Vorinostat in Treating Patients With Low-Grade Non-Hodgkin's Lymphoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00253630
• Collaborator: (none)
• Enrollment: 37
• Locations: 5
• Arm: 1
• Duration (Months): 128
• Patients Per Site: 7.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial is studying how well vorinostat works in treating patients with relapsed or refractory indolent non-Hodgkin's lymphoma. Drugs used in chemotherapy, such as vorinostat, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Nodal Marginal Zone Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma	Other: Laboratory Biomarker Analysis; Drug: Vorinostat	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the anti-tumor activity of SAHA (vorinostat) as assessed by the objective response rate, time to progression and survival in subjects with advanced lymphoma.

2. To assess the toxicity profile of SAHA in this patient population. III. To perform correlative laboratory investigations to confirm modulation of chromatin acetylation as the biologic target and attempt to gain insight into the downstream molecular mechanisms involved in the induction of apoptosis mediated by SAHA.

OUTLINE:

Patients receive vorinostat orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Suberoylanilide Hydroxamic Acid (SAHA) in Indolent Non-Hodgkin's Lymphoma
• Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: May 1, 2016
• Actual Study Completion Date: May 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (vorinostat) Patients receive vorinostat PO BID on days 1-14. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Vorinostat; Given PO; Other Names: L-001079038 MSK-390 SAHA Suberanilohydroxamic Acid Suberoylanilide Hydroxamic Acid Zolinza

Outcome Measures

Primary Outcome Measures

1. Response Rate [Up to 3 years]

   Radiological assessment by CT and/or PET scan after every three cycles (every 3 months). Response assessed by the standard Cheson criteria (Cheson et al, J Clin Oncol 17:1244, 1999). Complete Remission (CR) - (a) FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative (b) Variably FDG-avid or PET negative; regression to normal size on CT; Partial Remission (PR) - 50% or greater decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes (a) FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site (b) Variably FDG-avid or PET negative; regression on CT. Response Rate = CR + PR.

2. Number of Participants With Adverse Events [Up to 3 years]

   Grades 3 & 4 adverse events definitely, probably or possibly related to treatment, graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

Secondary Outcome Measures

1. Change in Histone Acetylation by Immunohistochemistry (IHC) [Baseline to up to day 14]

   Histone acetylation by IHC will be scored as -, +, ++, or +++, reflecting both the intensity of staining as well as the number of cells stained. Analysis will be descriptive, with the goal of describing baseline distributions and estimating the frequency and degree of changes from baseline.

2. Change in Histone Acetylation by Western Blot (WB) [Baseline to up to day 14]

   Histone acetylation by WB will be recorded as the ratio of acetylated histone (measured by photodensitometry) divided by the total histone (H3 or H4), in order to control for the amount of protein loaded. Analysis will be descriptive, with the goal of describing baseline distributions and estimating the frequency and degree of changes from baseline.

3. 2-Year Overall Survival [Until Death from any cause, up to 2 years]

   Estimated using the product-limit method of Kaplan and Meier.

4. 2-Year Progression Free-Survival [Until death or progression, up to 2 years]

   Estimated using the product-limit method of Kaplan and Meier. Progression defined as any new lesion or increase by greater than 50% of previously involved sites from nadir.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed relapsed/refractory indolent Non-Hodgkin's lymphoma (Included in this category are relapsed/refractory follicular center lymphomas grade I, II, III, relapsed /refractory marginal zone B-cell lymphoma (nodal and extranodal), relapsed/refractory mantle cell lymphoma)

• Patients must have measurable disease by computed tomography (CT) scan. positron emission tomography (PET) scan evaluations are desirable but not mandatory, so that patients with negative PET scans but measurable disease by CT are eligible

• Patients may have had up to four prior chemotherapeutic regimens; steroids alone and local radiation do not count as regimens (radiotherapy must have been completed at least 14 days prior to starting SAHA); rituxan alone does not count as a regimen, however, Bexxar or Zevalin do; the most recent therapy must have failed to induce a complete response, or there must be disease progression or recurrence after the most recent therapy

• Patients may be enrolled who relapse after autologous stem cell transplant if they are at least three months after transplant, and after allogeneic transplant if they are at least six months post transplant; to be eligible after either type of transplant, patients must have achieved platelet counts greater than 100,000/mcL, and white blood cell (WBC) greater than 1,000/mcL at some point after their transplant, and should have no active related infections (i.e. fungal or viral); in the case of allogeneic transplant relapse, there should be no active acute graft versus host disease (GvHD) of any grade, and no chronic graft versus host disease other than mild skin, oral, or ocular GvHD not requiring systemic immunosuppression

• Life expectancy of greater than 3 months

• Eastern Cooperative Oncology Group (ECOG) performance status #2 (Karnofsky >= 60%)

• Absolute neutrophil count >= 1,000/mcL

• Platelets >= 100,000/mcL

• Total bilirubin within normal institutional limits; patients with elevation of unconjugated bilirubin alone, as in Gilbert's Disease, are eligible

• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate [SGPT]) =< 2.5 x institutional upper limit of normal

• Creatinine up to and including 2 mg/dl

• Premenopausal women must have a negative serum pregnancy test prior to entry on this study; the effects of SAHA on the developing human fetus at the recommended therapeutic dose are unknown; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had chemotherapy within 4 weeks, rituximab within three months (unless there is evidence of progression) or radiotherapy within 2 weeks or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier are excluded; this does not include use of steroids, which may continue until two days prior to enrollment; low dose chlorambucil should be stopped two weeks prior to beginning SAHA; valproic acid should be stopped at least two weeks prior to enrollment; nitrosoureas and mitomycin should be stopped 6 weeks prior to enrollment

• Patients may not be receiving any other investigational agents

• Patients with known brain metastases are excluded from this clinical trial unless the metastases are controlled after therapy and have not been treated with steroids within the past two months

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to SAHA

• There must be no plans for the patient to receive concurrent hormonal, biological or radiation therapy

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with SAHA

• Human immunodeficiency virus (HIV)-positive patients receiving combination antiretroviral therapy are ineligible

• Patients with other active malignancies are ineligible for this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
2	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
4	City of Hope South Pasadena	South Pasadena	California	United States	91030
5	University of Pittsburgh Cancer Institute (UPCI)	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Leslie Popplewell, City of Hope Comprehensive Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00253630
• Other Study ID Numbers: NCI-2012-02843; NCI-2012-02843; PHII-63; PHII-63; 6963; N01CM17101; P30CA033572; U01CA062505; N01CM62209
• First Posted: Nov 15, 2005
• Last Update Posted: Mar 6, 2018
• Last Verified: Feb 1, 2018

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Recurrence; Vorinostat

Study Results

Participant Flow

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	Patients receive vorinostat PO BID on days 1-14. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Period Title: Overall Study
STARTED	37
COMPLETED	35
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	Patients receive vorinostat PO BID on days 1-14. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Overall Participants	35
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64.5
Sex: Female, Male (Count of Participants)
Female	12 34.3%
Male	23 65.7%
Region of Enrollment (Count of Participants)
United States	35 100%

Outcome Measures

1. Primary Outcome

Title	Response Rate
Description	Radiological assessment by CT and/or PET scan after every three cycles (every 3 months). Response assessed by the standard Cheson criteria (Cheson et al, J Clin Oncol 17:1244, 1999). Complete Remission (CR) - (a) FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative (b) Variably FDG-avid or PET negative; regression to normal size on CT; Partial Remission (PR) - 50% or greater decrease in SPD of up to 6 largest dominant masses; no increase in size of other nodes (a) FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site (b) Variably FDG-avid or PET negative; regression on CT. Response Rate = CR + PR.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	Patients receive vorinostat PO BID on days 1-14. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Measure Participants	35
Number (95% Confidence Interval) [percentage of participants]	29 82.9%

2. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Grades 3 & 4 adverse events definitely, probably or possibly related to treatment, graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	Patients receive vorinostat PO BID on days 1-14. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Measure Participants	35
ANC	6 17.1%
Anorexia	1 2.9%
Fatigue	3 8.6%
Hemoglobin	4 11.4%
Hypokalemia	1 2.9%
Hyponatremia	1 2.9%
Hypophosphatemia	2 5.7%
Infection -Skin (cellulitis)	1 2.9%
INR	2 5.7%
Leukocytes (total WBC)	4 11.4%
Lymphopenia	5 14.3%
Myalgia	1 2.9%
Mucositis/stomatitis	1 2.9%
Platelets	10 28.6%
Thrombosis/thrombus/embolism	2 5.7%

3. Secondary Outcome

Title	Change in Histone Acetylation by Immunohistochemistry (IHC)
Description	Histone acetylation by IHC will be scored as -, +, ++, or +++, reflecting both the intensity of staining as well as the number of cells stained. Analysis will be descriptive, with the goal of describing baseline distributions and estimating the frequency and degree of changes from baseline.
Time Frame	Baseline to up to day 14

Outcome Measure Data

Analysis Population Description

Immunohistochemistry data was not collected and is not available for analysis.

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	Patients receive vorinostat PO BID on days 1-14. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Measure Participants	0

4. Secondary Outcome

Title	Change in Histone Acetylation by Western Blot (WB)
Description	Histone acetylation by WB will be recorded as the ratio of acetylated histone (measured by photodensitometry) divided by the total histone (H3 or H4), in order to control for the amount of protein loaded. Analysis will be descriptive, with the goal of describing baseline distributions and estimating the frequency and degree of changes from baseline.
Time Frame	Baseline to up to day 14

Outcome Measure Data

Analysis Population Description

Western Blot data was not collected and is not available for analysis.

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	Patients receive vorinostat PO BID on days 1-14. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Measure Participants	0

5. Secondary Outcome

Title	2-Year Overall Survival
Description	Estimated using the product-limit method of Kaplan and Meier.
Time Frame	Until Death from any cause, up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	Patients receive vorinostat PO BID on days 1-14. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Measure Participants	35
Number (95% Confidence Interval) [percentage of participants]	77 220%

6. Secondary Outcome

Title	2-Year Progression Free-Survival
Description	Estimated using the product-limit method of Kaplan and Meier. Progression defined as any new lesion or increase by greater than 50% of previously involved sites from nadir.
Time Frame	Until death or progression, up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	Patients receive vorinostat PO BID on days 1-14. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
Measure Participants	35
Number (95% Confidence Interval) [percentage of participants]	37 105.7%

Adverse Events

Time Frame	All adverse events were collected over a period of 10 years, 8 months.
Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Treatment (Vorinostat)
Arm/Group Description	Patients receive vorinostat PO BID on days 1-14. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Vorinostat: Given PO
All Cause Mortality
	Treatment (Vorinostat)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Vorinostat)
	Affected / at Risk (%)	# Events
Total	9/35 (25.7%)
Blood and lymphatic system disorders
Hemoglobin decreased	1/35 (2.9%)	1
Cardiac disorders
Atrial fibrillation	1/35 (2.9%)	1
Gastrointestinal disorders
Ear, nose and throat examination abnormal	1/35 (2.9%)	1
Nausea	1/35 (2.9%)	1
Vomiting	1/35 (2.9%)	1
General disorders
Fatigue	1/35 (2.9%)	1
Infections and infestations
Skin infection	2/35 (5.7%)	2
Investigations
Platelet count decreased	3/35 (8.6%)	3
Metabolism and nutrition disorders
Dehydration	2/35 (5.7%)	2
Serum sodium decreased	1/35 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/35 (2.9%)	1
Pneumonitis	1/35 (2.9%)	1
Vascular disorders
Hypotension	1/35 (2.9%)	1
Thrombosis	1/35 (2.9%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Vorinostat)
	Affected / at Risk (%)	# Events
Total	35/35 (100%)
Blood and lymphatic system disorders
Hemoglobin decreased	30/35 (85.7%)
Hemolysis	1/35 (2.9%)
Cardiac disorders
Atrial fibrillation	1/35 (2.9%)
Atrioventricular block first degree	1/35 (2.9%)
Cardiac disorder	2/35 (5.7%)
Cardiac valve disease	1/35 (2.9%)
Palpitations	2/35 (5.7%)
Sinus bradycardia	3/35 (8.6%)
Sinus tachycardia	1/35 (2.9%)
Ear and labyrinth disorders
Ear pain	1/35 (2.9%)
External ear pain	1/35 (2.9%)
Tinnitus	1/35 (2.9%)
Eye disorders
Cataract	1/35 (2.9%)
Diplopia	1/35 (2.9%)
Dry eye syndrome	2/35 (5.7%)
Eye disorder	3/35 (8.6%)
Vision blurred	3/35 (8.6%)
Gastrointestinal disorders
Abdominal distension	3/35 (8.6%)
Abdominal pain	8/35 (22.9%)
Ascites	1/35 (2.9%)
Cheilitis	1/35 (2.9%)
Constipation	13/35 (37.1%)
Diarrhea	30/35 (85.7%)
Dry mouth	10/35 (28.6%)
Dyspepsia	14/35 (40%)
Dysphagia	3/35 (8.6%)
Ear, nose and throat examination abnormal	2/35 (5.7%)
Esophageal pain	1/35 (2.9%)
Flatulence	5/35 (14.3%)
Gastritis	4/35 (11.4%)
Gastrointestinal disorder	4/35 (11.4%)
Gastrointestinal pain	1/35 (2.9%)
Hemorrhoids	3/35 (8.6%)
Intra-abdominal hemorrhage	1/35 (2.9%)
Mucositis oral	6/35 (17.1%)
Nausea	26/35 (74.3%)
Oral hemorrhage	1/35 (2.9%)
Oral pain	3/35 (8.6%)
Periodontal disease	1/35 (2.9%)
Proctoscopy abnormal	1/35 (2.9%)
Rectal hemorrhage	1/35 (2.9%)
Small intestinal mucositis	1/35 (2.9%)
Stomach pain	11/35 (31.4%)
Vomiting	13/35 (37.1%)
General disorders
Chest pain	2/35 (5.7%)
Chills	9/35 (25.7%)
Edema limbs	13/35 (37.1%)
Fatigue	34/35 (97.1%)
Fever	4/35 (11.4%)
Flu-like symptoms	14/35 (40%)
Gait abnormal	1/35 (2.9%)
General symptom	2/35 (5.7%)
Localized edema	1/35 (2.9%)
Pain	8/35 (22.9%)
Immune system disorders
Hypersensitivity	1/35 (2.9%)
Infections and infestations
Bladder infection	2/35 (5.7%)
Infection	2/35 (5.7%)
Lip infection	1/35 (2.9%)
Pharyngitis	1/35 (2.9%)
Rhinitis infective	1/35 (2.9%)
Sinusitis	2/35 (5.7%)
Skin infection	1/35 (2.9%)
Upper respiratory infection	4/35 (11.4%)
Urinary tract infection	1/35 (2.9%)
Vulvitis	1/35 (2.9%)
Injury, poisoning and procedural complications
Bruising	3/35 (8.6%)
Wound dehiscence	1/35 (2.9%)
Investigations
Activated partial thromboplastin time prolonged	1/35 (2.9%)
Alanine aminotransferase increased	7/35 (20%)
Alkaline phosphatase increased	4/35 (11.4%)
Aspartate aminotransferase increased	14/35 (40%)
Bilirubin increased	2/35 (5.7%)
Coagulopathy	1/35 (2.9%)
Creatinine increased	20/35 (57.1%)
Hyperbilirubinemia	1/35 (2.9%)
Hypercholesterolemia	1/35 (2.9%)
INR increased	2/35 (5.7%)
Laboratory test abnormal	2/35 (5.7%)
Leukocyte count decreased	14/35 (40%)
Leukopenia	9/35 (25.7%)
Lymphocyte count decreased	4/35 (11.4%)
Lymphopenia	8/35 (22.9%)
Neutrophil count decreased	17/35 (48.6%)
Platelet count decreased	30/35 (85.7%)
Serum cholesterol increased	1/35 (2.9%)
Weight gain	4/35 (11.4%)
Weight loss	12/35 (34.3%)
Metabolism and nutrition disorders
Anorexia	25/35 (71.4%)
Blood bicarbonate decreased	4/35 (11.4%)
Blood glucose increased	11/35 (31.4%)
Dehydration	4/35 (11.4%)
Hypercalcemia	2/35 (5.7%)
Hyperglycemia	10/35 (28.6%)
Hyperkalemia	1/35 (2.9%)
Hypertriglyceridemia	3/35 (8.6%)
Hyperuricemia	1/35 (2.9%)
Hypoalbuminemia	14/35 (40%)
Hypocalcemia	7/35 (20%)
Hypoglycemia	4/35 (11.4%)
Hypokalemia	4/35 (11.4%)
Hyponatremia	7/35 (20%)
Hypophosphatemia	8/35 (22.9%)
Serum albumin decreased	13/35 (37.1%)
Serum calcium decreased	6/35 (17.1%)
Serum calcium increased	3/35 (8.6%)
Serum glucose decreased	8/35 (22.9%)
Serum magnesium decreased	2/35 (5.7%)
Serum magnesium increased	2/35 (5.7%)
Serum phosphate decreased	16/35 (45.7%)
Serum potassium decreased	5/35 (14.3%)
Serum potassium increased	3/35 (8.6%)
Serum sodium decreased	9/35 (25.7%)
Serum sodium increased	1/35 (2.9%)
Serum triglycerides increased	3/35 (8.6%)
Musculoskeletal and connective tissue disorders
Arthritis	1/35 (2.9%)
Back pain	10/35 (28.6%)
Bone pain	2/35 (5.7%)
Chest wall pain	2/35 (5.7%)
Joint disorder	1/35 (2.9%)
Joint pain	7/35 (20%)
Muscle weakness	7/35 (20%)
Muscle weakness lower limb	4/35 (11.4%)
Musculoskeletal disorder	6/35 (17.1%)
Myalgia	13/35 (37.1%)
Neck pain	3/35 (8.6%)
Pain in extremity	9/35 (25.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/35 (2.9%)
Nervous system disorders
Depressed level of consciousness	2/35 (5.7%)
Dizziness	16/35 (45.7%)
Extrapyramidal disorder	3/35 (8.6%)
Headache	12/35 (34.3%)
Neurological disorder NOS	2/35 (5.7%)
Peripheral sensory neuropathy	8/35 (22.9%)
Taste alteration	15/35 (42.9%)
Tremor	3/35 (8.6%)
Psychiatric disorders
Agitation	2/35 (5.7%)
Anxiety	2/35 (5.7%)
Confusion	3/35 (8.6%)
Depression	3/35 (8.6%)
Insomnia	5/35 (14.3%)
Renal and urinary disorders
Glomerular filtration rate decreased	1/35 (2.9%)
Hemorrhage urinary tract	1/35 (2.9%)
Kidney pain	1/35 (2.9%)
Protein urine positive	1/35 (2.9%)
Urinary frequency	2/35 (5.7%)
Reproductive system and breast disorders
Erectile dysfunction	1/35 (2.9%)
Pelvic pain	1/35 (2.9%)
Reproductive tract disorder	1/35 (2.9%)
Vaginal hemorrhage	1/35 (2.9%)
Vaginal inflammation	1/35 (2.9%)
Vaginal pain	1/35 (2.9%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	2/35 (5.7%)
Cough	11/35 (31.4%)
Dyspnea	13/35 (37.1%)
Hemorrhage nasal	6/35 (17.1%)
Pharyngeal stenosis	1/35 (2.9%)
Pharyngolaryngeal pain	6/35 (17.1%)
Pleural effusion	2/35 (5.7%)
Pleuritic pain	3/35 (8.6%)
Respiratory disorder	7/35 (20%)
Voice alteration	1/35 (2.9%)
Skin and subcutaneous tissue disorders
Acne	1/35 (2.9%)
Alopecia	9/35 (25.7%)
Decubitus ulcer	1/35 (2.9%)
Dry skin	9/35 (25.7%)
Nail disorder	5/35 (14.3%)
Petechiae	1/35 (2.9%)
Pruritus	3/35 (8.6%)
Rash acneiform	1/35 (2.9%)
Rash desquamating	7/35 (20%)
Skin disorder	3/35 (8.6%)
Skin induration	2/35 (5.7%)
Skin ulceration	2/35 (5.7%)
Sweating	4/35 (11.4%)
Vascular disorders
Hematoma	1/35 (2.9%)
Hemorrhage	2/35 (5.7%)
Hot flashes	1/35 (2.9%)
Hypertension	3/35 (8.6%)
Hypotension	5/35 (14.3%)
Thrombosis	1/35 (2.9%)
Vascular disorder	1/35 (2.9%)

Limitations/Caveats

Two enrolled patients were ineligible due to diffuse B-cell lymphoma at start of treatment. Their treatment was changed (within 2 months of enrollment) before a response evaluation. These patients were removed and are not included in the analysis.

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.