disease progression or unacceptable toxicity. bortezomib: Given IV lenalidomide: Given PO
Period Title: Overall Study
STARTED	53
COMPLETED	25
NOT COMPLETED	28

Baseline Characteristics

Arm/Group Title	Treatment (Antiangiogenesis Therapy, Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive induction therapy comprising bortezomib 1.3mg/m^2 IV over 3-5 seconds on days 1, 4, 8, and 11 and lenalidomide 20 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete or partial response as best response after completion of induction therapy receive maintenance therapy comprising bortezomib 1.3 mg/m^2 IV on days 1 and 8 and lenalidomide 15 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 6 years in the absence of disease progression or unacceptable toxicity. bortezomib: Given IV lenalidomide: Given PO
Overall Participants	53
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	67
Sex: Female, Male (Count of Participants)
Female	9 17%
Male	44 83%
Region of Enrollment (participants) [Number]
United States	53 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With an Overall Response Defined as Complete Response and Partial Response
Description	Response is assessed by investigator according to International Working Group (IWG) criteria. A complete response requires disappearance of all evidence of disease. A partial response is a >/= 50% decrease in the sum of products of 6 largest dominant nodes or nodal masses as well as for splenic and hepatic nodules. No increase in size of nodes, liver or spleen and no new sites of disease.
Time Frame	Duration of treatment (assessed up to 6 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Antiangiogenesis Therapy, Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive induction therapy comprising bortezomib 1.3mg/m^2 IV over 3-5 seconds on days 1, 4, 8, and 11 and lenalidomide 20 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete or partial response as best response after completion of induction therapy receive maintenance therapy comprising bortezomib 1.3 mg/m^2 IV on days 1 and 8 and lenalidomide 15 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 6 years in the absence of disease progression or unacceptable toxicity. bortezomib: Given IV lenalidomide: Given PO
Measure Participants	53
Number [participants]	21 39.6%

2. Secondary Outcome

Title	Incidence of Adverse Events
Description	Number of participants who experienced a maximum grade 3, 4 or 5 adverse event. The grading scales found in the revised NCI CTCAE version 4.0 was utilized for adverse event reporting
Time Frame	Duration of Treatment (up to 6 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Antiangiogenesis Therapy, Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive induction therapy comprising bortezomib 1.3mg/m^2 IV over 3-5 seconds on days 1, 4, 8, and 11 and lenalidomide 20 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete or partial response as best response after completion of induction therapy receive maintenance therapy comprising bortezomib 1.3 mg/m^2 IV on days 1 and 8 and lenalidomide 15 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 6 years in the absence of disease progression or unacceptable toxicity. bortezomib: Given IV lenalidomide: Given PO
Measure Participants	53
Grade 2	4 7.5%
Grade 3	29 54.7%
Grade 4	17 32.1%
Grade 5	1 1.9%

3. Secondary Outcome

Title	Time to Progression
Description	Time to progression (TTP) is defined as the time from study entry until progression or death due to any cause. The median TTP with 95% CI was estimated using the Kaplan-Meier method.
Time Frame	Assessed up to 6 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Antiangiogenesis Therapy, Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive induction therapy comprising bortezomib 1.3mg/m^2 IV over 3-5 seconds on days 1, 4, 8, and 11 and lenalidomide 20 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete or partial response as best response after completion of induction therapy receive maintenance therapy comprising bortezomib 1.3 mg/m^2 IV on days 1 and 8 and lenalidomide 15 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 6 years in the absence of disease progression or unacceptable toxicity. bortezomib: Given IV lenalidomide: Given PO
Measure Participants	53
Median (95% Confidence Interval) [years]	0.58

4. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) is defined as the time from study entry until death. The median OS with 95% CI was estimated using the Kaplan-Meier method..
Time Frame	Assessed up to 6 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Antiangiogenesis Therapy, Enzyme Inhibitor Therapy)
Arm/Group Description	Patients receive induction therapy comprising bortezomib 1.3mg/m^2 IV over 3-5 seconds on days 1, 4, 8, and 11 and lenalidomide 20 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving a complete or partial response as best response after completion of induction therapy receive maintenance therapy comprising bortezomib 1.3 mg/m^2 IV on days 1 and 8 and lenalidomide 15 mg/day PO once daily on days 1-14. Treatment repeats every 21 days for up to 6 years in the absence of disease progression or unacceptable toxicity. bortezomib: Given IV lenalidomide: Given PO
Measure Participants	53
Median (95% Confidence Interval) [years]	2.17

Adverse Events

Arm/Group Title	Treatment (Antiangiogenesis Therapy, Enzyme Inhibitor Therapy)
Arm/Group Description	lenalidomide: Given PO
All Cause Mortality
	Treatment (Antiangiogenesis Therapy, Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Antiangiogenesis Therapy, Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	24/53 (45.3%)
Blood and lymphatic system disorders
Febrile neutropenia	1/53 (1.9%)	1
Hemoglobin decreased	19/53 (35.8%)	23
Cardiac disorders
Mobitz type I	1/53 (1.9%)	1
Eye disorders
Diplopia	1/53 (1.9%)	1
Eye disorder	1/53 (1.9%)	1
Gastrointestinal disorders
Abdominal pain	4/53 (7.5%)	4
Constipation	3/53 (5.7%)	3
Diarrhea	8/53 (15.1%)	8
Dry mouth	1/53 (1.9%)	1
Dysphagia	1/53 (1.9%)	1
Ear, nose and throat examination abnormal	2/53 (3.8%)	2
Ileus	1/53 (1.9%)	1
Nausea	9/53 (17%)	9
Oral pain	1/53 (1.9%)	1
Vomiting	6/53 (11.3%)	6
General disorders
Disease progression	3/53 (5.7%)	3
Edema limbs	4/53 (7.5%)	4
Facial pain	1/53 (1.9%)	1
Fatigue	15/53 (28.3%)	18
Fever	6/53 (11.3%)	7
Infections and infestations
Abdominal infection	1/53 (1.9%)	1
Conjunctivitis infective	1/53 (1.9%)	1
Infection	2/53 (3.8%)	2
Otitis externa	1/53 (1.9%)	1
Pneumonia	2/53 (3.8%)	2
Sepsis	2/53 (3.8%)	2
Upper respiratory infection	1/53 (1.9%)	1
Injury, poisoning and procedural complications
Intraoperative complications	1/53 (1.9%)	1
Investigations
Activated partial thromboplastin time prolonged	1/53 (1.9%)	1
Alanine aminotransferase increased	5/53 (9.4%)	6
Alkaline phosphatase increased	5/53 (9.4%)	5
Aspartate aminotransferase increased	5/53 (9.4%)	5
Blood bilirubin increased	3/53 (5.7%)	4
Creatinine increased	7/53 (13.2%)	8
INR increased	1/53 (1.9%)	2
Leukocyte count decreased	11/53 (20.8%)	11
Lymphocyte count decreased	6/53 (11.3%)	8
Neutrophil count decreased	11/53 (20.8%)	12
Platelet count decreased	20/53 (37.7%)	24
Weight loss	2/53 (3.8%)	2
Metabolism and nutrition disorders
Anorexia	6/53 (11.3%)	6
Blood glucose increased	5/53 (9.4%)	6
Blood uric acid increased	2/53 (3.8%)	3
Dehydration	3/53 (5.7%)	3
Serum albumin decreased	8/53 (15.1%)	8
Serum calcium decreased	11/53 (20.8%)	12
Serum calcium increased	1/53 (1.9%)	1
Serum glucose decreased	1/53 (1.9%)	1
Serum magnesium decreased	2/53 (3.8%)	2
Serum phosphate decreased	3/53 (5.7%)	3
Serum potassium decreased	3/53 (5.7%)	3
Serum potassium increased	2/53 (3.8%)	2
Serum sodium decreased	4/53 (7.5%)	4
Serum sodium increased	2/53 (3.8%)	2
Musculoskeletal and connective tissue disorders
Back pain	3/53 (5.7%)	4
Muscle weakness	2/53 (3.8%)	2
Nervous system disorders
Dizziness	4/53 (7.5%)	4
Dysgeusia	1/53 (1.9%)	2
Facial muscle weakness	1/53 (1.9%)	1
Headache	1/53 (1.9%)	1
Ischemia cerebrovascular	1/53 (1.9%)	1
Neuralgia	1/53 (1.9%)	1
Neurological disorder NOS	2/53 (3.8%)	2
Oculomotor nerve disorder	1/53 (1.9%)	1
Peripheral motor neuropathy	3/53 (5.7%)	3
Peripheral sensory neuropathy	6/53 (11.3%)	8
Speech disorder	1/53 (1.9%)	1
Syncope	3/53 (5.7%)	3
Trigeminal nerve disorder	1/53 (1.9%)	1
Psychiatric disorders
Anxiety	1/53 (1.9%)	1
Confusion	1/53 (1.9%)	1
Insomnia	2/53 (3.8%)	2
Renal and urinary disorders
Renal failure	1/53 (1.9%)	1
Urogenital disorder	1/53 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	2/53 (3.8%)	2
Cough	3/53 (5.7%)	3
Dyspnea	8/53 (15.1%)	9
Hypoxia	2/53 (3.8%)	2
Pleural effusion	2/53 (3.8%)	2
Pneumonitis	3/53 (5.7%)	3
Skin and subcutaneous tissue disorders
Dry skin	3/53 (5.7%)	3
Hand-and-foot syndrome	1/53 (1.9%)	1
Petechiae	1/53 (1.9%)	1
Pruritus	2/53 (3.8%)	2
Rash desquamating	1/53 (1.9%)	1
Skin disorder	1/53 (1.9%)	1
Sweating	1/53 (1.9%)	1
Vascular disorders
Hemorrhage	1/53 (1.9%)	1
Hypertension	1/53 (1.9%)	1
Hypotension	5/53 (9.4%)	6
Thrombosis	2/53 (3.8%)	2
Other (Not Including Serious) Adverse Events
	Treatment (Antiangiogenesis Therapy, Enzyme Inhibitor Therapy)
	Affected / at Risk (%)	# Events
Total	48/53 (90.6%)
Blood and lymphatic system disorders
Hemoglobin decreased	38/53 (71.7%)	200
Lymph node pain	2/53 (3.8%)	4
Cardiac disorders
Cardiac pain	1/53 (1.9%)	1
Left ventricular failure	1/53 (1.9%)	1
Palpitations	1/53 (1.9%)	1
Sinus bradycardia	2/53 (3.8%)	5
Sinus tachycardia	1/53 (1.9%)	1
Ventricular trigeminy	1/53 (1.9%)	1
Ear and labyrinth disorders
Hearing impaired	1/53 (1.9%)	1
Endocrine disorders
Hypothyroidism	1/53 (1.9%)	1
Eye disorders
Diplopia	1/53 (1.9%)	1
Dry eye syndrome	2/53 (3.8%)	12
Eye disorder	2/53 (3.8%)	2
Flashing vision	1/53 (1.9%)	3
Vision blurred	5/53 (9.4%)	11
Gastrointestinal disorders
Abdominal distension	1/53 (1.9%)	2
Abdominal pain	8/53 (15.1%)	11
Ascites	1/53 (1.9%)	2
Colonic hemorrhage	1/53 (1.9%)	2
Constipation	20/53 (37.7%)	76
Diarrhea	22/53 (41.5%)	65
Dry mouth	2/53 (3.8%)	3
Dyspepsia	3/53 (5.7%)	4
Dysphagia	1/53 (1.9%)	3
Ear, nose and throat examination abnormal	2/53 (3.8%)	2
Esophagitis	1/53 (1.9%)	1
Flatulence	2/53 (3.8%)	3
Gastrointestinal disorder	3/53 (5.7%)	3
Nausea	18/53 (34%)	44
Oral pain	1/53 (1.9%)	1
Vomiting	10/53 (18.9%)	15
General disorders
Chills	4/53 (7.5%)	7
Edema limbs	11/53 (20.8%)	19
Fatigue	37/53 (69.8%)	187
Fever	6/53 (11.3%)	7
Flu-like symptoms	1/53 (1.9%)	1
General symptom	1/53 (1.9%)	2
Localized edema	1/53 (1.9%)	2
Pain	2/53 (3.8%)	3
Immune system disorders
Hypersensitivity	1/53 (1.9%)	2
Immune system disorder	1/53 (1.9%)	35
Infections and infestations
Bronchitis	3/53 (5.7%)	5
Eye infection	2/53 (3.8%)	4
Lip infection	1/53 (1.9%)	1
Peripheral nerve infection	1/53 (1.9%)	1
Pharyngitis	1/53 (1.9%)	2
Pneumonia	4/53 (7.5%)	4
Rhinitis infective	1/53 (1.9%)	1
Sinusitis	4/53 (7.5%)	10
Skin infection	4/53 (7.5%)	5
Upper respiratory infection	3/53 (5.7%)	4
Urinary tract infection	1/53 (1.9%)	1
Injury, poisoning and procedural complications
Bruising	1/53 (1.9%)	1
Investigations
Activated partial thromboplastin time prolonged	1/53 (1.9%)	2
Alanine aminotransferase increased	11/53 (20.8%)	21
Alkaline phosphatase increased	6/53 (11.3%)	11
Aspartate aminotransferase increased	11/53 (20.8%)	18
Blood bilirubin increased	3/53 (5.7%)	13
Creatinine increased	11/53 (20.8%)	17
INR increased	3/53 (5.7%)	5
Laboratory test abnormal	1/53 (1.9%)	2
Leukocyte count decreased	18/53 (34%)	106
Lymphocyte count decreased	14/53 (26.4%)	49
Neutrophil count decreased	21/53 (39.6%)	156
Platelet count decreased	36/53 (67.9%)	203
Weight loss	8/53 (15.1%)	13
Metabolism and nutrition disorders
Anorexia	16/53 (30.2%)	48
Blood glucose increased	13/53 (24.5%)	67
Blood uric acid increased	4/53 (7.5%)	16
Dehydration	2/53 (3.8%)	2
Serum albumin decreased	10/53 (18.9%)	27
Serum calcium decreased	9/53 (17%)	41
Serum phosphate decreased	6/53 (11.3%)	28
Serum potassium decreased	3/53 (5.7%)	4
Serum potassium increased	3/53 (5.7%)	6
Serum sodium decreased	8/53 (15.1%)	12
Serum sodium increased	1/53 (1.9%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	3/53 (5.7%)	20
Back pain	2/53 (3.8%)	7
Bone pain	3/53 (5.7%)	3
Muscle weakness	6/53 (11.3%)	9
Muscle weakness lower limb	1/53 (1.9%)	5
Musculoskeletal disorder	1/53 (1.9%)	1
Myalgia	3/53 (5.7%)	3
Pain in extremity	3/53 (5.7%)	7
Nervous system disorders
Ataxia	3/53 (5.7%)	3
Cognitive disturbance	1/53 (1.9%)	1
Dizziness	14/53 (26.4%)	33
Dysgeusia	3/53 (5.7%)	6
Extrapyramidal disorder	2/53 (3.8%)	8
Headache	5/53 (9.4%)	9
Neuralgia	4/53 (7.5%)	13
Neurological disorder NOS	2/53 (3.8%)	3
Peripheral motor neuropathy	7/53 (13.2%)	13
Peripheral sensory neuropathy	33/53 (62.3%)	281
Sinus pain	1/53 (1.9%)	2
Trigeminal nerve disorder	1/53 (1.9%)	1
Psychiatric disorders
Agitation	1/53 (1.9%)	1
Anxiety	1/53 (1.9%)	1
Confusion	1/53 (1.9%)	1
Depression	3/53 (5.7%)	5
Insomnia	5/53 (9.4%)	6
Psychosis	1/53 (1.9%)	1
Renal and urinary disorders
Urinary frequency	1/53 (1.9%)	1
Urinary incontinence	1/53 (1.9%)	1
Urinary retention	1/53 (1.9%)	1
Urogenital disorder	1/53 (1.9%)	3
Reproductive system and breast disorders
Testicular pain	1/53 (1.9%)	6
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	4/53 (7.5%)	4
Cough	15/53 (28.3%)	23
Dyspnea	20/53 (37.7%)	43
Epistaxis	2/53 (3.8%)	2
Pharyngolaryngeal pain	1/53 (1.9%)	1
Pleural effusion	1/53 (1.9%)	1
Pneumonitis	1/53 (1.9%)	2
Respiratory disorder	2/53 (3.8%)	2
Voice alteration	3/53 (5.7%)	3
Skin and subcutaneous tissue disorders
Alopecia	1/53 (1.9%)	1
Dry skin	3/53 (5.7%)	5
Hand-and-foot syndrome	2/53 (3.8%)	5
Nail disorder	1/53 (1.9%)	1
Petechiae	1/53 (1.9%)	1
Pruritus	11/53 (20.8%)	34
Rash acneiform	1/53 (1.9%)	1
Rash desquamating	14/53 (26.4%)	27
Skin disorder	4/53 (7.5%)	5
Skin ulceration	1/53 (1.9%)	1
Sweating	6/53 (11.3%)	10
Vascular disorders
Hypertension	2/53 (3.8%)	2
Hypotension	10/53 (18.9%)	16
Thrombosis	2/53 (3.8%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.