Nintedanib in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors

• Sponsor: Roswell Park Cancer Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02399215
• Collaborator: National Comprehensive Cancer Network (Other)
• Enrollment: 32
• Locations: 2
• Arm: 1
• Anticipated Duration (Months): 88.5
• Patients Per Site: 16
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial studies how well nintedanib works in treating patients with neuroendocrine tumors that have spread from where they started to nearby tissue or lymph nodes (locally advanced) or have spread from the primary site (place where they started) to other places in the body (metastatic). Nintedanib may stop the growth of tumor cells by slowing or stopping a certain type of receptor called vascular endothelial growth factor receptor (VEGFR) from attaching to its target. This may stop the growth of neuroendocrine tumors by blocking the growth of new blood vessels necessary for tumor growth.

Condition or Disease	Intervention/Treatment	Phase
Carcinoid Tumor; Metastatic Carcinoid Tumor; Neuroendocrine Neoplasm	Other: Laboratory Biomarker Analysis; Drug: Nintedanib; Other: Pharmacological Study; Other: Quality-of-Life Assessment	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess progression free survival (PFS), defined as the time interval from initiation of therapy, to its cessation for documentation of progressive disease (PD) or death.

SECONDARY OBJECTIVES:

1. To assess the clinical response (complete response + partial response) in all patients with measurable disease (using standard Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1 criteria).

2. To assess overall survival (OS) in all patients. III. Assess changes in quality of life (QOL) throughout treatment using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) - Gastrointestinal Neuroendocrine Tumors (NET) 21 (GI.NET21) questionnaire for carcinoid patients with gastrointestinal neuroendocrine tumors, in all patients who have filled out at least two QOL questionnaires and, will be reported by groups based on response (response, stable disease or progressive disease).

3. Steady-state pharmacokinetics (PK) of nintedanib, biomarkers, regulatory T cell (Treg) and cytokine expression and growth factors will be analyzed for all patients and reported in groups based on response.

4. Gene mutations and copy number alterations analysis in the mammalian target of rapamycin (mTOR) pathway (will be performed only on the first 10 patients), protein expression of activation of protein kinase B (Akt) (as well as other downstream targets).

5. Toxicity (graded using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) will be closely monitored and all toxicities will be tabulated.

OUTLINE:

Patients receive nintedanib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicenter Phase 2 Study of Nintedanib for Patients With Advanced Carcinoid Tumors
• Actual Study Start Date: May 15, 2015
• Actual Primary Completion Date: Sep 1, 2019
• Anticipated Study Completion Date: Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (nintedanib) Patients receive nintedanib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Nintedanib; Given PO; Other Names: BIBF 1120 BIBF-1120 Intedanib Multitargeted Tyrosine Kinase Inhibitor BIBF 1120 tyrosine kinase inhibitor BIBF 1120 Vargatef ; Other: Pharmacological Study; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment

Outcome Measures

Primary Outcome Measures

1. PFS [Time interval from initiation of therapy, to its cessation for documentation of PD or death, assessed up to 2 years]

   Will be reported using standard Kaplan-Meier methods. Ninety percent confidence intervals for the median PFS will be calculated using Greenwood's formula. Additionally, a confidence interval for the 16-week PFS rate will be obtained using Jeffrey's prior method. The association between survival and quantified variables will be investigated using the Cox-proportional hazard model.

Secondary Outcome Measures

1. Change in Quality of Life Score [Baseline to 30 days post-treatment]

   Quality of life will be investigated calculated by Subjects filing out EORTC Gastrointestinal Neuroendocrine Tumour 21 Questionnaire (QLQ-GI.NET21) A 21 question questionnaire that use a 4-point scale (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much). The scores for different scales (i.e. endocrine, gastrointestinal, treatment, social function, disease Related, and global) are calculated by summing related questions from the questionnaire. The range of the subscale scores are from 0 to 100, with higher scores being worse. After the subscale scores being calculated, the Change in quality of life is calculated by subtracting baseline score from end of treatment

2. Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline and Week 8 [Baseline to week 8]

   Sample collection will be obtained at baseline and week 8

3. Clinical Response (Complete Response + Partial Response) Measured Using Standard RECISTv1.1 Criteria [Up to 2 years]

   Exact 90% confidence interval estimates using the Clopper-Pearson method will be given for the response rates. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI, response rates are categorized as Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

4. Median OS [Up to 3 years (telephone contact is acceptable).]

   Will be reported using standard Kaplan-Meier methods. Ninety-five percent confidence intervals for the median OS will be calculated using Greenwood's formula. The association between survival and quantified variables will be investigated using the Cox-proportional hazard model.

5. Ratio of FGFR IIIb/IIIc and Ki-67 and Microvessel Density Scores [Baseline]

   Scores will be obtained to investigate association with PFS, clinical response, QOL and survival.

Other Outcome Measures

1. Biomarker Levels [Baseline]

   Will be analyzed for all patients and reported in groups based on response.

2. Change in Cytokine Expression [Baseline to 8 weeks]

   Will be analyzed for all patients and reported in groups based on response. Changes in pre- and post-treatment cytokine expression will be analyzed using permutation paired t-tests.

3. Change in Growth Factors [Baseline to 30 days post-treatment]

   Will be analyzed for all patients and reported in groups based on response. Changes in pre- and post-treatment growth factors will be analyzed using permutation paired t-tests.

4. Gene Mutations and Copy Number Alterations [Baseline]

   Gene mutations and copy number alterations in the several pathways particularly mTOR pathway will be evaluated. Will be analyzed for all patients and correlated with clinical outcomes.

5. Treg Levels [Baseline]

   Will be analyzed for all patients and reported in groups based on response.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patient must be on a stable dose of octreotide (Sandostatin®) long-acting release (LAR) or lanreotide for 3 months prior to study enrollment

• Patient must have histologically or cytologically confirmed well differentiated or moderately differentiated (low grade or intermediate grade) neuroendocrine tumor that is locally advanced or metastatic and not of pancreatic origin

• Measurable disease determined by computed tomography (CT) or magnetic resonance imaging (MRI)

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

• Life expectancy greater than 3 months

• Leukocytes >= 3,000/uL

• Absolute neutrophil count >= 1,500/uL

• Total bilirubin =< 2 mg/dL

• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 x upper limit of normal (ULN) and bilirubin =< ULN for patients without liver metastases

• AST/ALT =< 2.5 x ULN and bilirubin =< ULN for patients with liver metastases

• Patients with Gilbert syndrome and bilirubin < 2 x ULN and normal AST/ALT

• Creatinine =< 1.5 mg/dl

• Prior treatment will be permitted including surgery (>= 4 weeks), cytotoxic chemotherapy (maximum of 2 prior regimens); radiation, interferon, targeted growth factors (>= 4 weeks); and prior treatment with octreotide, will be allowed

• Ability to swallow and retain oral medication

• Participants of child-bearing potential (both male and female) must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

• Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

• Archival tissue of carcinoid biopsy must be available

Exclusion Criteria:

• Uncontrolled hypertension, unstable angina, New York Heart Association grade II or greater congestive heart failure, unstable symptomatic arrhythmia requiring medication, or clinically significant peripheral vascular disease (grade II or greater)

• Presence of brain metastases

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 0, or anticipated need for major surgical procedure during the course of the study, or fine needle aspirations or core biopsies within 7 days prior to day 0

• Significant proteinuria at baseline (>= 500 mg/24 hours [h])

• Serious non-healing wound, ulcer or bone fracture

• Evidence of bleeding diathesis or coagulopathy

• Recent (=< 6 months) arterial thromboembolic events, including transient ischemic attack, cerebrovascular accident, unstable angina, or myocardial infarction

• Poorly differentiated neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid, goblet cell carcinoma, or small cell carcinoma

• Hepatic artery embolization or ablation of hepatic metastasis within 3 months of enrollment, prior peptide receptor radionuclide therapy (PRRT) within 4 months or any other cancer therapy within 4 weeks (as long as all toxicities are resolved)

• Intolerance or hypersensitivity to octreotide

• Severe or uncontrolled medical conditions

• 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

• Pregnant or nursing female participants

• Unwilling or unable to follow protocol requirements

• Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
2	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Roswell Park Cancer Institute
• National Comprehensive Cancer Network

Investigators

• Principal Investigator: Renuka Iyer, Roswell Park Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 3, 2018

More Information

Publications

None provided.

• Responsible Party: Roswell Park Cancer Institute
• ClinicalTrials.gov Identifier: NCT02399215
• Other Study ID Numbers: I 259114; NCI-2015-00238; I 259114
• First Posted: Mar 26, 2015
• Last Update Posted: Jul 22, 2022
• Last Verified: Jul 1, 2022

• Additional relevant MeSH terms: Neoplasms; Carcinoid Tumor; Neuroendocrine Tumors; Nintedanib

Study Results

Participant Flow

Arm/Group Title	Treatment (Nintedanib)
Arm/Group Description	Patients receive nintedanib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nintedanib: Given PO Pharmacological Study: Correlative studies Quality-of-Life Assessment: Ancillary studies
Period Title: Overall Study
STARTED	32
COMPLETED	30
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Nintedanib)
Arm/Group Description	Patients receive nintedanib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nintedanib: Given PO Pharmacological Study: Correlative studies Quality-of-Life Assessment: Ancillary studies
Overall Participants	32
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 50%
>=65 years	16 50%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	15 46.9%
Male	17 53.1%
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	16 50%
White	16 50%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	32 100%

Outcome Measures

1. Primary Outcome

Title	PFS
Description	Will be reported using standard Kaplan-Meier methods. Ninety percent confidence intervals for the median PFS will be calculated using Greenwood's formula. Additionally, a confidence interval for the 16-week PFS rate will be obtained using Jeffrey's prior method. The association between survival and quantified variables will be investigated using the Cox-proportional hazard model.
Time Frame	Time interval from initiation of therapy, to its cessation for documentation of PD or death, assessed up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nintedanib)
Arm/Group Description	Patients receive nintedanib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nintedanib: Given PO Pharmacological Study: Correlative studies Quality-of-Life Assessment: Ancillary studies
Measure Participants	30
Median (90% Confidence Interval) [months]	11

2. Secondary Outcome

Title	Change in Quality of Life Score
Description	Quality of life will be investigated calculated by Subjects filing out EORTC Gastrointestinal Neuroendocrine Tumour 21 Questionnaire (QLQ-GI.NET21) A 21 question questionnaire that use a 4-point scale (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much). The scores for different scales (i.e. endocrine, gastrointestinal, treatment, social function, disease Related, and global) are calculated by summing related questions from the questionnaire. The range of the subscale scores are from 0 to 100, with higher scores being worse. After the subscale scores being calculated, the Change in quality of life is calculated by subtracting baseline score from end of treatment
Time Frame	Baseline to 30 days post-treatment

Outcome Measure Data

Analysis Population Description

Patients completed at least 2 EORTC QLQ-GI.NET21 questionnaires are included for this outcome estimate

Arm/Group Title	Treatment (Nintedanib)
Arm/Group Description	Patients receive nintedanib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nintedanib: Given PO Pharmacological Study: Correlative studies Quality-of-Life Assessment: Ancillary studies
Measure Participants	31
Change in endocrine scale	0
Change in gastrointestinal scale	0
Change in treatment scale	0
Change in social function scale	0
Change in Disease Related Worry Scale	-6
Change in Global scale	1

3. Secondary Outcome

Title	Plasma Concentrations at Steady State (Cpre,ss) of Nintedanib at Baseline and Week 8
Description	Sample collection will be obtained at baseline and week 8
Time Frame	Baseline to week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nintedanib)
Arm/Group Description	Patients receive nintedanib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nintedanib: Given PO Pharmacological Study: Correlative studies Quality-of-Life Assessment: Ancillary studies
Measure Participants	32
Median (Full Range) [ng/mL]	11.2

4. Secondary Outcome

Title	Clinical Response (Complete Response + Partial Response) Measured Using Standard RECISTv1.1 Criteria
Description	Exact 90% confidence interval estimates using the Clopper-Pearson method will be given for the response rates. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI, response rates are categorized as Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nintedanib)
Arm/Group Description	Patients receive nintedanib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nintedanib: Given PO Pharmacological Study: Correlative studies Quality-of-Life Assessment: Ancillary studies
Measure Participants	28
SD	26 81.3%
PD	1 3.1%
PR	1 3.1%

5. Secondary Outcome

Title	Median OS
Description	Will be reported using standard Kaplan-Meier methods. Ninety-five percent confidence intervals for the median OS will be calculated using Greenwood's formula. The association between survival and quantified variables will be investigated using the Cox-proportional hazard model.
Time Frame	Up to 3 years (telephone contact is acceptable).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Nintedanib)
Arm/Group Description	Patients receive nintedanib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nintedanib: Given PO Pharmacological Study: Correlative studies Quality-of-Life Assessment: Ancillary studies
Measure Participants	32
Median (90% Confidence Interval) [months]	32.7

6. Secondary Outcome

Title	Ratio of FGFR IIIb/IIIc and Ki-67 and Microvessel Density Scores
Description	Scores will be obtained to investigate association with PFS, clinical response, QOL and survival.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Biomarker Levels
Description	Will be analyzed for all patients and reported in groups based on response.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Change in Cytokine Expression
Description	Will be analyzed for all patients and reported in groups based on response. Changes in pre- and post-treatment cytokine expression will be analyzed using permutation paired t-tests.
Time Frame	Baseline to 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Change in Growth Factors
Description	Will be analyzed for all patients and reported in groups based on response. Changes in pre- and post-treatment growth factors will be analyzed using permutation paired t-tests.
Time Frame	Baseline to 30 days post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Gene Mutations and Copy Number Alterations
Description	Gene mutations and copy number alterations in the several pathways particularly mTOR pathway will be evaluated. Will be analyzed for all patients and correlated with clinical outcomes.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Other Pre-specified Outcome

Title	Treg Levels
Description	Will be analyzed for all patients and reported in groups based on response.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Routine AEs occurring at baseline, Cycle 1-Week 1-Day 1, Cycle 1-Week 3-Day 1, Day 1 of subsequent cycles, End of Treatment, and PFS Follow-Up, will be reported, up to 33 months.
Arm/Group Title	Treatment (Nintedanib)
Arm/Group Description	Patients receive nintedanib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Laboratory Biomarker Analysis: Correlative studies Nintedanib: Given PO Pharmacological Study: Correlative studies Quality-of-Life Assessment: Ancillary studies
All Cause Mortality
	Treatment (Nintedanib)
	Affected / at Risk (%)	# Events
Total	18/32 (56.3%)
Serious Adverse Events
	Treatment (Nintedanib)
	Affected / at Risk (%)	# Events
Total	14/32 (43.8%)
Blood and lymphatic system disorders
Anaemia	1/32 (3.1%)	1
Cardiac disorders
Acute myocardial infarction	1/32 (3.1%)	1
Atrial fibrillation	2/32 (6.3%)	3
Myocardial infarction	1/32 (3.1%)	1
Palpitations	1/32 (3.1%)	1
Eye disorders
Vision blurred	1/32 (3.1%)	3
Gastrointestinal disorders
Abdominal pain	1/32 (3.1%)	1
Ascites	1/32 (3.1%)	1
Diarrhoea	1/32 (3.1%)	1
Dysphagia	1/32 (3.1%)	1
Large intestinal obstruction	2/32 (6.3%)	2
Pancreatitis	1/32 (3.1%)	1
Small intestinal obstruction	1/32 (3.1%)	1
Vomiting	1/32 (3.1%)	1
General disorders
Early satiety	1/32 (3.1%)	1
Influenza like illness	1/32 (3.1%)	1
Therapeutic response decreased	1/32 (3.1%)	1
Hepatobiliary disorders
Cholangitis	1/32 (3.1%)	1
Infections and infestations
Cellulitis	1/32 (3.1%)	1
Lung infection	1/32 (3.1%)	1
Upper respiratory tract infection	1/32 (3.1%)	1
Injury, poisoning and procedural complications
Fall	1/32 (3.1%)	1
Incision site pain	1/32 (3.1%)	1
Seroma	1/32 (3.1%)	1
Investigations
Blood alkaline phosphatase increased	1/32 (3.1%)	1
Lymphocyte count decreased	1/32 (3.1%)	1
Weight decreased	1/32 (3.1%)	1
Metabolism and nutrition disorders
Decreased appetite	1/32 (3.1%)	3
Hyperglycaemia	1/32 (3.1%)	2
Hypoalbuminaemia	1/32 (3.1%)	2
Hypocalcaemia	1/32 (3.1%)	1
Hypomagnesaemia	1/32 (3.1%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/32 (3.1%)	2
Muscle spasms	1/32 (3.1%)	1
Nervous system disorders
Dizziness	1/32 (3.1%)	1
Dysarthria	1/32 (3.1%)	1
Dysgeusia	1/32 (3.1%)	1
Headache	1/32 (3.1%)	1
Syncope	1/32 (3.1%)	1
Psychiatric disorders
Agitation	1/32 (3.1%)	1
Renal and urinary disorders
Acute kidney injury	1/32 (3.1%)	1
Hydronephrosis	1/32 (3.1%)	1
Proteinuria	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/32 (9.4%)	3
Rhinorrhoea	1/32 (3.1%)	1
Vascular disorders
Hypertension	1/32 (3.1%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Nintedanib)
	Affected / at Risk (%)	# Events
Total	31/32 (96.9%)
Blood and lymphatic system disorders
Anaemia	9/32 (28.1%)	13
Leukocytosis	3/32 (9.4%)	4
Lymph node pain	1/32 (3.1%)	1
Cardiac disorders
Angina pectoris	1/32 (3.1%)	1
Aortic valve disease	1/32 (3.1%)	1
Cardiac failure	1/32 (3.1%)	1
Coronary artery disease	1/32 (3.1%)	1
Sinus bradycardia	4/32 (12.5%)	4
Sinus tachycardia	1/32 (3.1%)	1
Tachycardia	1/32 (3.1%)	1
Tricuspid valve disease	1/32 (3.1%)	1
Endocrine disorders
Adrenal insufficiency	1/32 (3.1%)	1
Hypothyroidism	1/32 (3.1%)	1
Eye disorders
Dry eye	1/32 (3.1%)	1
Eye disorder	1/32 (3.1%)	1
Photopsia	1/32 (3.1%)	1
Gastrointestinal disorders
Abdominal distension	2/32 (6.3%)	3
Abdominal pain	10/32 (31.3%)	20
Anal haemorrhage	1/32 (3.1%)	1
Angular cheilitis	1/32 (3.1%)	1
Ascites	1/32 (3.1%)	1
Constipation	2/32 (6.3%)	2
Dental caries	1/32 (3.1%)	1
Diarrhoea	12/32 (37.5%)	19
Dry mouth	3/32 (9.4%)	3
Dyspepsia	1/32 (3.1%)	1
Dysphagia	1/32 (3.1%)	1
Faeces pale	1/32 (3.1%)	1
Flatulence	2/32 (6.3%)	2
Gastrointestinal disorder	1/32 (3.1%)	1
Nausea	19/32 (59.4%)	28
Oral dysaesthesia	1/32 (3.1%)	1
Paraesthesia oral	1/32 (3.1%)	1
Stomatitis	1/32 (3.1%)	1
Tooth discolouration	1/32 (3.1%)	1
Vomiting	12/32 (37.5%)	17
General disorders
Chills	2/32 (6.3%)	2
Fatigue	12/32 (37.5%)	20
Influenza like illness	5/32 (15.6%)	5
Infusion site extravasation	1/32 (3.1%)	1
Localised oedema	2/32 (6.3%)	2
Non-cardiac chest pain	1/32 (3.1%)	3
Oedema peripheral	4/32 (12.5%)	5
Peripheral swelling	1/32 (3.1%)	1
Pyrexia	1/32 (3.1%)	1
Hepatobiliary disorders
Hepatic failure	1/32 (3.1%)	1
Immune system disorders
Contrast media allergy	1/32 (3.1%)	1
Infections and infestations
Cellulitis	2/32 (6.3%)	3
Gastroenteritis	1/32 (3.1%)	1
Hepatic infection	1/32 (3.1%)	1
Hordeolum	1/32 (3.1%)	1
Infection	1/32 (3.1%)	2
Peritonitis	1/32 (3.1%)	1
Sinusitis	1/32 (3.1%)	2
Stoma site infection	1/32 (3.1%)	1
Tooth infection	1/32 (3.1%)	2
Upper respiratory tract infection	1/32 (3.1%)	1
Urinary tract infection	1/32 (3.1%)	1
Vulvovaginal mycotic infection	1/32 (3.1%)	1
Injury, poisoning and procedural complications
Contusion	7/32 (21.9%)	7
Cystitis radiation	1/32 (3.1%)	1
Fall	2/32 (6.3%)	2
Injury	1/32 (3.1%)	1
Ligament sprain	1/32 (3.1%)	1
Rib fracture	1/32 (3.1%)	1
Skin laceration	1/32 (3.1%)	4
Stoma site pain	1/32 (3.1%)	1
Investigations
Activated partial thromboplastin time	1/32 (3.1%)	1
Alanine aminotransferase increased	9/32 (28.1%)	16
Aspartate aminotransferase increased	11/32 (34.4%)	27
Bacterial test positive	1/32 (3.1%)	1
Blood alkaline phosphatase	1/32 (3.1%)	1
Blood alkaline phosphatase increased	11/32 (34.4%)	19
Blood bilirubin increased	5/32 (15.6%)	11
Blood creatine increased	1/32 (3.1%)	1
Blood creatinine increased	3/32 (9.4%)	4
Blood glucose increased	1/32 (3.1%)	1
Brain natriuretic peptide	1/32 (3.1%)	1
Haemoglobin increased	1/32 (3.1%)	1
Hepatic enzyme increased	1/32 (3.1%)	1
International normalised ratio increased	2/32 (6.3%)	4
Lymphocyte count decreased	16/32 (50%)	57
Neutrophil count decreased	1/32 (3.1%)	1
Platelet count decreased	12/32 (37.5%)	16
Troponin I increased	3/32 (9.4%)	3
Weight decreased	13/32 (40.6%)	19
Weight increased	1/32 (3.1%)	1
White blood cell count decreased	9/32 (28.1%)	21
White blood cell count increased	1/32 (3.1%)	1
Metabolism and nutrition disorders
Decreased appetite	8/32 (25%)	10
Dehydration	1/32 (3.1%)	1
Diabetes mellitus	1/32 (3.1%)	1
Hypercalcaemia	1/32 (3.1%)	1
Hyperglycaemia	16/32 (50%)	46
Hypernatraemia	3/32 (9.4%)	8
Hypoalbuminaemia	6/32 (18.8%)	18
Hypocalcaemia	3/32 (9.4%)	3
Hypoglycaemia	2/32 (6.3%)	4
Hypokalaemia	5/32 (15.6%)	9
Hypomagnesaemia	1/32 (3.1%)	1
Hyponatraemia	4/32 (12.5%)	7
Musculoskeletal and connective tissue disorders
Arthralgia	3/32 (9.4%)	3
Back pain	4/32 (12.5%)	6
Flank pain	1/32 (3.1%)	1
Muscle spasms	1/32 (3.1%)	1
Muscular weakness	2/32 (6.3%)	3
Musculoskeletal chest pain	1/32 (3.1%)	1
Musculoskeletal pain	3/32 (9.4%)	4
Myalgia	2/32 (6.3%)	2
Pain in extremity	1/32 (3.1%)	1
Pain in jaw	1/32 (3.1%)	1
Trismus	1/32 (3.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	1/32 (3.1%)	1
Nervous system disorders
Amnesia	1/32 (3.1%)	1
Dizziness	4/32 (12.5%)	6
Dysgeusia	6/32 (18.8%)	8
Headache	6/32 (18.8%)	7
Memory impairment	1/32 (3.1%)	1
Paraesthesia	1/32 (3.1%)	1
Presyncope	1/32 (3.1%)	1
Syncope	2/32 (6.3%)	2
Psychiatric disorders
Anxiety	2/32 (6.3%)	2
Confusional state	1/32 (3.1%)	4
Depression	2/32 (6.3%)	2
Insomnia	1/32 (3.1%)	1
Stress	1/32 (3.1%)	1
Renal and urinary disorders
Acute kidney injury	3/32 (9.4%)	5
Chronic kidney disease	2/32 (6.3%)	2
Dysuria	1/32 (3.1%)	1
Proteinuria	2/32 (6.3%)	2
Reproductive system and breast disorders
Erectile dysfunction	1/32 (3.1%)	1
Gynaecomastia	1/32 (3.1%)	1
Nipple pain	1/32 (3.1%)	1
Vaginal discharge	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Cough	3/32 (9.4%)	3
Dysphonia	2/32 (6.3%)	2
Dyspnoea	6/32 (18.8%)	8
Epistaxis	2/32 (6.3%)	3
Pleural effusion	1/32 (3.1%)	1
Pneumonitis	1/32 (3.1%)	1
Productive cough	1/32 (3.1%)	1
Rhinitis allergic	2/32 (6.3%)	2
Sneezing	1/32 (3.1%)	1
Upper-airway cough syndrome	2/32 (6.3%)	3
Skin and subcutaneous tissue disorders
Alopecia	2/32 (6.3%)	2
Dermatitis acneiform	1/32 (3.1%)	1
Dermatitis bullous	1/32 (3.1%)	2
Hair colour changes	2/32 (6.3%)	2
Hyperhidrosis	1/32 (3.1%)	1
Hyperkeratosis	1/32 (3.1%)	1
Nail discolouration	1/32 (3.1%)	1
Nail ridging	1/32 (3.1%)	1
Rash	1/32 (3.1%)	1
Rash maculo-papular	2/32 (6.3%)	3
Skin disorder	1/32 (3.1%)	1
Social circumstances
Edentulous	1/32 (3.1%)	1
Surgical and medical procedures
Tooth extraction	1/32 (3.1%)	1
Vascular disorders
Flushing	5/32 (15.6%)	5
Hypertension	17/32 (53.1%)	38
Hypotension	6/32 (18.8%)	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.