NAXIVA: Study of Axitinib for Reducing Extent of Venous Tumour Thrombus in Renal Cancer With Venous Invasion

• Sponsor: Scottish Clinical Trials Research Unit (Other)
• Overall Status: Completed
• CT.gov ID: NCT03494816
• Collaborator: Pfizer (Industry)
• Enrollment: 24
• Locations: 7
• Arm: 1
• Actual Duration (Months): 29.8
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

NAXIVA is a study of axitinib in patients with metastatic and non-metastatic renal cell carcinoma with venous invasion. Patients will be given axitinib (twice daily) for 8 weeks (at an escalated dose) and the response of the venous invasion will be assessed.

Blood, urine and tumour tissue samples will be taken prior to and during therapy to evaluate biomarkers of treatment response.

The primary objective is to assess the response of the thrombus to axitinib. Its thought that axitinib will reduce the extent of the thrombus in the inferior vena cava will reduce the extent of surgical intervention.

Condition or Disease	Intervention/Treatment	Phase
Renal Cell Carcinoma; Metastatic Renal Cell Carcinoma; Non-metastatic Renal Cell Carcinoma	Drug: Axitinib Oral Tablet	Phase 2

Detailed Description

NAXIVA is a single arm, single agent, open label, phase II feasibility study of axitinib in patients with both metastatic and non-metastatic renal cell carcinoma of clear cell histology. 20 patients will be recruited from multiple centres within the United Kingdom.

Patients who have signed informed consent and who have met all eligibility criteria will be registered into the trial.

The starting dose of axitinib will be 5mg BID and escalated to 7mg BID and then 10mg BID. A dose modification assessment will take place every 2 weeks in clinic during the 8 week pre-surgical treatment period and will be dependent on tolerability of treatment. Patients will follow an aggressive axitinib dose escalation process within the 8 week period to a maximum of 10mg BID. Patients should stop axitinib a minimum of 36 hours and a maximum of 7 days prior to surgery in week 9.

Blood, urine and tissue samples will be taken prior to and during therapy to evaluate biomarkers of treatment response. Nephrectomy and IVC tumour thrombectomy will be planned for all patients on the trial.

Response to axitinib in VTT, primary tumour and any RECIST measureable lesion will be correlated with changes in molecular markers.

Patients will be followed up in clinic at 6 & 12 weeks post surgery.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: NAXIVA- Phase II Neoadjuvant Study of Axitinib for Reducing Extent of Venous Tumour Thrombus in Clear Cell Renal Cell Cancer With Venous Invasion
• Actual Study Start Date: Dec 15, 2017
• Actual Primary Completion Date: Mar 3, 2020
• Actual Study Completion Date: Jun 10, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Axitinib Axitinib - oral tablet twice daily for 8 weeks prior to surgery. Starting dose 5mg.

Drug: Axitinib Oral Tablet; Axitinib is an oral VEGF-receptor inhibitor. Patients are prescribed a starting dose of 5mg twice daily, escalating to 10mg in absence of dose limiting toxicities and blood pressure. Doses should be taken approximately 12 hours apart and patients should be instructed to take their doses at approximately the same times each day with or without food as per instruction. On clinic days only, patients will be advised to fast for 6 hours prior to their clinic visit. Patients should be advised to stop axitinib treatment a minimum of 36 hours and maximum of 7 days prior to week 9 nephrectomy and thrombectomy surgery. Dose adjustments, including dose increase or dose reduction, are permitted and should be based on clinical judgement and the guidelines provided in the protocol.; Other Names: Inlyta AG-013736

Outcome Measures

Primary Outcome Measures

1. Number of Patients With a Change in Mayo Classification [Surgery and radiology assessment at week 9 in comparison to pre-axitinib assessment.]

   The number and percentage of evaluable patients with a change in the Mayo Classification. A patient is defined as a responder if their Mayo level is lower at 9 weeks as compared to baseline; all other patients are defined as non-responders. The Mayo Classification levels are defined as follows, ordered by increasing severity: Level 0: thrombus limited to the renal vein Level 1: into IVC <2cm from renal vein ostium level Level 2: IVC extension >2cm from renal vein ostium and below hepatic vein Level 3: thrombus at the level of or above the hepatic veins but below the diaphragm Level 4: thrombus extending above the diaphragm

Secondary Outcome Measures

1. % Patients With Change in Surgical Management [Surgical planning will be conducted at week 1 (prior to axitinib) and compared to the actual outcome at week 9.]

   The percentage of patients with a change in surgical management. Tumour thrombus surgical management approaches are provided below, ordered by increasing invasiveness: Thrombus - Milked back into renal vein and side clamped Infra-hepatic (IVC clamping with no liver mobilisation) Retro-hepatic (liver mobilisation and clamping below hepatic veins) Retro-hepatic (liver mobilisation and clamping above hepatic veins) Supra-hepatic (infradiaphragmatic) Supra-hepatic (supradiaphragmatic)

2. Change in Venous Tumour Thrombus (VTT) Height [Radiology assessment- The VTT height will be measured prior to axitinib and compared with the VTT height just before surgery (week 9). Both pre-axitinib and week 9 scans will be centrally reviewed by the lead NAXIVA radiologists prior to analysis.]

   The percentage change in VTT height. VTT height is measured as follows: if the size of the tumour is X at baseline and Y at the later timepoint, the reduction value is calculated as follows: 1-(Y/X). Therefore, positive values indicate a reduction and negative values indicate an increase.

3. Number of Patients With RECIST Responses [Radiology assessment- The response rate (RECIST) will be assessed at week 9 in comparison to pre-axitinib measurements.Both pre-axitinib and week 9 scans will be centrally reviewed by the lead NAXIVA radiologists prior to analysis.]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI. In summary, the RECIST v1.1 response categories are: Complete Response (CR): disappearance of all target lesions Partial Response (PR): >=30% decrease in the sum of the longest diameter of target lesions Progressive Disease (PD): >=20% increase in the sum of diameters of target lesions AND an absolute increase of >5mm (or the appearence of 1+ new lesions) Stable Disease (SD): neither sufficient shrinkage to for PR nor sufficient increase for PD Eisenhauer et al., 2009. Eur J Cancer; 45(2): 228-47.

4. Surgical Complication Rates [Morbidity rates will be assessed by radiology assessment using pre-axitinib and week 9 scans. Both pre-axitinib and week 9 scans will be centrally reviewed by the lead NAXIVA radiologists prior to analysis.]

   Morbidity will be measured according to the Clavien-Dindo classification. A summary of the relevant categories is as follows: Grade I: Any deviation from the normal post-operative course not requiring surgical, endoscopic or radiological intervention (inc. certain drugs, physiotherapy and wound infections that are opened at the bedside) Grade II: Complications requiring drug treatments other than those allowed for Grade I complications (inc. blood transfusion and total parenteral nutrition (TPN)) Grade III: Complications requiring surgical, endoscopic or radiological intervention (IIIa=not under general anaesthetic/IIIb=under general anaesthetic) Grade IV: Life-threatening complications (inc. CNS complications requiring intensive care, but excludes transient ischaemic attacks (TIAs)) (IVa=single-organ dysfunction (inc. dialysis)/IVb=multi-organ dysfunction) Grade V: Death of the patient Dindo et al., 2004. Ann Surg;240(2):205-13.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Age ≥ 18. 2. Histologically proven clear cell RCC. 3. Immediate resection of the primary tumour considered technically possible. 4. Suitable for and willing to undergo nephrectomy (either cytoreductive or with curative intent) 4. cT3b, cT3c, cT3a (main renal vein) 5. N0, N1, or Nx 6. M0, or M1 7. ECOG performance status 0 - 1 8. Urinalysis <2+ protein. If dipstick is ≥2+ then a 24-hour urine collection should be performed and the patient may enter NAXIVA only if urinary protein is <2g per 24 hours.

2. All female patients with reproductive potential must have a negative serum or urine pregnancy test within a maximum of 14 days prior to starting trial treatment.

Exclusion Criteria:

1. For M1 patients: poor risk on Memorial Sloan Kettering Cancer Centre (MSKCC) score and deemed suitable for cytoreductive nephrectomy at time of enrolment.

2. The presence of active second malignancy. Patients will be eligible if they have adequately treated basal cell carcinoma, squamous cell skin cancer, in situ cervical cancer, stable prostate cancer or if treated with curative intent for any other cancer with no evidence of disease for 2 years. Patients with prostate cancer will be permitted entry if not receiving treatment and prostrate-specific antigen (PSA) is not rising.

3. Women who are pregnant or are breastfeeding. Female patients must be surgically sterile, be postmenopausal, or must agree to use effective contraception during the period of therapy and up to 1 week after treatment.

Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy and for 6 months after completion of study drug (Patients who do not meet this will not be are not eligible).

1. Current signs or symptoms of severe progressive or uncontrolled hepatic, endocrine or pulmonary disease other than directly related to RCC.

2. Gastrointestinal abnormalities including: a. inability to take oral medication; b. requirement for intravenous alimentation; c. prior surgical procedures affecting absorption including total gastric resection; d. treatment for active peptic ulcer disease in the past 6 months; e. active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy; f. malabsorption syndromes.

3. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (see section 4.4, concomitant therapy).

4. Current use, or anticipated need for treatment with, drugs that are known CYP3A4 inducers or substrates for CYP1A2 (see section 4.4, concomitant therapy).

5. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access device or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed.

6. Active seizure disorder, spinal cord compression, or carcinomatous meningitis.

7. Any of the following within 12 months prior to study entry: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack.

8. Uncontrolled hypertension (>160/100 mmHg despite optimised antihypertensive treatment).

9. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.

10. ALT or AST ≥ 1.5 x ULN; Bilirubin ≥ 1.5 x ULN.

11. Serum creatinine ≥ 1.5 x ULN

12. Neutrophil count < 1.0 x 109/L; platelet count < 100 x 109/L; Hb ≤ 90g/L.

13. Known severe hepatic impairment (Child-Pugh class C)

14. Known hypersensitivity to axitinib or any of its excipients. Specifically patients with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not enter the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Broomfield Hospital	Chelmsford	Essex	United Kingdom	CM1 7ET
2	Addenbrookes Hospital	Cambridge		United Kingdom	CB2 0QQ
3	Western General Hospital	Edinburgh		United Kingdom	EH4 2XU
4	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN
5	Royal Free Hospital	London		United Kingdom	NW3 2QG
6	St George's Hospital	London		United Kingdom	SW17 0QT
7	Royal Marsden	London		United Kingdom	SW3 6JJ

Sponsors and Collaborators

• Scottish Clinical Trials Research Unit
• Pfizer

Investigators

• Principal Investigator: Grant D Stewart, University of Cambridge

Study Documents (Full-Text)

• Study Protocol and Informed Consent Form - Sep 22, 2017
• Statistical Analysis Plan - Aug 20, 2020

More Information

Publications

None provided.

• Responsible Party: Scottish Clinical Trials Research Unit
• ClinicalTrials.gov Identifier: NCT03494816
• Other Study ID Numbers: NAXIVA; 2017-000619-17; ISRCTN96273644
• First Posted: Apr 11, 2018
• Last Update Posted: Jun 30, 2021
• Last Verified: Jun 1, 2021

• 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.: No
• Keywords provided by Scottish Clinical Trials Research Unit: Neoadjuvant; Venous Tumour Thrombus; Axitinib; Mayo Classification; Nephrectomy; Thrombectomy
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Thrombosis; Axitinib

Study Results

Participant Flow

Arm/Group Title	Single Arm
Arm/Group Description	Axitinib - oral tablet twice daily for 8 weeks prior to surgery. Starting dose 5mg. Axitinib Oral Tablet: Axitinib is an oral VEGF-receptor inhibitor. Patients are prescribed a starting dose of 5mg twice daily, escalating to 10mg in absence of dose limiting toxicities and blood pressure. Doses should be taken approximately 12 hours apart and patients should be instructed to take their doses at approximately the same times each day with or without food as per instruction. On clinic days only, patients will be advised to fast for 6 hours prior to their clinic visit. Patients should be advised to stop axitinib treatment a minimum of 36 hours and maximum of 7 days prior to week 9 nephrectomy and thrombectomy surgery. Dose adjustments, including dose increase or dose reduction, are permitted and should be based on clinical judgement and the guidelines provided in the protocol.
Period Title: Overall Study
STARTED	24
COMPLETED	18
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	ITT Population
Arm/Group Description	The Intention-to-treat (ITT) population includes all patients registered onto the study.
Overall Participants	24
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	7 29.2%
>=65 years	17 70.8%
Age (years) [Median (Standard Deviation) ]
Median (Standard Deviation) [years]	69 (7.94)
Sex: Female, Male (Count of Participants)
Female	7 29.2%
Male	17 70.8%
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	23 95.8%
More than one race	0 0%
Unknown or Not Reported	1 4.2%
Region of Enrollment (participants) [Number]
United Kingdom	24 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With a Change in Mayo Classification
Description	The number and percentage of evaluable patients with a change in the Mayo Classification. A patient is defined as a responder if their Mayo level is lower at 9 weeks as compared to baseline; all other patients are defined as non-responders. The Mayo Classification levels are defined as follows, ordered by increasing severity: Level 0: thrombus limited to the renal vein Level 1: into IVC <2cm from renal vein ostium level Level 2: IVC extension >2cm from renal vein ostium and below hepatic vein Level 3: thrombus at the level of or above the hepatic veins but below the diaphragm Level 4: thrombus extending above the diaphragm
Time Frame	Surgery and radiology assessment at week 9 in comparison to pre-axitinib assessment.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Evaluable Patients
Arm/Group Description	The evaluable population includes all patients in the ITT population who have received at least one dose of the study drug (including any patients who were enrolled in error, received study drug and were subsequently found to be ineligible).
Measure Participants	21
Responder	6 25%
Non-responder	15 62.5%

2. Secondary Outcome

Title	% Patients With Change in Surgical Management
Description	The percentage of patients with a change in surgical management. Tumour thrombus surgical management approaches are provided below, ordered by increasing invasiveness: Thrombus - Milked back into renal vein and side clamped Infra-hepatic (IVC clamping with no liver mobilisation) Retro-hepatic (liver mobilisation and clamping below hepatic veins) Retro-hepatic (liver mobilisation and clamping above hepatic veins) Supra-hepatic (infradiaphragmatic) Supra-hepatic (supradiaphragmatic)
Time Frame	Surgical planning will be conducted at week 1 (prior to axitinib) and compared to the actual outcome at week 9.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Surgical Population
Arm/Group Description	The group of evaluable patients who had surgery.
Measure Participants	17
Improvement in control of IVC/renal vein	6 25%
Deterioration in control of IVC/renal vein	0 0%
No change in control of IVC/renal vein	11 45.8%

3. Secondary Outcome

Title	Change in Venous Tumour Thrombus (VTT) Height
Description	The percentage change in VTT height. VTT height is measured as follows: if the size of the tumour is X at baseline and Y at the later timepoint, the reduction value is calculated as follows: 1-(Y/X). Therefore, positive values indicate a reduction and negative values indicate an increase.
Time Frame	Radiology assessment- The VTT height will be measured prior to axitinib and compared with the VTT height just before surgery (week 9). Both pre-axitinib and week 9 scans will be centrally reviewed by the lead NAXIVA radiologists prior to analysis.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Complete VTT Length Data at 9 Weeks
Arm/Group Description	3 patients (no 9wk scan) + 1 (ineligible) pts were not included in the assessment of this timepoint.
Measure Participants	17
Median (Standard Deviation) [percentage decrease in VTT length]	21.49 (27.60)

4. Secondary Outcome

Title	Number of Patients With RECIST Responses
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI. In summary, the RECIST v1.1 response categories are: Complete Response (CR): disappearance of all target lesions Partial Response (PR): >=30% decrease in the sum of the longest diameter of target lesions Progressive Disease (PD): >=20% increase in the sum of diameters of target lesions AND an absolute increase of >5mm (or the appearence of 1+ new lesions) Stable Disease (SD): neither sufficient shrinkage to for PR nor sufficient increase for PD Eisenhauer et al., 2009. Eur J Cancer; 45(2): 228-47.
Time Frame	Radiology assessment- The response rate (RECIST) will be assessed at week 9 in comparison to pre-axitinib measurements.Both pre-axitinib and week 9 scans will be centrally reviewed by the lead NAXIVA radiologists prior to analysis.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Complete RECIST Data
Arm/Group Description	3 evaluable pts did not have the relevant data and were removed from the analysis
Measure Participants	18
Complete response	0 0%
Partial response	3 12.5%
Stable disease	13 54.2%
Progressive disease	2 8.3%
Non-evaluable	0 0%

5. Secondary Outcome

Title	Surgical Complication Rates
Description	Morbidity will be measured according to the Clavien-Dindo classification. A summary of the relevant categories is as follows: Grade I: Any deviation from the normal post-operative course not requiring surgical, endoscopic or radiological intervention (inc. certain drugs, physiotherapy and wound infections that are opened at the bedside) Grade II: Complications requiring drug treatments other than those allowed for Grade I complications (inc. blood transfusion and total parenteral nutrition (TPN)) Grade III: Complications requiring surgical, endoscopic or radiological intervention (IIIa=not under general anaesthetic/IIIb=under general anaesthetic) Grade IV: Life-threatening complications (inc. CNS complications requiring intensive care, but excludes transient ischaemic attacks (TIAs)) (IVa=single-organ dysfunction (inc. dialysis)/IVb=multi-organ dysfunction) Grade V: Death of the patient Dindo et al., 2004. Ann Surg;240(2):205-13.
Time Frame	Morbidity rates will be assessed by radiology assessment using pre-axitinib and week 9 scans. Both pre-axitinib and week 9 scans will be centrally reviewed by the lead NAXIVA radiologists prior to analysis.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With Post-surgical Complications Within 30 Days
Arm/Group Description	While 17 patients had surgery on this trial, only 6 patients had post-surgical complications within 30 days.
Measure Participants	6
Grade I	1 4.2%
Grade II	3 12.5%
Grade IIIa	0 0%
Grade IIIb	0 0%
Grade IVa	0 0%
Grade IVb	1 4.2%
Grade V	1 4.2%

Adverse Events

Time Frame	Data were collected at screening, Week 1, Week 3, Week 5, Week 7, Week 9 (srugery), 6 weeks post-surgery, 12 weeks post-surgery.
Arm/Group Title	ITT Population
Arm/Group Description	The Intention-to-treat (ITT) population includes all patients registered onto the study.
All Cause Mortality
	ITT Population
	Affected / at Risk (%)	# Events
Total	4/24 (16.7%)
Serious Adverse Events
	ITT Population
	Affected / at Risk (%)	# Events
Total	8/24 (33.3%)
Cardiac disorders
Cardiac arrest	1/24 (4.2%)	1
Endocrine disorders
Hyperglycemia	1/24 (4.2%)	1
Injury, poisoning and procedural complications
Wound complication	1/24 (4.2%)	1
Metabolism and nutrition disorders
Hyperkalemia	1/24 (4.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pathological fracture	1/24 (4.2%)	1
Nervous system neoplasms malignant and unspecified NEC	1/24 (4.2%)	1
Nervous system disorders
Myasthenia gravis	1/24 (4.2%)	2
Middle cerebral artery infarct	1/24 (4.2%)	1
Psychiatric disorders
Confusional state	1/24 (4.2%)	1
Renal and urinary disorders
Hematuria	2/24 (8.3%)	2
Urinary retention	1/24 (4.2%)	2
Other (Not Including Serious) Adverse Events
	ITT Population
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Blood and lymphatic system disorders
Anemia	2/24 (8.3%)	3
Thrombocytosis	1/24 (4.2%)	1
Cardiac disorders
Cardiac murmur	1/24 (4.2%)	2
Chest pain	1/24 (4.2%)	1
Dyspnea exertional	3/24 (12.5%)	6
Sinus tachycardia	2/24 (8.3%)	4
Ear and labyrinth disorders
Deafness	1/24 (4.2%)	1
Endocrine disorders
Hypothyroidism	4/24 (16.7%)	6
Eye disorders
Lacrimation increased	1/24 (4.2%)	6
Vitreous floaters	1/24 (4.2%)	1
Gastrointestinal disorders
Abdominal pain	7/24 (29.2%)	13
Constipation	8/24 (33.3%)	13
Diarrhea	8/24 (33.3%)	14
Dyspepsia	4/24 (16.7%)	11
Nausea	7/24 (29.2%)	17
Oral candidiasis	1/24 (4.2%)	1
Oral pain	2/24 (8.3%)	6
Stomatitis	3/24 (12.5%)	4
Vomiting	4/24 (16.7%)	7
General disorders
Asthenia	2/24 (8.3%)	2
Fatigue	15/24 (62.5%)	47
Flank pain	1/24 (4.2%)	2
Incision site pain	1/24 (4.2%)	2
Lethargy	1/24 (4.2%)	2
Loose tooth	1/24 (4.2%)	2
Mucosal inflammation	9/24 (37.5%)	21
Night sweats	1/24 (4.2%)	1
Pain	1/24 (4.2%)	4
Pyrexia	2/24 (8.3%)	2
Hepatobiliary disorders
Hypoalbuminemia	1/24 (4.2%)	1
Infections and infestations
Pathological fracture	1/24 (4.2%)	1
Postoperative wound infection	1/24 (4.2%)	1
Respiratory tract infection viral	2/24 (8.3%)	2
Investigations
Alanine aminotransferase increased	3/24 (12.5%)	5
Blood creatinine increased	2/24 (8.3%)	4
Male genital examination abnormal	1/24 (4.2%)	5
Weight decreased	6/24 (25%)	14
Metabolism and nutrition disorders
Adrenal insufficiency	1/24 (4.2%)	2
Decreased appetite	2/24 (8.3%)	2
Hyperglycemia	2/24 (8.3%)	3
Hyperkalemia	2/24 (8.3%)	3
Hyponatremia	1/24 (4.2%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	3/24 (12.5%)	7
Back pain	8/24 (33.3%)	13
Groin pain	1/24 (4.2%)	2
Musculoskeletal pain	3/24 (12.5%)	6
Myalgia	1/24 (4.2%)	1
Pain in extremity	2/24 (8.3%)	4
Pain in jaw	1/24 (4.2%)	1
Nervous system disorders
Dizziness	1/24 (4.2%)	1
Dysgeusia	4/24 (16.7%)	9
Headache	3/24 (12.5%)	4
Hypoesthesia	1/24 (4.2%)	2
Migraine	1/24 (4.2%)	1
Muscular weakness	6/24 (25%)	13
Myasthenia gravis	1/24 (4.2%)	4
Neuropathy peripheral	1/24 (4.2%)	1
Paraesthesia	2/24 (8.3%)	2
Psychiatric disorders
Anxiety	2/24 (8.3%)	5
Dysphonia	10/24 (41.7%)	30
Insomnia	7/24 (29.2%)	16
Renal and urinary disorders
Dysuria	3/24 (12.5%)	4
Nocturia	1/24 (4.2%)	1
Pollakiuria	1/24 (4.2%)	1
Proteinuria	10/24 (41.7%)	25
Renal pain	1/24 (4.2%)	3
Urinary tract infection	1/24 (4.2%)	1
Reproductive system and breast disorders
Hematuria	3/24 (12.5%)	5
Respiratory, thoracic and mediastinal disorders
Cough	6/24 (25%)	14
Pulmonary embolism	1/24 (4.2%)	2
Skin and subcutaneous tissue disorders
Alopecia	1/24 (4.2%)	1
Dermatitis	1/24 (4.2%)	1
Dry skin	6/24 (25%)	15
Palmar-plantar erythrodysaesthesia syndrome	3/24 (12.5%)	10
Pruritus	2/24 (8.3%)	2
Rash	2/24 (8.3%)	4
Vascular disorders
Epistaxis	3/24 (12.5%)	3
Hypertension	19/24 (79.2%)	85
Hypotension	1/24 (4.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.