Panobinostat and Everolimus in Treating Patients With Metastatic or Unresectable Renal Cell Cancer That Does Not Respond to Treatment With Sunitinib Malate or Sorafenib Tosylate

• Sponsor: Roswell Park Cancer Institute (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01582009
• Collaborator: Novartis (Industry)
• Enrollment: 26
• Locations: 2
• Arm: 1
• Duration (Months): 69
• Patients Per Site: 13
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Panobinostat and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor.

PURPOSE: This phase I/II trial is studying the side effects and best dose of giving panobinostat together with everolimus and to see how well they work in treating patients with metastatic or unresectable renal cell cancer that does not respond to treatment with sunitinib malate or sorafenib tosylate

Condition or Disease	Intervention/Treatment	Phase
Clear Cell Renal Cell Carcinoma; Recurrent Renal Cell Cancer; Stage III Renal Cell Cancer; Stage IV Renal Cell Cancer	Drug: panobinostat; Drug: everolimus; Other: laboratory biomarker analysis; Other: pharmacological study; Other: liquid chromatography; Other: mass spectrometry; Other: enzyme-linked immunosorbent assay; Other: immunohistochemistry staining method	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To evaluate the safety and tolerability and determine the recommended dosing for the combination of LBH589 and Everolimus in patients with metastatic renal cell carcinoma. (Phase

1. 1. To assess the preliminary evidence of tumor response in patients treated with LBH589 and Everolimus. (Phase I) III. To evaluate the effect of LBH589 and Everolimus on the progression-free survival event rate. (Phase II) IV. To determine the clinical response rate of LBH589 and Everolimus in patients with metastatic renal cell carcinoma. (Phase II)

SECONDARY OBJECTIVES:

1. To determine the toxicity of the combination of LBH589 and Everolimus in patients with metastatic renal cell carcinoma. (Phase II) II. To evaluate the effect of LBH589 and Everolimus on time-to-tumor-progression (TTP), disease-free survival and overall survival. (Phase II) III. To assess the pharmacodynamic effects of LBH589 and Everolimus in peripheral blood mononuclear cells (PBMNC) and tumor that are accessible before and after treatment, if available. (Phase II) IV. To evaluate the modulation of tumor metabolism and blood in patients treated with LBH589 and Everolimus by FDG and 015 water PET/CT scan. (Phase II)

OUTLINE: This is a dose-escalation study of panobinostat and everolimus, followed by a phase II study.

Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for at least 4 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of the HDAC Inhibitor LBH-589 in Combination With the mTOR Inhibitor Everolimus (RAD001) in Metastatic Renal Cell Carcinoma
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Oct 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Arm I: Oral Panobinostat and Oral Everolimus Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: panobinostat; Given orally; Other Names: Faridak HDAC inhibitor LBH589 histone deacetylase inhibitor LBH589 LBH589 ; Drug: everolimus; Given orally; Other Names: 42-O-(2-hydroxy)ethyl rapamycin Afinitor RAD001 ; Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies ; Other: liquid chromatography; Correlative studies; Other Names: LC ; Other: mass spectrometry; Correlative studies; Other: enzyme-linked immunosorbent assay; Correlative studies; Other Names: ELISA ; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [The time from registration to documentation of disease progression up to 3 years]

   6 month PFS survival rate. Calculated as the total number of failures (deaths or progression) divided by the total follow-up or exposure time of patients on study. Assessed using Kaplan Meier and Proportional Hazards.

2. Number of Participants With Clinical Response [The time from registration up to 3 years]

   Number of participants with clinical response. Response will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors ver 1.0 Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST ver. 1.0 criteria.

Secondary Outcome Measures

1. Number of Participants With an Adverse Event. [The time from registration up to 3 years]

   Number of participants with an adverse event. Please refer to the adverse event reporting for more detail.

2. Median Progression Free Survival [The time from registration up to 3 years]

   Median progression free survival. Assessed using Kaplan Meier and Proportional Hazards.

3. 6-month Overall Survival Rate [The time from registration up to 3 years]

   6-month overall survival rate

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have histologically confirmed metastatic or unresectable renal cell carcinoma

• Predominant clear cell component is required

• Patients must have metastatic disease which has progressed on or within 6 months of stopping treatment with VEGFR receptor tyrosine kinase inhibitors

• Previous therapy with bevacizumab, interleukin 2, or interferon alpha is also permitted

• Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed

• Serum albumin >= 3g/dL

• AST/SGOT and ALT/SGPT =< 2.5 x upper limit of normal (ULN)

• Serum bilirubin =< 1.5 x ULN

• Serum creatinine =< 1.5 x ULN or 24-hour creatinine clearance >= 50 ml/min

• Serum potassium >= LLN

• Serum phosphorous >= LLN

• Serum total calcium (corrected for serum albumin) or serum ionized calcium >= LLN

• Serum magnesium >= LLN

• TSH and free T4 within normal limits (WNL); patients may be on thyroid hormone replacement

• ANC >= 1.5 x 10^9/L

• Platelets >= 100 x 10^9/L

• Hb > 9 g/dL

• INR < 1.3 (or < 3 on anticoagulants)

• Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN (in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication

• Baseline MUGA or ECHO must demonstrate LVEF >= the lower limit of the institutional normal

• ECOG Performance Status of =< 2

Exclusion Criteria:

• Pure papillary and chromophobe renal cell carcinoma, collecting duct tumors and transitional cell carcinoma are not eligible

• Prior treatment with a pan-HDAC or mTOR inhibitor

• Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.)

• Patients who have had a major surgery of significant traumatic injury within 4 weeks of start of study drug and who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study

• Prior treatment with any investigational drug within the preceding 4 weeks

• Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent; topical or inhaled corticosteroids are allowed

• Patients should not receive immunization with attenuated live vaccines within one weeks of study entry or during study period; close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus (Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY2a typhoid vaccines)

• Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases

• Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin

• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

• 1. Symptomatic congestive heart failure of New York Heart Association Class III or 4
• 1. Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
• 1. Concomitant use of drugs with a risk of causing torsades de pointes
• 1. Severely impaired lung functions as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air
• 1. Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN; optimal glycemic control should be achieved before starting trial therapy
• 1. Active (acute or chronic) or uncontrolled severe infections
• 1. Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis; a detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients; HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection

• A known HIV seropositivity

• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

• Patients with an active, bleeding diathesis

• Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods; adequate contraception must be used throughout the trial and for 8 weeks after the last dose of study drug by both sexes

• Adults of reproductive potential who are not using effective birth control methods; if barrier contraceptive are being used, these must be continued throughout this trial by both sexes; hormonal contraceptives are not acceptable as a sole method of contraception

• Women of childbearing potential must have a negative urine or serum pregnancy test within 14 days prior to administration of everolimus

• Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus)

• Patients with a known hypersensitivity to everolimus (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients

• History of noncompliance to medical regimens

• Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment

• Patients unwilling to or unable to comply with the protocol

• Patients currently receiving strong or moderate CYP3A4 inhibitors or inducers; patients should not begin study drugs until at least 72 hours after the last dose (or longer, as indicated) of the inhibitor or inducer

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
2	University of Rochester Medical Center	Rochester	New York	United States	14642

Sponsors and Collaborators

• Roswell Park Cancer Institute
• Novartis

Investigators

• Principal Investigator: Saby George, MD, Roswell Park Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Roswell Park Cancer Institute
• ClinicalTrials.gov Identifier: NCT01582009
• Other Study ID Numbers: I146308; NCI-2009-01599; NCT01037257
• First Posted: Apr 20, 2012
• Last Update Posted: Aug 15, 2022
• Last Verified: Aug 1, 2022

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Everolimus; Panobinostat; Histone Deacetylase Inhibitors

Study Results

Participant Flow

Arm/Group Title	Arm I: Oral Panobinostat and Oral Everolimus
Arm/Group Description	Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. panobinostat: Given orally everolimus: Given orally laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies liquid chromatography: Correlative studies mass spectrometry: Correlative studies enzyme-linked immunosorbent assay: Correlative studies immunohistochemistry staining method: Correlative studies
Period Title: Overall Study
STARTED	26
COMPLETED	24
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Arm I: Oral Panobinostat and Oral Everolimus
Arm/Group Description	Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. panobinostat: Given orally everolimus: Given orally laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies liquid chromatography: Correlative studies mass spectrometry: Correlative studies enzyme-linked immunosorbent assay: Correlative studies immunohistochemistry staining method: Correlative studies
Overall Participants	26
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	14 53.8%
>=65 years	12 46.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.4 (10.6)
Sex: Female, Male (Count of Participants)
Female	3 11.5%
Male	23 88.5%
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	3 11.5%
White	22 84.6%
More than one race	0 0%
Unknown or Not Reported	1 3.8%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	6 month PFS survival rate. Calculated as the total number of failures (deaths or progression) divided by the total follow-up or exposure time of patients on study. Assessed using Kaplan Meier and Proportional Hazards.
Time Frame	The time from registration to documentation of disease progression up to 3 years

Outcome Measure Data

Analysis Population Description

All treated and eligible patients

Arm/Group Title	Arm I: Oral Panobinostat and Oral Everolimus
Arm/Group Description	Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. panobinostat: Given orally everolimus: Given orally laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies liquid chromatography: Correlative studies mass spectrometry: Correlative studies enzyme-linked immunosorbent assay: Correlative studies immunohistochemistry staining method: Correlative studies
Measure Participants	26
Number (95% Confidence Interval) [percentage of participants]	28 107.7%

2. Primary Outcome

Title	Number of Participants With Clinical Response
Description	Number of participants with clinical response. Response will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors ver 1.0 Committee [JNCI 92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST ver. 1.0 criteria.
Time Frame	The time from registration up to 3 years

Outcome Measure Data

Analysis Population Description

All treated and eligible patients

Arm/Group Title	Arm I: Oral Panobinostat and Oral Everolimus
Arm/Group Description	Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. panobinostat: Given orally everolimus: Given orally laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies liquid chromatography: Correlative studies mass spectrometry: Correlative studies enzyme-linked immunosorbent assay: Correlative studies immunohistochemistry staining method: Correlative studies
Measure Participants	26
Count of Participants [Participants]	0 0%

3. Secondary Outcome

Title	Number of Participants With an Adverse Event.
Description	Number of participants with an adverse event. Please refer to the adverse event reporting for more detail.
Time Frame	The time from registration up to 3 years

Outcome Measure Data

Analysis Population Description

All treated and eligible patients

Arm/Group Title	Arm I: Oral Panobinostat and Oral Everolimus
Arm/Group Description	Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. panobinostat: Given orally everolimus: Given orally laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies liquid chromatography: Correlative studies mass spectrometry: Correlative studies enzyme-linked immunosorbent assay: Correlative studies immunohistochemistry staining method: Correlative studies
Measure Participants	26
Count of Participants [Participants]	26 100%

4. Secondary Outcome

Title	Median Progression Free Survival
Description	Median progression free survival. Assessed using Kaplan Meier and Proportional Hazards.
Time Frame	The time from registration up to 3 years

Outcome Measure Data

Analysis Population Description

All treated and eligible patients

Arm/Group Title	Arm I: Oral Panobinostat and Oral Everolimus
Arm/Group Description	Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. panobinostat: Given orally everolimus: Given orally laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies liquid chromatography: Correlative studies mass spectrometry: Correlative studies enzyme-linked immunosorbent assay: Correlative studies immunohistochemistry staining method: Correlative studies
Measure Participants	26
Median (95% Confidence Interval) [months]	5.3

5. Secondary Outcome

Title	6-month Overall Survival Rate
Description	6-month overall survival rate
Time Frame	The time from registration up to 3 years

Outcome Measure Data

Analysis Population Description

All treated and eligible patients. Assessed using Kaplan Meier and Proportional Hazards.

Arm/Group Title	Arm I: Oral Panobinostat and Oral Everolimus
Arm/Group Description	Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. panobinostat: Given orally everolimus: Given orally laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies liquid chromatography: Correlative studies mass spectrometry: Correlative studies enzyme-linked immunosorbent assay: Correlative studies immunohistochemistry staining method: Correlative studies
Measure Participants	26
Number (95% Confidence Interval) [percentage of participants]	96 369.2%

Adverse Events

Arm/Group Title	Arm I: Oral Panobinostat and Oral Everolimus
Arm/Group Description	Patients receive oral panobinostat once daily on days 1, 3, 4, 8, 10, and 12 and oral everolimus once daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. panobinostat: Given orally everolimus: Given orally laboratory biomarker analysis: Correlative studies pharmacological study: Correlative studies liquid chromatography: Correlative studies mass spectrometry: Correlative studies enzyme-linked immunosorbent assay: Correlative studies immunohistochemistry staining method: Correlative studies
All Cause Mortality
	Arm I: Oral Panobinostat and Oral Everolimus
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm I: Oral Panobinostat and Oral Everolimus
	Affected / at Risk (%)	# Events
Total	9/26 (34.6%)
Blood and lymphatic system disorders
Thrombocytopenia	1/26 (3.8%)	2
Cardiac disorders
Atrial fibrillation	1/26 (3.8%)	2
Supraventricular tachycardia	1/26 (3.8%)	2
Gastrointestinal disorders
Abdominal hernia	1/26 (3.8%)	2
Abdominal pain lower	1/26 (3.8%)	2
General disorders
Disease progression	1/26 (3.8%)	2
Infections and infestations
Pneumocystis jiroveci pneumonia	1/26 (3.8%)	2
Pneumonia	1/26 (3.8%)	2
Injury, poisoning and procedural complications
Contusion	1/26 (3.8%)	2
Metabolism and nutrition disorders
Dehydration	1/26 (3.8%)	2
Musculoskeletal and connective tissue disorders
Muscular weakness	1/26 (3.8%)	2
Psychiatric disorders
Confusional state	1/26 (3.8%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/26 (3.8%)	2
Other (Not Including Serious) Adverse Events
	Arm I: Oral Panobinostat and Oral Everolimus
	Affected / at Risk (%)	# Events
Total	26/26 (100%)
Blood and lymphatic system disorders
Anaemia	1/26 (3.8%)	6
Leukopenia	2/26 (7.7%)	4
Lymphadenopathy	1/26 (3.8%)	2
Neutropenia	3/26 (11.5%)	8
Thrombocytopenia	6/26 (23.1%)	28
Cardiac disorders
Atrial fibrillation	2/26 (7.7%)	6
Eye disorders
Ocular hyperaemia	1/26 (3.8%)	2
Photophobia	1/26 (3.8%)	2
Visual impairment	1/26 (3.8%)	2
Gastrointestinal disorders
Abdominal distension	1/26 (3.8%)	2
Abdominal pain	2/26 (7.7%)	8
Abdominal pain lower	1/26 (3.8%)	2
Constipation	3/26 (11.5%)	6
Diarrhoea	7/26 (26.9%)	22
Dry mouth	1/26 (3.8%)	2
Dyspepsia	2/26 (7.7%)	4
Flatulence	1/26 (3.8%)	2
Mouth ulceration	2/26 (7.7%)	4
Nausea	6/26 (23.1%)	16
Stomatitis	3/26 (11.5%)	6
Tongue ulceration	1/26 (3.8%)	2
Vomiting	2/26 (7.7%)	6
General disorders
Chills	4/26 (15.4%)	8
Fatigue	14/26 (53.8%)	30
Mucosal inflammation	8/26 (30.8%)	20
Oedema	1/26 (3.8%)	2
Oedema peripheral	5/26 (19.2%)	10
Pain	3/26 (11.5%)	8
Pyrexia	1/26 (3.8%)	2
Infections and infestations
Cellulitis	1/26 (3.8%)	2
Cystitis	1/26 (3.8%)	2
Nasopharyngitis	1/26 (3.8%)	2
Pneumonia	1/26 (3.8%)	4
Upper respiratory tract infection	1/26 (3.8%)	2
Urethritis	1/26 (3.8%)	2
Injury, poisoning and procedural complications
Contusion	1/26 (3.8%)	2
Muscle strain	1/26 (3.8%)	2
Investigations
Alanine aminotransferase increased	1/26 (3.8%)	2
Aspartate aminotransferase increased	3/26 (11.5%)	8
Blood albumin decreased	1/26 (3.8%)	2
Blood alkaline phosphatase increased	3/26 (11.5%)	6
Blood calcium decreased	1/26 (3.8%)	2
Blood creatinine increased	5/26 (19.2%)	16
Blood fibrinogen increased	1/26 (3.8%)	4
Blood magnesium increased	2/26 (7.7%)	4
Blood phosphorus	2/26 (7.7%)	6
Blood phosphorus decreased	2/26 (7.7%)	6
Blood triglycerides increased	5/26 (19.2%)	34
Body temperature increased	1/26 (3.8%)	2
Electrocardiogram QT interval	1/26 (3.8%)	2
Electrocardiogram QT prolonged	2/26 (7.7%)	4
Gamma-glutamyltransferase increased	2/26 (7.7%)	4
Haemoglobin decreased	4/26 (15.4%)	20
High density lipoprotein decreased	1/26 (3.8%)	2
Low density lipoprotein increased	1/26 (3.8%)	2
Platelet count decreased	1/26 (3.8%)	2
Protein total increased	1/26 (3.8%)	2
White blood cell count decreased	1/26 (3.8%)	12
Metabolism and nutrition disorders
Decreased appetite	4/26 (15.4%)	10
Dehydration	1/26 (3.8%)	4
Hypercholesterolaemia	3/26 (11.5%)	12
Hyperglycaemia	6/26 (23.1%)	26
Hyperkalaemia	1/26 (3.8%)	2
Hyperlipidaemia	1/26 (3.8%)	2
Hypermagnesaemia	1/26 (3.8%)	4
Hypernatraemia	1/26 (3.8%)	2
Hypertriglyceridaemia	1/26 (3.8%)	2
Hypoalbuminaemia	1/26 (3.8%)	6
Hypokalaemia	1/26 (3.8%)	2
Hyponatraemia	3/26 (11.5%)	6
Hypophosphataemia	1/26 (3.8%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	4/26 (15.4%)	8
Back pain	2/26 (7.7%)	4
Bursitis	1/26 (3.8%)	2
Groin pain	1/26 (3.8%)	2
Musculoskeletal chest pain	1/26 (3.8%)	2
Musculoskeletal pain	2/26 (7.7%)	6
Myalgia	1/26 (3.8%)	4
Pain in extremity	5/26 (19.2%)	12
Pain in jaw	1/26 (3.8%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm malignant	1/26 (3.8%)	2
Nervous system disorders
Dysgeusia	2/26 (7.7%)	4
Headache	4/26 (15.4%)	10
Hemicephalalgia	1/26 (3.8%)	2
Hypogeusia	1/26 (3.8%)	2
Neuropathy peripheral	1/26 (3.8%)	2
Peripheral motor neuropathy	1/26 (3.8%)	2
Tremor	3/26 (11.5%)	6
Psychiatric disorders
Insomnia	1/26 (3.8%)	2
Renal and urinary disorders
Dysuria	1/26 (3.8%)	2
Nocturia	1/26 (3.8%)	2
Proteinuria	1/26 (3.8%)	2
Urinary incontinence	1/26 (3.8%)	2
Reproductive system and breast disorders
Erectile dysfunction	1/26 (3.8%)	2
Respiratory, thoracic and mediastinal disorders
Cough	4/26 (15.4%)	8
Dyspnoea	5/26 (19.2%)	10
Epistaxis	2/26 (7.7%)	4
Pleuritic pain	1/26 (3.8%)	2
Pneumonitis	3/26 (11.5%)	8
Pulmonary embolism	1/26 (3.8%)	2
Pulmonary haemorrhage	1/26 (3.8%)	2
Skin and subcutaneous tissue disorders
Alopecia	2/26 (7.7%)	4
Hyperhidrosis	1/26 (3.8%)	2
Nail disorder	1/26 (3.8%)	2
Pruritus	1/26 (3.8%)	2
Rash	3/26 (11.5%)	6
Rash generalised	1/26 (3.8%)	2
Rash macular	1/26 (3.8%)	2
Skin lesion	1/26 (3.8%)	2
Skin ulcer	1/26 (3.8%)	2
Vascular disorders
Deep vein thrombosis	1/26 (3.8%)	2
Embolism	1/26 (3.8%)	2
Hypertension	1/26 (3.8%)	2
Hypotension	3/26 (11.5%)	8

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.