An Open-label, Phase 2 Study of ACP-196 in Subjects With Waldenström Macroglobulinemia

• Sponsor: Acerta Pharma BV (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02180724
• Collaborator: (none)
• Enrollment: 106
• Locations: 38
• Arm: 1
• Anticipated Duration (Months): 147.7
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics, and activity of acalabrutinib in treating subjects with WM.

Condition or Disease	Intervention/Treatment	Phase
Waldenström Macroglobulinemia (WM)	Drug: Acalabrutinib (ACP-196)	Phase 2

Detailed Description

Clinical studies have shown that targeting the B-cell receptor (BCR) signaling pathway by inhibiting Bruton tyrosine kinase (BTK) produces significant clinical benefit in patients with non-Hodgkin lymphoma, including Waldenström macroglobulinemia (WM). Ibrutinib (IMBRUVICA®), an oral, small-molecule BTK inhibitor has been approved for the treatment for chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and WM.

Acerta Pharma BV (AcertaPharma) has developed a novel BTK inhibitor, acalabrutinib, that achieves significant oral bioavailability and potency in preclinical models.

The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics, and activity of acalabrutinib in treating subjects with WM.

Study Design

• Study Type: Interventional
• Actual Enrollment: 106 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Phase 2 Study of ACP-196 in Subjects With Waldenström Macroglobulinemia
• Actual Study Start Date: Sep 8, 2014
• Actual Primary Completion Date: Oct 1, 2019
• Anticipated Study Completion Date: Dec 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Previously Treated/Naive Previously treated, N=92 Treatment Naïve, N=14	Drug: Acalabrutinib (ACP-196); Other Names: Acalabrutinib

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) of Acalabrutinib in Subjects as Assessed by Investigator [Up to approximately 3.8 years. Data cut at when last patient have completed Cycle 27 (28 days per Cycle).]

   ORR defined as the rate of subjects achieving a Miner Response (MR) or better including complete response (CR), very good partial response (VGPR), partial response (PR) and MR; The definition of responses are evaluated by investigators using both Modified 6th criteria (refer to protocol table 4-2 , 4-3) and Modified 3rd International Workshop of Waldenström Macroglobulinemia (IWWM) criteria (refer to protocol table 4-4 and table 4-5 for definition). For Modified 6th criteria, MR is defined as (1) monoclonal IgM protein is detectable, (2) no new signs or symptoms of active disease, (3) and patient has >=25% but < 50% reduction in serum monoclonal IgM level from baseline. PR and VGPR both require (1) and (2) as MR, but PR also requires the >=50% and <90% reduction in serum monoclonal IgM level as well as reduction in extramedullary disease. VGPR requires >= 90% reduction in serum IgM and complete resolution of extramedullary disease.

Secondary Outcome Measures

1. Progression-free Survival (PFS) of Acalabrutinib by Investigator [Up to approximately 3.8 years. Data cut at last subject have completed Cycle 27 (28 days per Cycle).]

   Kaplan-Meier (K-M) estimates of the PFS assessments and its 95% confidence interval are provided using both modified 3rd and 6th IWWM criteria by investigator. K-M estimates at a certain time (ex. all subjects complete Cycle 27) provides the estimated percentage of the subjects who are still alive or have not progressed by the given time over all patients at risk. Per 6th IWWM criteria, the progressive disease is defined as >= 25% increase in serum IgM level with an absolute increase of at least 500 mg/dL from lowest nadir (requires confirmation on at least 2 consecutive measurements at least 4 weeks apart) and/or progression of clinical features attributable to the disease. Per modified 3rd IWWM criteria, besides IgM requirement as 6th criteria, it could also includes progression of clinically significant disease related symptoms and/or death from any cause or initiation of a new anti-neoplastic therapy.

2. Overall Survival (OS) of Acalabrutinib by Investigator [Primary analysis occur when all subjects have completed Cycle 27 or have discontinued before Cycle 27.]

   Kaplan-Meier (K-M) estimates of the OS assessments and its 95% confidence interval are provided using both 3rd and 6th IWWM criteria by investigator. K-M estimates at a certain time (ex. all subjects complete Cycle 27) provides the estimated percentage of the subjects who are still alive by the given time over all patients at risk.

3. Summary of Duration of Response (DOR) [Primary analysis occur when all subjects have completed Cycle 27 or have excit the study]

   DOR is defined as the interval from the first documentation of Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR) or Minor Response (MR) to the earlier of the first documentation of definitive PD or death from any cause. The summary statistics are provided for DOR.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Men and women ≥18 years of age.

2. Previously treated cohort only: A confirmed diagnosis of WM, which has relapsed after, or been refractory to ≥1prior therapy for WM and which requires treatment.

3. Previously untreated cohort only: A confirmed diagnosis of previously untreated WM in subjects who require treatment and do not want to receive chemoimmunotherapy or have comorbidities that would preclude chemoimmunotherapy such as:

• Symptomatic hyperviscosity with an IgM ≥5,000mg/dL

• Disease-related neuropathy

1. Serum concentration of IgM, as measured by SPEP and IFE, that exceeds the upper limits of normal or measurable nodal WM (defined as the presence of ≥1lymph node that measures ≥2.0 cm in the longest diameter and ≥1.0cm in the longest perpendicular diameter).

2. ECOG performance status of ≤2.

3. Women who are sexually active and can bear children must agree to use highly effective forms of contraception during the study and for 2 days after the last dose of acalabrutinib.

4. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.

5. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).

Exclusion Criteria:

1. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for ≥2 years or which will not limit survival to <2 years. Note: These cases must be discussed with the medical monitor.

2. A life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of acalabrutinib, or put the study outcomes at undue risk.

3. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or QTc >480 msec.

4. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.

5. Any immunotherapy within 4 weeks of first dose of study drug.

6. For subjects with recent chemotherapy or experimental therapy, the first dose of study drug must occur after 5 times the half-life of the agent(s).

7. Prior exposure to a BCR inhibitor (e.g., BTK,PI3K, or SYK inhibitors) or BCL-2 inhibitors (e.g., ABT-199).

8. Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids for treatment of WM or other conditions. Note: Subjects may use topical or inhaled corticosteroids or low-dose steroids (≤10 mg of prednisone or equivalent per day) as therapy for comorbid conditions. During study participation, subjects may also receive systemic or enteric corticosteroids as needed for treatment-emergent comorbid conditions.

9. Grade ≥2 toxicity (other than alopecia) continuing from prior anticancer therapy including radiation.

10. Known history of HIV or active infection with HCV or hepatitis B virus (HBV) or any uncontrolled active systemic infection.

11. Major surgery within 4 weeks before first dose of study drug.

12. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.

13. History of a bleeding diathesis (e.g., hemophilia, von Willebrand disease).

14. History of stroke or intracranial hemorrhage within 6 months before the first dose of acalabrutinib.

15. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 28 days of first dose of study drug.

16. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole).

17. ANC <0.75 x 109/L or platelet count <50 x 109/L. For subjects with disease involvement in the bone marrow, ANC <0.50 x 109/L or platelet count <30x109/L.

18. Creatinine >2.5 x institutional ULN; total bilirubin >2.5 x ULN; or AST or ALT >3.0 x ULN.

19. Lactating or pregnant.

20. Concurrent participation in another therapeutic clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Santa Barbara	California	United States	93105
2	Research Site	Aurora	Colorado	United States	80012
3	Research Site	Washington	District of Columbia	United States	20007
4	Research Site	Minneapolis	Minnesota	United States	55404
5	Research Site	New York	New York	United States	10021
6	Research Site	Nashville	Tennessee	United States	37203
7	Research Site	Austin	Texas	United States	78705
8	Research Site	Bedford	Texas	United States	76022
9	Research Site	Houston	Texas	United States	77030
10	Research Site	Vancouver	Washington	United States	98684
11	Research Site	Aurillac Cedex		France	15002
12	Research Site	Clermond Ferrand		France	63003
13	Research Site	Marseille CEDEX		France	13273
14	Research Site	Montpellier		France	34295
15	Research Site	Nantes		France	44093
16	Research Site	Paris cedex 13		France	75651
17	Research Site	Paris		France	75015
18	Research Site	Pierre Benite Cedex		France	69495
19	Research Site	Poitiers		France	86021
20	Research Site	Reims Cedex		France	51092
21	Research Site	Rennes Cedex		France	35000
22	Research Site	Toulouse Cedex		France	31059
23	Research Site	Vandoeuvre-les-Nancy		France	54500
24	Research Site	Athens		Greece	11528
25	Research Site	Bologna		Italy	40138
26	Research Site	Milan		Italy	20162
27	Research Site	Novara		Italy	28100
28	Research Site	Amsterdam		Netherlands	1105AZ
29	Research Site	Utrecht		Netherlands	2508GA
30	Research Site	Salamanca		Spain	37007
31	Research Site	Bournemouth		United Kingdom	BH7 7DW
32	Research Site	Leeds		United Kingdom	LS9 7TF
33	Research Site	Leicester		United Kingdom	LE1 7RH
34	Research Site	London		United Kingdom	NW1 2BU
35	Research Site	London		United Kingdom	SW3 6JJ
36	Research Site	Oxford		United Kingdom	OX3 7LE
37	Research Site	Plymouth		United Kingdom	PL6 8DH
38	Research Site	Southampton		United Kingdom	SO16 6YD

Sponsors and Collaborators

• Acerta Pharma BV

Investigators

• Study Director: AstraZeneca Clinical study Information Center, 1-877-240-9479 [e-mail]

Study Documents (Full-Text)

• Study Protocol - Apr 16, 2019
• Statistical Analysis Plan - Jan 31, 2018

More Information

Publications

None provided.

• Responsible Party: Acerta Pharma BV
• ClinicalTrials.gov Identifier: NCT02180724
• Other Study ID Numbers: ACE-WM-001
• First Posted: Jul 3, 2014
• Last Update Posted: Mar 18, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Acerta Pharma BV: Bruton tyrosine kinase inhibitor; Btk; Waldenström Macroglobulinemia; WM; Waldenström; Macroglobulinemia
• Additional relevant MeSH terms: Waldenstrom Macroglobulinemia; Acalabrutinib

Study Results

Participant Flow

Arm/Group Title	Previously Treated WM Patients	Treatment Naïve WM Patients
Arm/Group Description	Previously treated WM Patients, Total 92 patients including 87 patients administered 100mg acalabrutinib twice daily, 12 hours apart (BID dosing = total daily dose 200 mg) orally, with or without food, and 5 patients administered 200mg once daily dose (QD) at beginning then switched to 100mg BID thereafter.	Treatment naïve WM Patients, Total 14 patients including 13 patients administered 100mg acalabrutinib twice daily, 12 hours apart (BID dosing = total daily dose 200 mg) orally, with or without food, and 1 patient administered 200mg once daily dose (QD) at beginning then switched to 100mg BID dose thereafter.
Period Title: Overall Study
STARTED	92	14
Enrolled	92	14
Received Study Medication	92	14
Discontinued Study	14	3
Discontinued Treatment	23	7
COMPLETED	0	0
NOT COMPLETED	92	14

Baseline Characteristics

Arm/Group Title	Previously Treated	Treatment Naive	Total
Arm/Group Description	Previously treated, N= 92	Treatment naïve, N=14	Total of all reporting groups
Overall Participants	92	14	106
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	26 28.3%	4 28.6%	30 28.3%
>=65 years	66 71.7%	10 71.4%	76 71.7%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	68.7 (9.84)	70 (13)	68.9 (10.25)
Sex: Female, Male (Count of Participants)
Female	29 31.5%	4 28.6%	33 31.1%
Male	63 68.5%	10 71.4%	73 68.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 2.2%	0 0%	2 1.9%
White	80 87%	14 100%	94 88.7%
More than one race	1 1.1%	0 0%	1 0.9%
Unknown or Not Reported	9 9.8%	0 0%	9 8.5%
Region of Enrollment (Count of Participants)
United States	19 20.7%	9 64.3%	28 26.4%
Europe	73 79.3%	5 35.7%	78 73.6%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR) of Acalabrutinib in Subjects as Assessed by Investigator
Description	ORR defined as the rate of subjects achieving a Miner Response (MR) or better including complete response (CR), very good partial response (VGPR), partial response (PR) and MR; The definition of responses are evaluated by investigators using both Modified 6th criteria (refer to protocol table 4-2 , 4-3) and Modified 3rd International Workshop of Waldenström Macroglobulinemia (IWWM) criteria (refer to protocol table 4-4 and table 4-5 for definition). For Modified 6th criteria, MR is defined as (1) monoclonal IgM protein is detectable, (2) no new signs or symptoms of active disease, (3) and patient has >=25% but < 50% reduction in serum monoclonal IgM level from baseline. PR and VGPR both require (1) and (2) as MR, but PR also requires the >=50% and <90% reduction in serum monoclonal IgM level as well as reduction in extramedullary disease. VGPR requires >= 90% reduction in serum IgM and complete resolution of extramedullary disease.
Time Frame	Up to approximately 3.8 years. Data cut at when last patient have completed Cycle 27 (28 days per Cycle).

Outcome Measure Data

Analysis Population Description

200mg QD patients eventually switched to 100mg BID

Arm/Group Title	Previously Treated (N=92)	Treatment Naive (N=14)
Arm/Group Description	100 mg BID N=87 + 200 mg QD N= 5	100 mg BID N= 13 + 200 mg QD N=1
Measure Participants	92	14
ORR 6th IWWM criteria (CR+VGPR+PR+MR)	86 93.5%	13 92.9%
CR (6th)	0 0%	0 0%
VGPR (6th)	8 8.7%	0 0%
PR (6th)	66 71.7%	11 78.6%
MR (6th)	12 13%	2 14.3%
ORR 3rd IWWM criteria (CR+VGPR+PR+MR)	86 93.5%	13 92.9%
CR (3rd)	0 0%	0 0%
VGPR (3rd)	30 32.6%	1 7.1%
PR (3rd)	42 45.7%	10 71.4%
MR (3rd)	14 15.2%	2 14.3%

2. Secondary Outcome

Title	Progression-free Survival (PFS) of Acalabrutinib by Investigator
Description	Kaplan-Meier (K-M) estimates of the PFS assessments and its 95% confidence interval are provided using both modified 3rd and 6th IWWM criteria by investigator. K-M estimates at a certain time (ex. all subjects complete Cycle 27) provides the estimated percentage of the subjects who are still alive or have not progressed by the given time over all patients at risk. Per 6th IWWM criteria, the progressive disease is defined as >= 25% increase in serum IgM level with an absolute increase of at least 500 mg/dL from lowest nadir (requires confirmation on at least 2 consecutive measurements at least 4 weeks apart) and/or progression of clinical features attributable to the disease. Per modified 3rd IWWM criteria, besides IgM requirement as 6th criteria, it could also includes progression of clinically significant disease related symptoms and/or death from any cause or initiation of a new anti-neoplastic therapy.
Time Frame	Up to approximately 3.8 years. Data cut at last subject have completed Cycle 27 (28 days per Cycle).

Outcome Measure Data

Analysis Population Description

200mg QD patients eventually switch to 100mg BID and will be summarized in the 100 mg Arm in the results

Arm/Group Title	Previously Treated (N=92)	Treatment Naive (N=14)
Arm/Group Description	100 mg BID N=87 + 200 mg QD N= 5	100 mg BID N= 13 + 200 mg QD N=1
Measure Participants	92	14
K-M Point Est. for PFS by 6th IWWM criteria	81.9	90.0
K-M Point Est. for PFS by 3rd IWWM criteria	81.9	90.0

3. Secondary Outcome

Title	Overall Survival (OS) of Acalabrutinib by Investigator
Description	Kaplan-Meier (K-M) estimates of the OS assessments and its 95% confidence interval are provided using both 3rd and 6th IWWM criteria by investigator. K-M estimates at a certain time (ex. all subjects complete Cycle 27) provides the estimated percentage of the subjects who are still alive by the given time over all patients at risk.
Time Frame	Primary analysis occur when all subjects have completed Cycle 27 or have discontinued before Cycle 27.

Outcome Measure Data

Analysis Population Description

200mg QD patients eventually switch to 100mg BID and will be summarized in the 100 mg Arm in the results

Arm/Group Title	Previously Treated (N=92)	Treatment Naive (N=14)
Arm/Group Description	100 mg BID N=87 + 200 mg QD N= 5	100 mg BID N= 13 + 200 mg QD N=1
Measure Participants	92	14
Number (95% Confidence Interval) [Percentage of subjects]	88.9	91.7

4. Secondary Outcome

Title	Summary of Duration of Response (DOR)
Description	DOR is defined as the interval from the first documentation of Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR) or Minor Response (MR) to the earlier of the first documentation of definitive PD or death from any cause. The summary statistics are provided for DOR.
Time Frame	Primary analysis occur when all subjects have completed Cycle 27 or have excit the study

Outcome Measure Data

Analysis Population Description

200mg QD patients eventually switch to 100mg BID and will be summarized in the 100 mg Arm in the results

Arm/Group Title	Previously Treated (N=92)	Treatment Naive (N=14)
Arm/Group Description	100 mg BID N=87 + 200 mg QD N= 5	100 mg BID N= 13 + 200 mg QD N=1
Measure Participants	86	13
DOR by Modified 3rd IWWM criteria	21.9 (8.1)	19.6 (8.41)
DOR by 6th IWWM Criteria	21.7 (8.11)	19.5 (8.45)

Adverse Events

Time Frame	Reported Treatment Emergent Adverse Events (TEAEs) include events starting on or after Day 0 and on or before last patient complete Cycle 27 (28 days per Cycle).
Arm/Group Title	Previously Treated		Treatment Naïve
Arm/Group Description	Previously treated, N= 92		Treatment naïve, N=14
All Cause Mortality
	Previously Treated		Treatment Naïve
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/92 (13%)		1/14 (7.1%)
Serious Adverse Events
	Previously Treated		Treatment Naïve
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/92 (54.3%)		6/14 (42.9%)
Blood and lymphatic system disorders
Febrile neutropenia	2/92 (2.2%)		0/14 (0%)
Anaemia	1/92 (1.1%)		0/14 (0%)
Neutropenia	1/92 (1.1%)		0/14 (0%)
Cardiac disorders
Angina pectoris	1/92 (1.1%)		0/14 (0%)
Atrial fibrillation	1/92 (1.1%)		0/14 (0%)
Coronary artery disease	0/92 (0%)		1/14 (7.1%)
Myocardial ischaemia	0/92 (0%)		1/14 (7.1%)
Nodal arrhythmia	1/92 (1.1%)		0/14 (0%)
Gastrointestinal disorders
Abdominal pain	2/92 (2.2%)		0/14 (0%)
Vomiting	2/92 (2.2%)		0/14 (0%)
Ascites	1/92 (1.1%)		0/14 (0%)
Diarrhoea	1/92 (1.1%)		0/14 (0%)
Gastric ulcer	1/92 (1.1%)		0/14 (0%)
Haematemesis	1/92 (1.1%)		0/14 (0%)
Pancreatitis acute	1/92 (1.1%)		0/14 (0%)
General disorders
Pyrexia	4/92 (4.3%)		0/14 (0%)
Asthenia	1/92 (1.1%)		0/14 (0%)
Non-cardiac chest pain	1/92 (1.1%)		0/14 (0%)
Infections and infestations
Lower respiratory tract infection	7/92 (7.6%)		0/14 (0%)
Pneumonia	7/92 (7.6%)		0/14 (0%)
Cellulitis	3/92 (3.3%)		0/14 (0%)
Sepsis	3/92 (3.3%)		0/14 (0%)
Epiglottitis	2/92 (2.2%)		0/14 (0%)
Neutropenic sepsis	2/92 (2.2%)		0/14 (0%)
Rhinovirus infection	2/92 (2.2%)		0/14 (0%)
Urinary tract infection	1/92 (1.1%)		1/14 (7.1%)
Empyema	1/92 (1.1%)		0/14 (0%)
Gastroenteritis	1/92 (1.1%)		0/14 (0%)
Infective exacerbation of bronchiectasis	1/92 (1.1%)		0/14 (0%)
Influenza	1/92 (1.1%)		0/14 (0%)
Lung infection	1/92 (1.1%)		0/14 (0%)
Pharyngitis streptococcal	1/92 (1.1%)		0/14 (0%)
Prostatitis Escherichia coli	1/92 (1.1%)		0/14 (0%)
Pulmonary sepsis	1/92 (1.1%)		0/14 (0%)
Respiratory tract infection	1/92 (1.1%)		0/14 (0%)
Rotavirus infection	1/92 (1.1%)		0/14 (0%)
Subcutaneous abscess	1/92 (1.1%)		0/14 (0%)
Upper respiratory tract infection	1/92 (1.1%)		0/14 (0%)
Urosepsis	1/92 (1.1%)		0/14 (0%)
Viral upper respiratory tract infection	1/92 (1.1%)		0/14 (0%)
Injury, poisoning and procedural complications
Fall	4/92 (4.3%)		1/14 (7.1%)
Femoral neck fracture	1/92 (1.1%)		0/14 (0%)
Head injury	0/92 (0%)		1/14 (7.1%)
Hip fracture	1/92 (1.1%)		0/14 (0%)
Investigations
Blood viscosity increased	1/92 (1.1%)		0/14 (0%)
Transaminases increased	1/92 (1.1%)		1/14 (7.1%)
Musculoskeletal and connective tissue disorders
Pain in extremity	0/92 (0%)		1/14 (7.1%)
Rhabdomyolysis	0/92 (0%)		1/14 (7.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma	2/92 (2.2%)		0/14 (0%)
Basal cell carcinoma	1/92 (1.1%)		0/14 (0%)
Colon adenoma	1/92 (1.1%)		0/14 (0%)
Glioblastoma multiforme	1/92 (1.1%)		0/14 (0%)
Malignant ascites	1/92 (1.1%)		0/14 (0%)
Metastatic malignant melanoma	1/92 (1.1%)		0/14 (0%)
Oesophageal carcinoma	1/92 (1.1%)		0/14 (0%)
Squamous cell carcinoma of the tongue	1/92 (1.1%)		0/14 (0%)
Nervous system disorders
Cerebrovascular accident	1/92 (1.1%)		0/14 (0%)
Intracranial haematoma	1/92 (1.1%)		0/14 (0%)
Presyncope	1/92 (1.1%)		0/14 (0%)
Seizure	1/92 (1.1%)		0/14 (0%)
Syncope	1/92 (1.1%)		0/14 (0%)
Renal and urinary disorders
Acute kidney injury	2/92 (2.2%)		0/14 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/92 (1.1%)		0/14 (0%)
Prostatitis	1/92 (1.1%)		0/14 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/92 (1.1%)		1/14 (7.1%)
Bronchiectasis	1/92 (1.1%)		0/14 (0%)
Epistaxis	1/92 (1.1%)		0/14 (0%)
Vascular disorders
Hypotension	1/92 (1.1%)		0/14 (0%)
Orthostatic hypotension	1/92 (1.1%)		0/14 (0%)
Vasculitis	1/92 (1.1%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Previously Treated		Treatment Naïve
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	92/92 (100%)		14/14 (100%)
Blood and lymphatic system disorders
Neutropenia	17/92 (18.5%)		0/14 (0%)
Increased tendency to bruise	9/92 (9.8%)		2/14 (14.3%)
Anaemia	10/92 (10.9%)		0/14 (0%)
Thrombocytopenia	5/92 (5.4%)		0/14 (0%)
Eye disorders
Dry eye	5/92 (5.4%)		1/14 (7.1%)
Vision blurred	5/92 (5.4%)		1/14 (7.1%)
Gastrointestinal disorders
Diarrhoea	30/92 (32.6%)		4/14 (28.6%)
Nausea	20/92 (21.7%)		3/14 (21.4%)
Constipation	18/92 (19.6%)		4/14 (28.6%)
Vomiting	14/92 (15.2%)		3/14 (21.4%)
Dyspepsia	9/92 (9.8%)		2/14 (14.3%)
Abdominal pain upper	5/92 (5.4%)		2/14 (14.3%)
Abdominal discomfort	5/92 (5.4%)		1/14 (7.1%)
Abdominal pain	6/92 (6.5%)		0/14 (0%)
Mouth ulceration	5/92 (5.4%)		1/14 (7.1%)
General disorders
Fatigue	21/92 (22.8%)		3/14 (21.4%)
Pyrexia	13/92 (14.1%)		2/14 (14.3%)
Oedema peripheral	8/92 (8.7%)		2/14 (14.3%)
Influenza like illness	4/92 (4.3%)		3/14 (21.4%)
Peripheral swelling	5/92 (5.4%)		0/14 (0%)
Infections and infestations
Upper respiratory tract infection	20/92 (21.7%)		3/14 (21.4%)
Lower respiratory tract infection	14/92 (15.2%)		0/14 (0%)
Sinusitis	10/92 (10.9%)		2/14 (14.3%)
Respiratory tract infection	10/92 (10.9%)		0/14 (0%)
Rhinitis	10/92 (10.9%)		0/14 (0%)
Urinary tract infection	10/92 (10.9%)		0/14 (0%)
Influenza	7/92 (7.6%)		1/14 (7.1%)
Nasopharyngitis	8/92 (8.7%)		0/14 (0%)
Bronchitis	6/92 (6.5%)		0/14 (0%)
Oral herpes	5/92 (5.4%)		0/14 (0%)
Injury, poisoning and procedural complications
Contusion	27/92 (29.3%)		4/14 (28.6%)
Fall	7/92 (7.6%)		0/14 (0%)
Investigations
Weight decreased	6/92 (6.5%)		1/14 (7.1%)
Metabolism and nutrition disorders
Decreased appetite	14/92 (15.2%)		2/14 (14.3%)
Hyponatraemia	5/92 (5.4%)		0/14 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	16/92 (17.4%)		5/14 (35.7%)
Back pain	17/92 (18.5%)		2/14 (14.3%)
Pain in extremity	11/92 (12%)		2/14 (14.3%)
Myalgia	8/92 (8.7%)		2/14 (14.3%)
Musculoskeletal pain	6/92 (6.5%)		0/14 (0%)
Nervous system disorders
Headache	37/92 (40.2%)		4/14 (28.6%)
Dizziness	22/92 (23.9%)		5/14 (35.7%)
Paraesthesia	7/92 (7.6%)		1/14 (7.1%)
Hypoaesthesia	6/92 (6.5%)		1/14 (7.1%)
Psychiatric disorders
Insomnia	7/92 (7.6%)		3/14 (21.4%)
Respiratory, thoracic and mediastinal disorders
Cough	16/92 (17.4%)		2/14 (14.3%)
Epistaxis	12/92 (13%)		0/14 (0%)
Dyspnoea	9/92 (9.8%)		2/14 (14.3%)
Dyspnoea exertional	5/92 (5.4%)		1/14 (7.1%)
Productive cough	6/92 (6.5%)		0/14 (0%)
Skin and subcutaneous tissue disorders
Rash	15/92 (16.3%)		1/14 (7.1%)
Skin lesion	10/92 (10.9%)		2/14 (14.3%)
Erythema	8/92 (8.7%)		3/14 (21.4%)
Pruritus	10/92 (10.9%)		0/14 (0%)
Petechiae	6/92 (6.5%)		3/14 (21.4%)
Dry skin	7/92 (7.6%)		1/14 (7.1%)
Ecchymosis	6/92 (6.5%)		1/14 (7.1%)
Actinic keratosis	5/92 (5.4%)		0/14 (0%)
Vascular disorders
Orthostatic hypotension	6/92 (6.5%)		1/14 (7.1%)
Haematoma	6/92 (6.5%)		0/14 (0%)
Hypertension	5/92 (5.4%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.