Neodjuvant Nivolumab and Lirilumab, Followed by Surgery, Followed by Adjuvant Nivolumab and Lirilumab, in SCCHN

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03341936
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 29
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 99.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This research study is studying a combination of two immunotherapy drugs, as a possible treatment for locoregionally recurrent squamous cell carcinoma of the head and neck.

The immunotherapy drugs involved in this study are:

• Nivolumab (Opdivo™)

• Lirilumab

Condition or Disease	Intervention/Treatment	Phase
Squamous Cell Carcinoma of the Head and Neck	Drug: Nivolumab; Drug: Lirilumab	Phase 2

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug or combination of drugs to learn whether it works in treating a specific disease. "Investigational" means that the drug/s is being studied.

The purpose of this study is to evaluate effectiveness (how well the drug/s work) of nivolumab in combination with lirilumab in participants with SCCHN.

Nivolumab and lirilumab are types of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells. Both nivolumab and lirilumab have been demonstrated to activate the immune system to attack cancer cells in participants with different types of cancers.

In November, 2016, the Food and Drug Administration (FDA) approved nivolumab for the treatment of participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Lirilumab is not FDA approved as of now.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Neodjuvant Nivolumab and Lirilumab, Followed by Surgery, Followed by Adjuvant Nivolumab and Lirilumab, in Patients With Relapsed, Resectable Squamous Cell Carcinoma of the Head and Neck
• Actual Study Start Date: Mar 15, 2018
• Actual Primary Completion Date: Jul 6, 2021
• Anticipated Study Completion Date: Jul 6, 2026

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Nivolumab+Lirilumab The drugs will be administered intravenously. A single dose of Nivolumab and Lirilumab will be administered prior Salvage surgical resection. In Cycle 1-3: Nivolumab will be administered on Days 1 and 15 and lirilumab will be administered on Day 1 of each 28 day long cycle In Cycle 4-6 and beyond: Nivolumab and lirilumab will be administered on Day 1 of each 28 day long cycle.

Drug: Nivolumab; Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells; Drug: Lirilumab; Lirilumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells

Outcome Measures

Primary Outcome Measures

1. 1-Year Disease-Free Survival Percentage [1 year since salvage surgery, up to 1 year and 23 days since treatment start]

   The percentage of patients who were alive and disease free at one year past salvage surgery. Patients who were alive at last contact prior to the one year mark are censored. Data analysis conducted through Kaplan Meier methods.

Secondary Outcome Measures

1. Response at Time of Salvage Surgery [At the time of salvage surgery, up to 23 days from treatment start date.]

   Response is classified using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Complete Response - Disappearance of all lesions and pathologic lymph nodes. Partial Response - At least 30% decrease in sum of longest diameters (SLD) for the target lesions, no new lesions, and no progression of non-target lesions. Progressive Disease - At least 20% increase in SLD compared to smallest SLD in study or progression of non-target lesions or development of new lesions Stable Disease - No Partial Response and no Progressive Disease.

2. Median Disease-Free Survival Rate [Up to 27.2 months post salvage surgery, up to 28 months total.]

   The median time that patients were alive and disease free after salvage surgery. Patients who were alive at last contact are censored at last contact. Data analysis conducted through Kaplan Meier methods

3. 1-Year Overall Survival Percentage [1 year post salvage surgery, up to 1 year and 23 days post treatment start.]

   Percentage of participants who were alive at 1 year since salvage surgery. Patients alive at last contact prior to 1 year were censored.

4. Median Change in Programmed Cell Death Ligand - 1 Combined Positive Score [Measured at baseline and then at time of salvage surgery, up to 23 days.]

   The median change in Programmed Cell Death Ligand - 1 Combined Positive Score (PD-L1 CPS) from baseline to surgery. The score is derived from tumor tissue samples that measures the presence of both tumor and immune cell staining for the PD-L1 marker. Scored from 0-100, a higher score suggests the patient might respond better to treatment. A pathological responder is defined as having less than 50% viable tumor at the time of surgery.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subject must have histologically or cytologically confirmed locoregionally recurrent squamous cell carcinoma of the head and neck (including any primary site, such as oral cavity, oropharynx, larynx or hypopharynx, and nasopharyngeal carcinoma)

• Must be a candidate for salvage surgery

• Willing to provide blood and tissue from diagnostic biopsy and at the time of surgery

• Has documented disease-free interval (DFI) > 8 weeks after completion of initial therapy; DFI is from the time of completion of initial treatment to the diagnosis of local or locoregional recurrence

• Any HPV status or smoking history is permitted. Oropharyngeal cancer patients are required to undergo HPV testing with p16 immunohistochemistry and/or confirmatory HPV PCR or ISH testing

• Age 18 years or older

• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

• Participant must have normal organ and marrow function as defined below within 21 days prior to study registration:

• leukocytes ≥3,000/mcL

• absolute neutrophil count ≥1,500/mcL

• platelets ≥100,000/mcL

• total bilirubin ≤2.0 g/dL

• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

• creatinine within normal institutional limits OR

• creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal

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

• Women of childbearing potential (WOCBP) must agree to use appropriate method(s) of contraception. WOCBP should plan to use an adequate method to avoid pregnancy for 5 months (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug

• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 iu/l or equivalent units of hcg) within 24 hours prior to the start of nivolumab

• "Women of childbearing potential (WOCBP)" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL

• Men who are sexually active with WOCBP must agree to use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception

Exclusion Criteria:

• Existing significant autoimmune conditions. Patients with a history of Hashimoto thyroiditis who are stable on replacement hormone therapy are not excluded. Patients cannot be on long-term (> 4 weeks) corticosteroids at doses exceeding prednisone 20 mg (or its equivalent) prior to enrollment. Short-term corticosteroid dosing is permitted as long as steroids are discontinued within 2 weeks of study enrollment.

• Subject who has had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

• Subject who has been treated with immunotherapy. This includes prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways

• Subject with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. However, baseline brain imaging is not required prior to enrollment in the study if patients are asymptomatic.

• 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.

• Known human immunodeficiency virus carrier or a diagnosis of immunodeficiency. Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C antibody (anti-HCV) positive (except if HCV-RNA negative).

• Known non-infectious pneumonitis or any history of interstitial lung disease.

• Receipt of a live vaccine within 30 days of start of study treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Glenn J. Hanna, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 16, 2019

More Information

Publications

None provided.

• Responsible Party: Glenn J. Hanna, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03341936
• Other Study ID Numbers: 17-411
• First Posted: Nov 14, 2017
• Last Update Posted: Jun 16, 2022
• Last Verified: May 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
• Keywords provided by Glenn J. Hanna, Principal Investigator, Dana-Farber Cancer Institute: Squamous Cell Carcinoma
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Nivolumab

Study Results

Participant Flow

Recruitment Details	Enrollment Period March 2018 to May 2020

Arm/Group Title	Nivolumab+Lirilumab
Arm/Group Description	The drugs will be administered intravenously. A single dose of Nivolumab and Lirilumab will be administered prior Salvage surgical resection. In Cycle 1-3: Nivolumab will be administered on Days 1 and 15 and lirilumab will be administered on Day 1 of each 28 day long cycle In Cycle 4-6 and beyond: Nivolumab and lirilumab will be administered on Day 1 of each 28 day long cycle. Nivolumab: Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells Lirilumab: Lirilumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells
Period Title: Overall Study
STARTED	29
Treated	28
COMPLETED	18
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	Nivolumab+Lirilumab
Arm/Group Description	The drugs will be administered intravenously. A single dose of Nivolumab and Lirilumab will be administered prior Salvage surgical resection. In Cycle 1-3: Nivolumab will be administered on Days 1 and 15 and lirilumab will be administered on Day 1 of each 28 day long cycle In Cycle 4-6 and beyond: Nivolumab and lirilumab will be administered on Day 1 of each 28 day long cycle. Nivolumab: Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells Lirilumab: Lirilumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells
Overall Participants	28
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66
Sex: Female, Male (Count of Participants)
Female	5 17.9%
Male	23 82.1%
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	1 3.6%
White	26 92.9%
More than one race	0 0%
Unknown or Not Reported	1 3.6%

Outcome Measures

1. Primary Outcome

Title	1-Year Disease-Free Survival Percentage
Description	The percentage of patients who were alive and disease free at one year past salvage surgery. Patients who were alive at last contact prior to the one year mark are censored. Data analysis conducted through Kaplan Meier methods.
Time Frame	1 year since salvage surgery, up to 1 year and 23 days since treatment start

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nivolumab+Lirilumab
Arm/Group Description	The drugs will be administered intravenously. A single dose of Nivolumab and Lirilumab will be administered prior Salvage surgical resection. In Cycle 1-3: Nivolumab will be administered on Days 1 and 15 and lirilumab will be administered on Day 1 of each 28 day long cycle In Cycle 4-6 and beyond: Nivolumab and lirilumab will be administered on Day 1 of each 28 day long cycle. Nivolumab: Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells Lirilumab: Lirilumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells
Measure Participants	28
Number (95% Confidence Interval) [percentage of participants]	55.2 197.1%

2. Secondary Outcome

Title	Response at Time of Salvage Surgery
Description	Response is classified using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Complete Response - Disappearance of all lesions and pathologic lymph nodes. Partial Response - At least 30% decrease in sum of longest diameters (SLD) for the target lesions, no new lesions, and no progression of non-target lesions. Progressive Disease - At least 20% increase in SLD compared to smallest SLD in study or progression of non-target lesions or development of new lesions Stable Disease - No Partial Response and no Progressive Disease.
Time Frame	At the time of salvage surgery, up to 23 days from treatment start date.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nivolumab+Lirilumab
Arm/Group Description	The drugs will be administered intravenously. A single dose of Nivolumab and Lirilumab will be administered prior Salvage surgical resection. In Cycle 1-3: Nivolumab will be administered on Days 1 and 15 and lirilumab will be administered on Day 1 of each 28 day long cycle In Cycle 4-6 and beyond: Nivolumab and lirilumab will be administered on Day 1 of each 28 day long cycle. Nivolumab: Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells Lirilumab: Lirilumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells
Measure Participants	28
Stable Disease	27 96.4%
Progressive Disease	1 3.6%

3. Secondary Outcome

Title	Median Disease-Free Survival Rate
Description	The median time that patients were alive and disease free after salvage surgery. Patients who were alive at last contact are censored at last contact. Data analysis conducted through Kaplan Meier methods
Time Frame	Up to 27.2 months post salvage surgery, up to 28 months total.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nivolumab+Lirilumab
Arm/Group Description	The drugs will be administered intravenously. A single dose of Nivolumab and Lirilumab will be administered prior Salvage surgical resection. In Cycle 1-3: Nivolumab will be administered on Days 1 and 15 and lirilumab will be administered on Day 1 of each 28 day long cycle In Cycle 4-6 and beyond: Nivolumab and lirilumab will be administered on Day 1 of each 28 day long cycle. Nivolumab: Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells Lirilumab: Lirilumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells
Measure Participants	28
Median (95% Confidence Interval) [months]	12.9

4. Secondary Outcome

Title	1-Year Overall Survival Percentage
Description	Percentage of participants who were alive at 1 year since salvage surgery. Patients alive at last contact prior to 1 year were censored.
Time Frame	1 year post salvage surgery, up to 1 year and 23 days post treatment start.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nivolumab+Lirilumab
Arm/Group Description	The drugs will be administered intravenously. A single dose of Nivolumab and Lirilumab will be administered prior Salvage surgical resection. In Cycle 1-3: Nivolumab will be administered on Days 1 and 15 and lirilumab will be administered on Day 1 of each 28 day long cycle In Cycle 4-6 and beyond: Nivolumab and lirilumab will be administered on Day 1 of each 28 day long cycle. Nivolumab: Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells Lirilumab: Lirilumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells
Measure Participants	28
Number (95% Confidence Interval) [percentage of participants]	85.7 306.1%

5. Secondary Outcome

Title	Median Change in Programmed Cell Death Ligand - 1 Combined Positive Score
Description	The median change in Programmed Cell Death Ligand - 1 Combined Positive Score (PD-L1 CPS) from baseline to surgery. The score is derived from tumor tissue samples that measures the presence of both tumor and immune cell staining for the PD-L1 marker. Scored from 0-100, a higher score suggests the patient might respond better to treatment. A pathological responder is defined as having less than 50% viable tumor at the time of surgery.
Time Frame	Measured at baseline and then at time of salvage surgery, up to 23 days.

Outcome Measure Data

Analysis Population Description

Outcomes were compared among responders and non-responders.

Arm/Group Title	Nivolumab+Lirilumab
Arm/Group Description	The drugs will be administered intravenously. A single dose of Nivolumab and Lirilumab will be administered prior Salvage surgical resection. In Cycle 1-3: Nivolumab will be administered on Days 1 and 15 and lirilumab will be administered on Day 1 of each 28 day long cycle In Cycle 4-6 and beyond: Nivolumab and lirilumab will be administered on Day 1 of each 28 day long cycle. Nivolumab: Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells Lirilumab: Lirilumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells
Measure Participants	28
Responder	2.5
Non-Responder	0

Adverse Events

Time Frame	All-Cause Mortality was monitored for 1 year post salvage surgery, up to 1 year and 23 days post treatment start. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored from baseline to end of adjuvant therapy, up to 9 months.
Adverse Event Reporting Description	A serious adverse event is classified using physician's discretion. All adverse events resulting in death, life threatening events, significant disability, prolonged hospitalization, congenital abnormality/birth defect, or new cancer will be considered a serious adverse event.
Arm/Group Title	Nivolumab+Lirilumab
Arm/Group Description	The drugs will be administered intravenously. A single dose of Nivolumab and Lirilumab will be administered prior Salvage surgical resection. In Cycle 1-3: Nivolumab will be administered on Days 1 and 15 and lirilumab will be administered on Day 1 of each 28 day long cycle In Cycle 4-6 and beyond: Nivolumab and lirilumab will be administered on Day 1 of each 28 day long cycle. Nivolumab: Nivolumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells Lirilumab: Lirilumab is a type of immunotherapy. Immunotherapy works by encouraging the body's own immune system to attack cancer cells
All Cause Mortality
	Nivolumab+Lirilumab
	Affected / at Risk (%)	# Events
Total	7/28 (25%)
Serious Adverse Events
	Nivolumab+Lirilumab
	Affected / at Risk (%)	# Events
Total	12/28 (42.9%)
Cardiac disorders
Cardiac arrest	1/28 (3.6%)
Chest pain - cardiac	1/28 (3.6%)
Myocardial infarction	1/28 (3.6%)
Gastrointestinal disorders
Dysphagia	3/28 (10.7%)
Nausea	1/28 (3.6%)
General disorders
Infusion related reaction	1/28 (3.6%)
Infections and infestations
Lung infection	1/28 (3.6%)
Wound infection	2/28 (7.1%)
Infections and infestations - Other, specify	1/28 (3.6%)
Injury, poisoning and procedural complications
Wound dehiscence	1/28 (3.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	4/28 (14.3%)
Hypoxia	1/28 (3.6%)
Laryngeal fistula	1/28 (3.6%)
Productive cough	2/28 (7.1%)
Respiratory failure	1/28 (3.6%)
Other (Not Including Serious) Adverse Events
	Nivolumab+Lirilumab
	Affected / at Risk (%)	# Events
Total	28/28 (100%)
Blood and lymphatic system disorders
Anemia	7/28 (25%)
Cardiac disorders
Sinus bradycardia	2/28 (7.1%)
Ear and labyrinth disorders
Ear pain	8/28 (28.6%)
Hearing impaired	4/28 (14.3%)
Tinnitus	2/28 (7.1%)
Endocrine disorders
Hypothyroidism	18/28 (64.3%)
Endocrine disorders - Other, specify	1/28 (3.6%)
Eye disorders
Conjunctivitis	1/28 (3.6%)
Retinal detachment	1/28 (3.6%)
Gastrointestinal disorders
Abdominal pain	3/28 (10.7%)
Bloating	1/28 (3.6%)
Cheilitis	2/28 (7.1%)
Constipation	6/28 (21.4%)
Diarrhea	11/28 (39.3%)
Dry mouth	11/28 (39.3%)
Dysphagia	27/28 (96.4%)
Esophageal stenosis	3/28 (10.7%)
Flatulence	1/28 (3.6%)
Gastritis	1/28 (3.6%)
Gastroesophageal reflux disease	5/28 (17.9%)
Hemorrhoids	1/28 (3.6%)
Lip pain	1/28 (3.6%)
Nausea	6/28 (21.4%)
Oral cavity fistula	1/28 (3.6%)
Oral dysesthesia	1/28 (3.6%)
Oral pain	9/28 (32.1%)
Stomach pain	1/28 (3.6%)
Vomiting	4/28 (14.3%)
Gastrointestinal disorders - Other, specify	2/28 (7.1%)
General disorders
Chills	6/28 (21.4%)
Edema face	1/28 (3.6%)
Edema limbs	2/28 (7.1%)
Facial pain	1/28 (3.6%)
Fatigue	20/28 (71.4%)
Fever	5/28 (17.9%)
Gait disturbance	3/28 (10.7%)
Infusion related reaction	2/28 (7.1%)
Localized edema	2/28 (7.1%)
Neck edema	4/28 (14.3%)
Non-cardiac chest pain	2/28 (7.1%)
Pain	14/28 (50%)
General disorders and administration site conditions - Other, specify	1/28 (3.6%)
Infections and infestations
Biliary tract infection	1/28 (3.6%)
Conjunctivitis infective	1/28 (3.6%)
Lung infection	3/28 (10.7%)
Mucosal infection	2/28 (7.1%)
Pharyngitis	1/28 (3.6%)
Sinusitis	1/28 (3.6%)
Stoma site infection	2/28 (7.1%)
Tooth infection	2/28 (7.1%)
Upper respiratory infection	1/28 (3.6%)
Urinary tract infection	2/28 (7.1%)
Infections and infestations - Other, specify	2/28 (7.1%)
Injury, poisoning and procedural complications
Fall	1/28 (3.6%)
Seroma	3/28 (10.7%)
Tracheostomy site bleeding	1/28 (3.6%)
Wound complication	2/28 (7.1%)
Wound dehiscence	3/28 (10.7%)
Injury, poisoning and procedural complications - Other, specify	1/28 (3.6%)
Investigations
Alanine aminotransferase increased	5/28 (17.9%)
Alkaline phosphatase increased	4/28 (14.3%)
Aspartate aminotransferase increased	8/28 (28.6%)
Blood bilirubin increased	1/28 (3.6%)
Cholesterol high	2/28 (7.1%)
Creatinine increased	4/28 (14.3%)
Weight loss	3/28 (10.7%)
Investigations - Other, specify	3/28 (10.7%)
Metabolism and nutrition disorders
Anorexia	4/28 (14.3%)
Dehydration	1/28 (3.6%)
Hypercalcemia	1/28 (3.6%)
Hyperglycemia	1/28 (3.6%)
Hyperkalemia	2/28 (7.1%)
Hypermagnesemia	2/28 (7.1%)
Hypoglycemia	1/28 (3.6%)
Hypokalemia	1/28 (3.6%)
Hypomagnesemia	1/28 (3.6%)
Hyponatremia	3/28 (10.7%)
Hypophosphatemia	2/28 (7.1%)
Metabolism and nutrition disorders - Other, specify	2/28 (7.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/28 (14.3%)
Arthritis	2/28 (7.1%)
Back pain	5/28 (17.9%)
Generalized muscle weakness	3/28 (10.7%)
Muscle weakness left-sided	1/28 (3.6%)
Myalgia	2/28 (7.1%)
Neck pain	10/28 (35.7%)
Osteonecrosis of jaw	1/28 (3.6%)
Pain in extremity	1/28 (3.6%)
Musculoskeletal and connective tissue disorder - Other, specify	1/28 (3.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	2/28 (7.1%)
Nervous system disorders
Aphonia	1/28 (3.6%)
Dizziness	3/28 (10.7%)
Dysarthria	4/28 (14.3%)
Dysgeusia	3/28 (10.7%)
Headache	2/28 (7.1%)
Movements involuntary	1/28 (3.6%)
Paresthesia	3/28 (10.7%)
Peripheral sensory neuropathy	3/28 (10.7%)
Presyncope	2/28 (7.1%)
Vasovagal reaction	1/28 (3.6%)
Psychiatric disorders
Anxiety	5/28 (17.9%)
Confusion	2/28 (7.1%)
Delirium	1/28 (3.6%)
Depression	7/28 (25%)
Insomnia	1/28 (3.6%)
Psychosis	1/28 (3.6%)
Renal and urinary disorders
Hematuria	1/28 (3.6%)
Urinary retention	2/28 (7.1%)
Renal and urinary disorders - Other, specify	4/28 (14.3%)
Respiratory, thoracic and mediastinal disorders
Aspiration	2/28 (7.1%)
Cough	10/28 (35.7%)
Dyspnea	5/28 (17.9%)
Epistaxis	1/28 (3.6%)
Hypoxia	2/28 (7.1%)
Nasal congestion	1/28 (3.6%)
Pharyngeal fistula	1/28 (3.6%)
Productive cough	4/28 (14.3%)
Sore throat	6/28 (21.4%)
Tracheal fistula	2/28 (7.1%)
Tracheal stenosis	1/28 (3.6%)
Voice alteration	13/28 (46.4%)
Respiratory, thoracic and mediastinal disorders - Other, specify	15/28 (53.6%)
Skin and subcutaneous tissue disorders
Alopecia	1/28 (3.6%)
Dry skin	2/28 (7.1%)
Erythema multiforme	2/28 (7.1%)
Pain of skin	1/28 (3.6%)
Pruritus	4/28 (14.3%)
Rash maculo-papular	3/28 (10.7%)
Skin induration	1/28 (3.6%)
Skin and subcutaneous tissue disorders - Other, specify	1/28 (3.6%)
Vascular disorders
Hematoma	2/28 (7.1%)
Hypertension	7/28 (25%)
Hypotension	3/28 (10.7%)

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.