Acalabrutinib With Bendamustine / Rituximab Followed by Cytarabine / Rituximab for Untreated Mantle Cell Lymphoma

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03623373
• Collaborator: Acerta Pharma BV (Industry)
• Enrollment: 13
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 74.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study is designed to evaluate the efficacy and safety of acalabrutinib plus bendamustine and rituximab followed by acalabrutinib plus cytarabine and rituximab in subjects with treatment naïve mantle cell lymphoma (MCL), as a preparation for a larger cooperative group trial with the goal of achieving a standard induction regimen for MCL in transplant eligible patients. The investigators hypothesize that the addition of acalabrutinib to BR/CR regimen will prove safe and increase the complete response (CR) rate as well as minimal residual disease (MRD) negativity pre-transplant, thus improving clinical outcomes.

Condition or Disease	Intervention/Treatment	Phase
Mantle Cell Lymphoma	Drug: Bendamustine; Drug: Rituximab; Drug: Acalabrutinib; Drug: Cytarabine; Procedure: Leukapheresis; Procedure: Peripheral blood; Procedure: Oral rinse; Procedure: Bone marrow collection	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Acalabrutinib With Bendamustine / Rituximab Followed by Cytarabine / Rituximab for Untreated Mantle Cell Lymphoma
• Actual Study Start Date: Nov 29, 2018
• Actual Primary Completion Date: Feb 9, 2020
• Anticipated Study Completion Date: Feb 5, 2025

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Bendamustine/Rituximab/Acalabrutinib/Cytarabine Patients will receive (6) 28 day cycles Cycles 1-3 will consist of bendamustine on Days 1 and 2, rituximab on Day 1, and acalabrutinib twice per day (BID) on Days 1 through 28. Cycles 4-6 will consist of rituximab on Day 1, cytarabine every 12 hours on Days 1 and 2, acalabrutinib BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, one week on), and growth factors as per institutional standard After Cycle 6, patients will undergo leukapheresis

Drug: Bendamustine; Bendamustine will be administered at a dose of 90 mg/m^2 IV over 30 minutes on Days 1 and 2 of Cycles 1-3; Other Names: Treanda Bendeka ; Drug: Rituximab; In Cycle 1, rituximab will be administered at a dose of 375 mg/m^2 IV on Day 1 or 2 at the investigator's discretion in order to reduce the risk of a first infusion reaction. Rituximab will be given on Day 1 of Cycles 1 through 6.; Other Names: Rituxan Rituxan Hycela ; Drug: Acalabrutinib; The capsules should be swallowed intact with water and with or without food.; Other Names: Calquence® ; Drug: Cytarabine; On Days 1 and 2 of Cycles 4-6, following rituximab dosing, cytarabine will be administered IV every 12 hours for a total of 4 doses.; Other Names: Cytosar-U ; Procedure: Leukapheresis; Until collection of ≥ 2 x 106 CD34+ stem cells / kg; Procedure: Peripheral blood; -Baseline, end of Cycle 3, 4-6 weeks after Cycle 6 Day 1, and if the patient discontinues protocol therapy prior to completion of Cycle 6; Procedure: Oral rinse; -Baseline; Procedure: Bone marrow collection; -Bone marrow will be collected at baseline if the patient requires a marrow for staging purposes and at end of treatment if the patient requires a marrow for restaging.

Outcome Measures

Primary Outcome Measures

1. Stem Cell Mobilization Success Rate With Cytarabine and Rituximab [Through 5 courses of apheresis (up to 5 days)]

   -Stem cell mobilization success is defined as a yield of >2x10^6 CD34+ stem cells/kg with a maximum of 5 courses of apheresis

Secondary Outcome Measures

1. Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher [30 days following completion of treatment (estimated to be 7 months)]

   -Toxicity is measured using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

2. Overall Response Rate (ORR = Complete Response (CR) + Partial Response (PR)) of Subjects [Through completion of treatment (estimated to be 6 months)]

   -For definitions of CR and PR please refer to the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification

3. Pre-transplant Complete Response Rate [Through completion of treatment (estimated to be 6 months)]

   -For definitions of CR, please refer to the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification

4. Progression-free Survival (PFS) [Through 5 years]

   PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first London Deauville score of 4 or 5 in individual target nodes/masses with an increase in intensity of uptake from the baseline and/or new FDG avid foci consistent with lymphoma at interim or end of treatment assessment; New FDG avid foci of extranodal disease consistent with lymphoma. If there is concern regarding the etiology of the new lesions, biopsy or interval scan may be considered; New or recurrent FDG avid foci in the bone marrow

5. Overall Survival (OS) [Through 5 years]

   -OS=time from study registration until death from any cause

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed mantle cell lymphoma with documented expression of Cyclin D1 by immune-histochemical stains and/or t(11;14) by cytogenetics or FISH.

• Presence of evaluable disease by PET imaging per the Lugano classification.

• Eligible for autologous stem cell transplantation.

• Between 18 and 70 years of age, inclusive.

• ECOG performance status ≤ 2

• Normal bone marrow and organ function as defined below:

• Absolute neutrophil count ≥ 1,000/mcL unless, in the opinion of the treating physician, neutropenia is due to splenomegaly or bone marrow involvement

• Platelets ≥ 100,000/mcL unless, in the opinion of the treating physician, thrombocytopenia is due to splenomegaly or bone marrow involvement

• Total bilirubin ≤ 2.0 x IULN and AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN except when, in the opinion of the treating physician, elevation is due to direct involvement of lymphoma (e.g. hepatic infiltration or biliary obstruction due to lymphoma) or Gilbert's disease

• Creatinine ≤ IULN OR creatinine clearance ≥ 40 mL/min for patients with creatinine levels above institutional normal

• Women of childbearing 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 must inform her treating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• Any previous chemotherapy or radiation for mantle cell lymphoma. Short course of steroids for symptom relief prior to presentation is permissible.

• Symptomatic meningeal or parenchymal brain lymphoma.

• Prior exposure to a BTK inhibitor.

• Currently receiving any other investigational agents.

• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to acalabrutinib, rituximab, cytarabine, bendamustine, or other agents used in the study.

• Received a live virus vaccination within 28 days of first dose of study drug.

• Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti-infective treatment within 2 weeks before first dose of study drug.

• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec at screening. Exception: subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study.

• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.

• Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand disease).

• Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura).

• Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.

• Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.

• Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug.

• Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) >2x ULN. Exception: Subjects receiving warfarin are excluded; however, those receiving other anticoagulant therapy who have a higher INR/aPTT may be permitted to enroll to this study after discussion with the PI.

• Requires treatment with proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.

• History of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug.

• Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.

• Subjects with serologic status reflecting active viral hepatitis B or C infection. Subjects who are hepatitis B core antibody positive but surface antigen negative will need negative polymerase chain reaction (PCR) prior to enrollment. Hepatitis B surface antigen positive or PCR positive patients will be excluded. Subjects who are hepatitis C antibody positive will need negative PCR prior to enrollment. Subjects with positive hepatitis C PCR will be excluded.

• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 14 days of study entry.

• Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with acalabrutinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine
• Acerta Pharma BV

Investigators

• Principal Investigator: Brad S Kahl, M.D., Washington University School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 18, 2019

More Information

Additional Information:

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Publications

None provided.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT03623373
• Other Study ID Numbers: 201809111
• First Posted: Aug 9, 2018
• Last Update Posted: Feb 4, 2022
• Last Verified: Feb 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Cytarabine; Rituximab; Bendamustine Hydrochloride; Acalabrutinib

Study Results

Participant Flow

Arm/Group Title	Bendamustine/Rituximab/Acalabrutinib/Cytarabine
Arm/Group Description	Patients will receive (6) 28 day cycles Cycles 1-3 will consist of bendamustine on Days 1 and 2, rituximab on Day 1, and acalabrutinib twice per day (BID) on Days 1 through 28. Cycles 4-6 will consist of rituximab on Day 1, cytarabine every 12 hours on Days 1 and 2, acalabrutinib BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, one week on), and growth factors as per institutional standard After Cycle 6, patients will undergo leukapheresis
Period Title: Overall Study
STARTED	13
COMPLETED	13
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Bendamustine/Rituximab/Acalabrutinib/Cytarabine
Arm/Group Description	Patients will receive (6) 28 day cycles Cycles 1-3 will consist of bendamustine on Days 1 and 2, rituximab on Day 1, and acalabrutinib twice per day (BID) on Days 1 through 28. Cycles 4-6 will consist of rituximab on Day 1, cytarabine every 12 hours on Days 1 and 2, acalabrutinib BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, one week on), and growth factors as per institutional standard After Cycle 6, patients will undergo leukapheresis
Overall Participants	13
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57
Sex: Female, Male (Count of Participants)
Female	1 7.7%
Male	12 92.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	13 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	13 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Stem Cell Mobilization Success Rate With Cytarabine and Rituximab
Description	-Stem cell mobilization success is defined as a yield of >2x10^6 CD34+ stem cells/kg with a maximum of 5 courses of apheresis
Time Frame	Through 5 courses of apheresis (up to 5 days)

Outcome Measure Data

Analysis Population Description

9 participants are not evaluable because they did not receive stem cell transplant.

Arm/Group Title	Bendamustine/Rituximab/Acalabrutinib/Cytarabine
Arm/Group Description	Patients will receive (6) 28 day cycles Cycles 1-3 will consist of bendamustine on Days 1 and 2, rituximab on Day 1, and acalabrutinib twice per day (BID) on Days 1 through 28. Cycles 4-6 will consist of rituximab on Day 1, cytarabine every 12 hours on Days 1 and 2, acalabrutinib BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, one week on), and growth factors as per institutional standard After Cycle 6, patients will undergo leukapheresis
Measure Participants	4
Count of Participants [Participants]	4 30.8%

2. Secondary Outcome

Title	Safety and Tolerability of Regimen in Subjects With MCL as Measured by Treatment Related Non-hematologic Toxicity of Grade 3 or Higher
Description	-Toxicity is measured using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time Frame	30 days following completion of treatment (estimated to be 7 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bendamustine/Rituximab/Acalabrutinib/Cytarabine
Arm/Group Description	Patients will receive (6) 28 day cycles Cycles 1-3 will consist of bendamustine on Days 1 and 2, rituximab on Day 1, and acalabrutinib twice per day (BID) on Days 1 through 28. Cycles 4-6 will consist of rituximab on Day 1, cytarabine every 12 hours on Days 1 and 2, acalabrutinib BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, one week on), and growth factors as per institutional standard After Cycle 6, patients will undergo leukapheresis
Measure Participants	13
Diarrhea	1 7.7%
Infusion related reaction	1 7.7%
Upper respiratory infection	1 7.7%
Skin infection	1 7.7%
Perirectal abscess	1 7.7%
Peritoneal infection	1 7.7%
Blood bilirubin increased	1 7.7%
Ejection fraction decreased	1 7.7%
Alanine aminotransferase increased	1 7.7%

3. Secondary Outcome

Title	Overall Response Rate (ORR = Complete Response (CR) + Partial Response (PR)) of Subjects
Description	-For definitions of CR and PR please refer to the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification
Time Frame	Through completion of treatment (estimated to be 6 months)

Outcome Measure Data

Analysis Population Description

1 participant did not complete 2 cycles and was not evaluable for response

Arm/Group Title	Bendamustine/Rituximab/Acalabrutinib/Cytarabine
Arm/Group Description	Patients will receive (6) 28 day cycles Cycles 1-3 will consist of bendamustine on Days 1 and 2, rituximab on Day 1, and acalabrutinib twice per day (BID) on Days 1 through 28. Cycles 4-6 will consist of rituximab on Day 1, cytarabine every 12 hours on Days 1 and 2, acalabrutinib BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, one week on), and growth factors as per institutional standard After Cycle 6, patients will undergo leukapheresis
Measure Participants	12
Count of Participants [Participants]	10 76.9%

4. Secondary Outcome

Title	Pre-transplant Complete Response Rate
Description	-For definitions of CR, please refer to the Recommendations for Initial Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification
Time Frame	Through completion of treatment (estimated to be 6 months)

Outcome Measure Data

Analysis Population Description

1 participant did not complete 2 cycles and was not evaluable for response

Arm/Group Title	Bendamustine/Rituximab/Acalabrutinib/Cytarabine
Arm/Group Description	Patients will receive (6) 28 day cycles Cycles 1-3 will consist of bendamustine on Days 1 and 2, rituximab on Day 1, and acalabrutinib twice per day (BID) on Days 1 through 28. Cycles 4-6 will consist of rituximab on Day 1, cytarabine every 12 hours on Days 1 and 2, acalabrutinib BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, one week on), and growth factors as per institutional standard After Cycle 6, patients will undergo leukapheresis
Measure Participants	12
Count of Participants [Participants]	9 69.2%

5. Secondary 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 occurs first London Deauville score of 4 or 5 in individual target nodes/masses with an increase in intensity of uptake from the baseline and/or new FDG avid foci consistent with lymphoma at interim or end of treatment assessment; New FDG avid foci of extranodal disease consistent with lymphoma. If there is concern regarding the etiology of the new lesions, biopsy or interval scan may be considered; New or recurrent FDG avid foci in the bone marrow
Time Frame	Through 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Overall Survival (OS)
Description	-OS=time from study registration until death from any cause
Time Frame	Through 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse events were collected through 30 days after the last dose of study treatment (approximately 7 months)
Arm/Group Title	Bendamustine/Rituximab/Acalabrutinib/Cytarabine
Arm/Group Description	Patients will receive (6) 28 day cycles Cycles 1-3 will consist of bendamustine on Days 1 and 2, rituximab on Day 1, and acalabrutinib twice per day (BID) on Days 1 through 28. Cycles 4-6 will consist of rituximab on Day 1, cytarabine every 12 hours on Days 1 and 2, acalabrutinib BID on Days 1 through 7 and 22 through 28 (one week on, two weeks off, one week on), and growth factors as per institutional standard After Cycle 6, patients will undergo leukapheresis
All Cause Mortality
	Bendamustine/Rituximab/Acalabrutinib/Cytarabine
	Affected / at Risk (%)	# Events
Total	3/13 (23.1%)
Serious Adverse Events
	Bendamustine/Rituximab/Acalabrutinib/Cytarabine
	Affected / at Risk (%)	# Events
Total	8/13 (61.5%)
Blood and lymphatic system disorders
Febrile neutropenia	3/13 (23.1%)
Eye disorders
Retinal vein thrombosis	1/13 (7.7%)
General disorders
Flu like symptoms	1/13 (7.7%)
Infusion related reaction	1/13 (7.7%)
Infections and infestations
Skin infection	1/13 (7.7%)
Perirectal abscess	1/13 (7.7%)
Metabolism and nutrition disorders
Hyponatremia	1/13 (7.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Carcinoma of undetermined source	1/13 (7.7%)
Other (Not Including Serious) Adverse Events
	Bendamustine/Rituximab/Acalabrutinib/Cytarabine
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
Anemia	12/13 (92.3%)
Cardiac disorders
Palpitations	1/13 (7.7%)
Tachycardia	1/13 (7.7%)
Eye disorders
Cataract	1/13 (7.7%)
Gastrointestinal disorders
Abdominal pain	1/13 (7.7%)
Constipation	4/13 (30.8%)
Diarrhea	7/13 (53.8%)
Gastroesophageal reflux disease	1/13 (7.7%)
Flatulence	2/13 (15.4%)
Bloating	4/13 (30.8%)
Mucositis oral	3/13 (23.1%)
Nausea	8/13 (61.5%)
Stomach cramps	1/13 (7.7%)
Tooth ache	1/13 (7.7%)
Vomiting	9/13 (69.2%)
General disorders
Body aches	2/13 (15.4%)
Night sweats	1/13 (7.7%)
Chills	1/13 (7.7%)
Fever	2/13 (15.4%)
Edema limbs	1/13 (7.7%)
Malaise	1/13 (7.7%)
Fatigue	9/13 (69.2%)
Infusion related reaction	5/13 (38.5%)
Swelling	1/13 (7.7%)
Pain	3/13 (23.1%)
Immune system disorders
Allergic reaction	1/13 (7.7%)
Infections and infestations
Upper respiratory infection	3/13 (23.1%)
Folliculitis	1/13 (7.7%)
Lung infection	1/13 (7.7%)
Peritoneal infection	1/13 (7.7%)
Urinary tract infection	1/13 (7.7%)
Shingles	1/13 (7.7%)
Sinusitis	2/13 (15.4%)
Tooth infection	1/13 (7.7%)
Injury, poisoning and procedural complications
Bruising	3/13 (23.1%)
Burning sensation at injection site	1/13 (7.7%)
Investigations
Lymphocyte count decreased	13/13 (100%)
Blood bilirubin increased	3/13 (23.1%)
Neutrophil count decreased	13/13 (100%)
Platelet count decreased	13/13 (100%)
Ejection fraction decreased	1/13 (7.7%)
White blood cell decreased	13/13 (100%)
Alkaline phosphatase increased	5/13 (38.5%)
Aspartate aminotransferase increased	3/13 (23.1%)
Alanine aminotransferase increased	4/13 (30.8%)
Creatinine increased	5/13 (38.5%)
Metabolism and nutrition disorders
Anorexia	3/13 (23.1%)
Hyperglycemia	3/13 (23.1%)
Hyperkalemia	3/13 (23.1%)
Hypermagnesemia	1/13 (7.7%)
Hypernatremia	1/13 (7.7%)
Hyperuricemia	5/13 (38.5%)
Hypoalbuminemia	5/13 (38.5%)
Hypocalcemia	3/13 (23.1%)
Hypokalemia	1/13 (7.7%)
Hyponatremia	3/13 (23.1%)
Hypophosphatemia	4/13 (30.8%)
Musculoskeletal and connective tissue disorders
Back pain	2/13 (15.4%)
Arthralgia	1/13 (7.7%)
Bone pain	1/13 (7.7%)
Flank pain	1/13 (7.7%)
Myalgia	1/13 (7.7%)
Osteoarthritis	1/13 (7.7%)
Muscle cramps	1/13 (7.7%)
Nervous system disorders
Dizziness	4/13 (30.8%)
Encephalopathy	1/13 (7.7%)
Headache	6/13 (46.2%)
Neuralgia	2/13 (15.4%)
Syncope	1/13 (7.7%)
Dysgeusia	1/13 (7.7%)
Psychiatric disorders
Anxiety	3/13 (23.1%)
Depression	3/13 (23.1%)
Hallucinations	1/13 (7.7%)
Insomnia	2/13 (15.4%)
Irritability	2/13 (15.4%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/13 (7.7%)
Cough	1/13 (7.7%)
Dyspnea	2/13 (15.4%)
Sore throat	1/13 (7.7%)
Epistaxis	3/13 (23.1%)
Nasal congestion	1/13 (7.7%)
Sinus inflammation	1/13 (7.7%)
Skin and subcutaneous tissue disorders
Alopecia	1/13 (7.7%)
Rash maculo-papular	6/13 (46.2%)
Erythema multiforme	1/13 (7.7%)
Pruritus	1/13 (7.7%)
Keratosis	1/13 (7.7%)
Rash	3/13 (23.1%)
Scalp scabs	1/13 (7.7%)
Diaphoresis	1/13 (7.7%)
Vascular disorders
Hematoma	1/13 (7.7%)
Hypotension	2/13 (15.4%)
Flushing	1/13 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

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