Brentuximab Vedotin and Chemotherapy in CD30+ PMBL, Diffuse Large B-Cell, and Grey Zone Lymphoma Patients

• Sponsor: Abramson Cancer Center of the University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT01994850
• Collaborator: (none)
• Enrollment: 32
• Location: 1
• Arm: 1
• Actual Duration (Months): 62
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This is a Phase I/II multicenter single arm non-randomized open label study of the investigational drug, brentuximab vedotin, given in combination with routine chemotherapy (rituximab, cyclophosphamide, doxorubicin and prednisone) every 3 weeks for a total of 6 cycles.

Condition or Disease	Intervention/Treatment	Phase
CD30 Positive Primary Mediastinal Large B-cell Lymphoma; CD30-Positive Diffuse Large B-Cell Lymphoma; CD30-Positive Gray Zone Lymphoma	Drug: brentuximab vedotin	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study Of Brentuximab Vedotin In Combination With Multi-Agent Chemotherapy As Front-Line Treatment In Patients With CD30 Positive Primary Mediastinal Large B-Cell, Diffuse Large B-Cell, And Grey Zone Lymphomas
• Actual Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Aug 1, 2017
• Actual Study Completion Date: Jan 1, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Phase I/II Total of six 21-day cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP). Cycle 1 rituximab dose divided between Days 1 and 2 to prevent severe infusion reactions in rituximab naïve patients; brentuximab vedotin and cytotoxic chemotherapy administered on Day 2. Cycles 2 through 6 brentuximab vedotin and R-CHP administered on Day 1. Prednisone (or steroid equivalent) administered Days 1-5 of each cycle (prior to rituximab infusion). Cycle 1: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 100 mg/m2 IV; Day 2: Rituximab 275 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg or 1.2 mg/kg (Phase I data established a MTD of 1.8 mg/kg brentuximab vedotin) Cycles 2-6: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg

Drug: brentuximab vedotin; Trade name: Adcetris

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Dose-limiting Toxicities [21 days (Cycle 1)]

   Dose-limiting toxicity (DLT) is any grade 3 or 4 new non-hematologic toxicity occurring during Cycle 1 requiring a dose delay of >14 days from the planned Day 1 of Cycle 2 (21 days from Day 1 of Cycle 1). The initial planned dose of brentuximab vedotin for the Phase I cohort of 6 patients is 1.8 mg/kg. This cohort will be evaluated for DLT in the first cycle of treatment. Dose de-escalation to 1.2 mg/kg will occur if ≥ 2 of 6 patients at the 1.8 mg/kg dose level experience a DLT.

2. Overall Response Rate (ORR) [Three to five weeks after the completion of Cycle 6 (approximately 5 months after start if treatment)]

   Overall response rate (ORR) is defined as the proportion of patients with CR or PR according to the International Working Group Response Criteria for non-Hodgkin Lymphoma at the conclusion of systemic therapy.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age 18 and above

• Histologically confirmed CD30-positive, CD20-positive untreated primary mediastinal B-cell lymphoma (any Ann Arbor stage), diffuse large B-cell lymphoma (Ann Arbor stage III or IV), or grey zone lymphoma (any Ann Arbor stage). Patients with heterogeneous, weak or equivocal CD30 staining will also be included (no specific cut off percentage for CD30 stain is required).

• Measurable disease, defined by the Revised Response Criteria for Malignant Lymphoma

• Absolute neutrophil count ≥1,000/mmᶟ and platelet count ≥75,000/µL(unless documented bone marrow involvement with lymphoma).

• Normal left ventricular ejection fraction of ≥50% estimated by MUGA scan or echocardiogram.

• Estimated creatinine clearance (using Cockcroft-Gault equation) must be >50 mL/min.

• Serum bilirubin ≤1.5 x upper limit of normal (ULN). Bilirubin ≤ 3 x ULN is permitted in individuals with documented liver involvement by lymphoma or if due to known Gilbert syndrome.

• Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase ≤ 3 x ULN.

• Performance status of ECOG 0-2; patients with ECOG of 3 may be allowed to enroll after discussion with the Regulatory-Sponsor/Principal Investigator and medical monitor, and if the performance status is believed to be secondary to lymphoma related symptoms and performance status is expected to improve once chemotherapy commences.

• Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent. In patients who are not able to consent to the trial due to medical circumstances, the next of kin or power

• Females of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (b-hcG) pregnancy test result within 7 days prior to the first dose of brentuximab vedotin and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug; females of non-childbearing potential are those who are post-menopausal for more than 1 year or who have had bilateral tubal ligation or hysterectomy.

• Males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 6 months following the last dose of study drug.

• Must be able to comply with the study and follow-up requirements.

Exclusion Criteria:

• Previous use of investigational agents, chemotherapy or immunotherapy for lymphoma any time prior to enrollment (i.e. must have untreated disease). Prior allogeneic or autologous transplants are also not allowed.

• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol. Consolidative radiation therapy (RT) after completion of planned course and/or concurrent intrathecal chemotherapy for CNS disease prophylaxis is permissible.

• Treatment with systemic steroids for > 4 weeks prior to Cycle 1 Day 1 of study therapy. Prior radiation therapy, with the exception of an abbreviated course (not more than 3 days) if used for SVC syndrome.

• History of serious organ dysfunction or disease involving the heart (left ventricular ejection fraction < 50%; unstable angina, acute myocardial infarction within 6 months prior to randomization, congestive heart failure NYHA III-IV, and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities.), the kidney (creatinine clearance <50 mL/min), the liver (chronic hepatitis B as defined below or elevated AST, ALT or alkaline phosphatase > 3 ULN; serum bilirubin > 1.5 x ULN; bilirubin up to 3 x ULN is permitted in individuals with documented liver involvement by lymphoma or if due to known Gilbert syndrome) ot other organ system that may place the patient at undue risk to undergo treatment.

• Uncontrolled systemic fungal, bacterial, viral, or serious infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment). May be enrolled if controlled on treatment.

• Significant concurrent disease, illness or psychiatric disorder that would compromise patient safety or compliance, interfere with consent, study participation, follow-up, or interpretation of study results.

• Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involved with lymphoma or stable chronic liver disease per investigator's assessment).

• History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae.

• Other malignancy, unless the patient has been disease-free for at least 3 years following the completion of curative intent therapy, with the following exceptions: Treated non-melanoma skin cancer, any in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease -free duration, are eligible for this study if definitive treatment for the condition has been completed.Organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated, or radical prostatectomy or definitive prostate irradiation has been performed.

• Positive test for the Human Immunodeficiency Virus (HIV) unless undetectable viral load within 3 months of enrollment (HIV RNA less than 48 copies/mL) and on HAART therapy.

• Positive serology for hepatitis B (HB) defined as a positive test for hepatitis B surface antigen or hepatitis B core antibody.

• Active involvement of the central nervous system (CNS) by lymphoma. Work-up for CNS involvement at diagnosis will be directed as per the treating physician and will depend on specific clinical circumstances (no brain imaging or lumbar puncture is required by this protocol).

• Pregnant or lactating women.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Abramson Cancer Center of the University of Pennsylvania

Investigators

• Principal Investigator: Jakub Svoboda, MD, Abramson Cancer Center of the University of Pennsylvania

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 21, 2018

More Information

Additional Information:

• Abstract: Revised response criteria for malignant lymphoma.

Publications

None provided.

• Responsible Party: Abramson Cancer Center of the University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT01994850
• Other Study ID Numbers: UPCC 17413
• First Posted: Nov 26, 2013
• Last Update Posted: Jan 5, 2021
• Last Verified: Dec 1, 2020

• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Brentuximab Vedotin

Study Results

Participant Flow

Arm/Group Title	Phase I/II
Arm/Group Description	Total of six 21-day cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP). Cycle 1 rituximab dose divided between Days 1 and 2 to prevent severe infusion reactions in rituximab naïve patients; brentuximab vedotin and cytotoxic chemotherapy administered on Day 2. Cycles 2 through 6 brentuximab vedotin and R-CHP administered on Day 1. Prednisone (or steroid equivalent) administered Days 1-5 of each cycle (prior to rituximab infusion). Cycle 1: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 100 mg/m2 IV; Day 2: Rituximab 275 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg or 1.2 mg/kg (Phase I data established a MTD of 1.8 mg/kg brentuximab vedotin) Cycles 2-6: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg
Period Title: Overall Study
STARTED	32
COMPLETED	30
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Phase I/II
Arm/Group Description	Total of six 21-day cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP). Cycle 1 rituximab dose divided between Days 1 and 2 to prevent severe infusion reactions in rituximab naïve patients; brentuximab vedotin and cytotoxic chemotherapy administered on Day 2. Cycles 2 through 6 brentuximab vedotin and R-CHP administered on Day 1. Prednisone (or steroid equivalent) administered Days 1-5 of each cycle (prior to rituximab infusion). Cycle 1: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 100 mg/m2 IV; Day 2: Rituximab 275 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg or 1.2 mg/kg (Phase I data established a MTD of 1.8 mg/kg brentuximab vedotin) Cycles 2-6: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg
Overall Participants	32
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	29 90.6%
>=65 years	3 9.4%
Sex: Female, Male (Count of Participants)
Female	16 50%
Male	16 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	28 87.5%
Unknown or Not Reported	4 12.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 3.1%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 9.4%
White	27 84.4%
More than one race	0 0%
Unknown or Not Reported	1 3.1%
Region of Enrollment (participants) [Number]
United States	32 100%
Lymphoma subtype (Count of Participants)
Primary Mediastinal Large B-cell Lymphoma	23 71.9%
Diffuse Large B-Cell Lymphoma	6 18.8%
Gray Zone Lymphoma	2 6.3%
Not included (Subject withdrew)	1 3.1%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Dose-limiting Toxicities
Description	Dose-limiting toxicity (DLT) is any grade 3 or 4 new non-hematologic toxicity occurring during Cycle 1 requiring a dose delay of >14 days from the planned Day 1 of Cycle 2 (21 days from Day 1 of Cycle 1). The initial planned dose of brentuximab vedotin for the Phase I cohort of 6 patients is 1.8 mg/kg. This cohort will be evaluated for DLT in the first cycle of treatment. Dose de-escalation to 1.2 mg/kg will occur if ≥ 2 of 6 patients at the 1.8 mg/kg dose level experience a DLT.
Time Frame	21 days (Cycle 1)

Outcome Measure Data

Analysis Population Description

A total of 6 subjects were evaluated for dose limiting toxicities during Phase I. Since no DLTs were observed, the Phase I subjects were included in the efficacy analysis as they received the same dose of brentuximab vedotin 1.8 mg/kg as the Phase II subjects.

Arm/Group Title	Phase I/II
Arm/Group Description	Total of six 21-day cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP). Cycle 1 rituximab dose divided between Days 1 and 2 to prevent severe infusion reactions in rituximab naïve patients; brentuximab vedotin and cytotoxic chemotherapy administered on Day 2. Cycles 2 through 6 brentuximab vedotin and R-CHP administered on Day 1. Prednisone (or steroid equivalent) administered Days 1-5 of each cycle (prior to rituximab infusion). Cycle 1: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 100 mg/m2 IV; Day 2: Rituximab 275 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg or 1.2 mg/kg (Phase I data established a MTD of 1.8 mg/kg brentuximab vedotin) Cycles 2-6: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg
Measure Participants	6
Count of Participants [Participants]	0 0%

2. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Overall response rate (ORR) is defined as the proportion of patients with CR or PR according to the International Working Group Response Criteria for non-Hodgkin Lymphoma at the conclusion of systemic therapy.
Time Frame	Three to five weeks after the completion of Cycle 6 (approximately 5 months after start if treatment)

Outcome Measure Data

Analysis Population Description

32 patients were enrolled: 1 patient withdrew, 1 was removed for protocol non-compliance, 1 was removed due to regimen violation; a total of 29 were evaluable for efficacy.

Arm/Group Title	Phase I/II
Arm/Group Description	Total of six 21-day cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP). Cycle 1 rituximab dose divided between Days 1 and 2 to prevent severe infusion reactions in rituximab naïve patients; brentuximab vedotin and cytotoxic chemotherapy administered on Day 2. Cycles 2 through 6 brentuximab vedotin and R-CHP administered on Day 1. Prednisone (or steroid equivalent) administered Days 1-5 of each cycle (prior to rituximab infusion). Cycle 1: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 100 mg/m2 IV; Day 2: Rituximab 275 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg or 1.2 mg/kg (Phase I data established a MTD of 1.8 mg/kg brentuximab vedotin) Cycles 2-6: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg
Measure Participants	29
Complete response	25 78.1%
Partial resonse	4 12.5%

Adverse Events

Time Frame	Adverse event data were collected from the initiation of the first study treatment (Cycle 1/Day 1) to 30 days following the last administration of study treatment, which is approximately 5 months.
Arm/Group Title	Phase I/II
Arm/Group Description	Total of six 21-day cycles of brentuximab vedotin in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP). Cycle 1 rituximab dose divided between Days 1 and 2 to prevent severe infusion reactions in rituximab naïve patients; brentuximab vedotin and cytotoxic chemotherapy administered on Day 2. Cycles 2 through 6 brentuximab vedotin and R-CHP administered on Day 1. Prednisone (or steroid equivalent) administered Days 1-5 of each cycle (prior to rituximab infusion). Cycle 1: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 100 mg/m2 IV; Day 2: Rituximab 275 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg or 1.2 mg/kg (Phase I data established a MTD of 1.8 mg/kg brentuximab vedotin) Cycles 2-6: Days 1-5: Prednisone (or equivalent) 100 mg PO/IV; Day 1: Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV, Doxorubicin 50 mg/m² IV, Brentuximab vedotin 1.8 mg/kg
All Cause Mortality
	Phase I/II
	Affected / at Risk (%)	# Events
Total	2/31 (6.5%)
Serious Adverse Events
	Phase I/II
	Affected / at Risk (%)	# Events
Total	12/31 (38.7%)
Blood and lymphatic system disorders
Febrile neutropenia	6/31 (19.4%)	7
Cardiac disorders
Left ventricular systolic dysfunction	1/31 (3.2%)	1
General disorders
Fever	1/31 (3.2%)	1
Infections and infestations
Abdominal infection	1/31 (3.2%)	1
Gum infection	1/31 (3.2%)	1
Urinary tract infection	1/31 (3.2%)	1
MRSA bacteremia	1/31 (3.2%)	1
Catheter related infection	1/31 (3.2%)	1
Metabolism and nutrition disorders
Lactic acidosis	1/31 (3.2%)	2
Vascular disorders
Thromboembolic event	1/31 (3.2%)	1
Other (Not Including Serious) Adverse Events
	Phase I/II
	Affected / at Risk (%)	# Events
Total	29/31 (93.5%)
Blood and lymphatic system disorders
Anemia	21/31 (67.7%)
Hemolytic uremic syndrome	1/31 (3.2%)
Cardiac disorders
Palpitations	2/31 (6.5%)
Sinus tachycardia	1/31 (3.2%)
Ear and labyrinth disorders
Other, left ear fullness	1/31 (3.2%)
Hearing impaired	1/31 (3.2%)
Vertigo	1/31 (3.2%)
Eye disorders
Blurred vision	2/31 (6.5%)
other	3/31 (9.7%)
Gastrointestinal disorders
Abdominal pain	4/31 (12.9%)
Constipation	16/31 (51.6%)
Dry mouth	1/31 (3.2%)
Diarrhea	13/31 (41.9%)
Dyspepsia	1/31 (3.2%)
Esophageal pain	1/31 (3.2%)
Flatulence	1/31 (3.2%)
Gastroesophageal reflux disease	6/31 (19.4%)
Gingival pain	2/31 (6.5%)
Other	2/31 (6.5%)
Hemorrhoidal hemorrhage	1/31 (3.2%)
Nausea	21/31 (67.7%)
Oral dysesthesia	1/31 (3.2%)
Mucositis oral	9/31 (29%)
Toothache	1/31 (3.2%)
Vomiting	4/31 (12.9%)
Edema limbs	2/31 (6.5%)
General disorders
Chills	3/31 (9.7%)
Edema face	2/31 (6.5%)
Edema trunk	1/31 (3.2%)
Fatigue	20/31 (64.5%)
Fever	7/31 (22.6%)
Infusion related reaction	4/31 (12.9%)
Infusion site extravasation	1/31 (3.2%)
Irritability	1/31 (3.2%)
Non-cardiac chest pain	2/31 (6.5%)
Pain	5/31 (16.1%)
Immune system disorders
Allergic reaction	2/31 (6.5%)
Infections and infestations
Bronchial infection	1/31 (3.2%)
Thrush	1/31 (3.2%)
Papulopustular rash	1/31 (3.2%)
Sinusitis	1/31 (3.2%)
Upper respiratory infection	1/31 (3.2%)
Urinary tract infection	4/31 (12.9%)
Injury, poisoning and procedural complications
Bruising	2/31 (6.5%)
Fall	1/31 (3.2%)
Investigations
Alanine aminotransferase increased	5/31 (16.1%)
Alkaline phosphatase increased	4/31 (12.9%)
Aspartate aminotransferase increased	6/31 (19.4%)
Creatinine increased	1/31 (3.2%)
Lymphocyte count decreased	26/31 (83.9%)
Neutrophil count decreased	18/31 (58.1%)
Platelet count decreased	7/31 (22.6%)
Weight loss	1/31 (3.2%)
White blood cell decreased	24/31 (77.4%)
Metabolism and nutrition disorders
Anorexia	4/31 (12.9%)
Hyperglycemia	5/31 (16.1%)
Hyperuricemia	2/31 (6.5%)
Hypoalbuminemia	3/31 (9.7%)
Hypocalcemia	3/31 (9.7%)
Hypoglycemia	1/31 (3.2%)
Hypokalemia	3/31 (9.7%)
Hyponatremia	10/31 (32.3%)
Hypophosphatemia	2/31 (6.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/31 (9.7%)
Bone pain	1/31 (3.2%)
Muscle weakness lower limb	2/31 (6.5%)
Myalgia	3/31 (9.7%)
Neck pain	1/31 (3.2%)
Pain in extremity	2/31 (6.5%)
Dysgeusia	2/31 (6.5%)
Nervous system disorders
Dizziness	9/31 (29%)
Headache	11/31 (35.5%)
Paresthesia	1/31 (3.2%)
Peripheral motor neuropathy	2/31 (6.5%)
Peripheral sensory neuropathy	19/31 (61.3%)
Psychiatric disorders
Anxiety	4/31 (12.9%)
Depression	1/31 (3.2%)
Insomnia	3/31 (9.7%)
Renal and urinary disorders
Hematuria	1/31 (3.2%)
Urinary frequency	3/31 (9.7%)
Urinary retention	1/31 (3.2%)
Urinary urgency	1/31 (3.2%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	4/31 (12.9%)
Cough	6/31 (19.4%)
Dyspnea	5/31 (16.1%)
Hoarseness	1/31 (3.2%)
Nasal congestion	2/31 (6.5%)
Pneumonitis	1/31 (3.2%)
Pneumothorax	1/31 (3.2%)
Postnasal drip	1/31 (3.2%)
Sore throat	1/31 (3.2%)
Voice alteration	1/31 (3.2%)
Wheezing	1/31 (3.2%)
Skin and subcutaneous tissue disorders
Alopecia	6/31 (19.4%)
Hyperhidrosis	2/31 (6.5%)
Nail discoloration	1/31 (3.2%)
Pruritus	1/31 (3.2%)
Other skin irritation	1/31 (3.2%)
Rash acneiform	1/31 (3.2%)
Rash maculo-papular	2/31 (6.5%)
Scalp pain	1/31 (3.2%)
Other psoriasis	1/31 (3.2%)
Skin hyperpigmentation	1/31 (3.2%)
Night sweats	1/31 (3.2%)
Vascular disorders
Hematoma	1/31 (3.2%)
Hot flashes	4/31 (12.9%)
Hypertension	2/31 (6.5%)
Hypotension	1/31 (3.2%)
Phlebitis	1/31 (3.2%)
Thromboembolic event	3/31 (9.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the information provided by the sponsor for the purposes of performing the study, will be published or passed on to any third party without the consent of the study sponsor. Any investigator involved with this study is obligated to provide the sponsor with complete test results and all data derived from the study.