SELECT-3: Assess Safety & Efficacy of Selumetinib When Given in Combination With Standard First Line Treatment for Advanced Non-small Cell Lung Cancer
Sponsor
AstraZeneca (Industry)
Overall Status
Completed
CT.gov ID
NCT01809210
Collaborator
(none)
55
4
1
33
13.8
0.4
Study Details
Study Description
Brief Summary
This is a Phase I, open label multicentre study of selumetinib administered orally in combination with first line chemotherapy regimens to patients with advanced/metastatic NSCLC. The study has been designed to allow an investigation of the optimal dose of selumetinib in combination with various standard first line double-platinum chemotherapy regimens. Initial assessment will be based on tolerability of selumetinib in combination with one or more selected regimens that are considered to be tolerated also being assessed for preliminary evidence of activity.
This study is a dose finding and optional cohort expansion; In addition all patients will be assessed for anti-cancer efficacy of the combination of selumetinib and chemotherapy.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Detailed Description
A Phase I, Open Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Selumetinib (AZD6244; ARRY-142886) in Combination with First Line Chemotherapy Regimens in Patients with Non-Small Cell Lung Cancer (NSCLC)
Study Design
Study Type:
Interventional
Actual Enrollment
:
55 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I, Open Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Selumetinib (AZD6244; ARRY-142886) in Combination With First Line Chemotherapy Regimens in Patients With Non-Small Cell Lung Cancer (NSCLC)
Actual Study Start Date
:
Apr 4, 2013
Actual Primary Completion Date
:
Jan 4, 2016
Actual Study Completion Date
:
Jan 4, 2016
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Selumetinib+standard chemotherapy Selumetinib plus gemcitabine; or pemetrexed and cisplatin or carboplatin |
Drug: selumetinib
2 x 25mg capsules bd continuously in cohort 1 (with gemcitabine and cisplatin). If tolerated - next cohort 3 x 25mg capsules bd continuously. if higher doses are explored, required number of capsules will be provided. Option to administer on D2-19 of each 21 day cycle if required to assess tolerability of combinations with chemotherapy
Drug: gemcitabine
1250 mg/m2 iv on Day 1 and 8 of each 21 day cycle. If combination not tolerated, option to give 1000 mg/m2 iv on Day 1 and Day 8 of each 21 day cycle
Drug: cisplatin
75 mg/m2 iv on Day 1 of each 21 day cycle. If combination not tolerated, option to give 50 mg/m2 iv on Day 1 or 25mg/m2 iv on Day 1 and Day 8 of each 21 day cycle
Drug: carboplatin
If it is not possible to identify a tolerable combination of selumetinib, gemcitabine and cisplatin, cisplatin may be replaced with carboplatin (AUC5) iv on Day 1 of each 21 day cycle
Drug: pemetrexed
Gemcitabine may be replaced with pemetrexed 500 mg/m2 iv on Day 1 of each 21 day cycle.
|
Outcome Measures
Primary Outcome Measures
- Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib [The first dose on Cycle 1 Day 1 up to the time before dosing on Cycle 2 Day 1, assessed up to 3 weeks]
Any toxicity not attributable to the disease or disease-related processess under investigation, considered related to the combination of chemotherapy plus selumetinib, which occurs within the timeframe and is dose limiting
Secondary Outcome Measures
- Best Objective Response [Screening, week 6 and week 12]
The best response a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); Progressive Disease (PD), >=20% increase in the sum of the longest diameter of target lesions, the sum must also demonstrate an absolute increase of >=5mm; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm
- Percentage Change From Baseline at 6 Weeks in Target Lesion Size [Week 6]
The percentage change in the sum of the diameters of target lesions
- Best Percentage Change From Baseline in Target Lesion Size [Screening, week 6 and week 12]
The best percentage change in tumour size a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Percentage change was derived at each visit by the percentage change in the sum of the diameters of target lesions
- Objective Response Rate (ORR) [Up until progression or last evaluable assessment in the absence of progression, up to 9 months]
The number of patients who had at least 1 confirmed visit response of Complete Response (CR) or Partial Response (PR) prior to any evidence of progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm; Objective Response Rate (ORR) = CR + PR
- AUC (0-tau) [Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose]
Area under the concentration time curve (AUC) over a dosing interval at steady state (0-tau)
- Cmax,ss [Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose]
Maximum plasma concentration at steady state
- Tmax,ss [Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose]
Time to reach maximum plasma concentration at steady state
- CL/F [Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose]
Apparent oral plasma clearance
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 99 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Provision of signed, written and dated consent prior to any study specific procedures
-
Male or female, aged 18 years or older
-
Histological or cytological confirmation of locally advanced or metastatic NSCLC (IIIB-IV)
-
Female patients must not be breast-feeding and have a negative pregnancy test prior to start of dosing or must have evidence of non-child-bearing potential
-
Patients must be eligible to receive treatment with the platinum doublet combination with which selumetinib is being combined and in accordance with the local product information
Exclusion Criteria:
-
Prior chemotherapy or other systemic anti-cancer treatment for advanced NSCLC.
-
Prior surgery or radiotherapy within 6 months or palliative radiotherapy within 4 weeks of start of study treatment.
-
Female patients who are breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
-
Another primary malignancy within 5 years of starting study treatment, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ.
-
As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, active bleeding diatheses, renal transplant, or active infection
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Glasgow | United Kingdom | G12 0YN | |
| 2 | Research Site | London | United Kingdom | W1G 6AD | |
| 3 | Research Site | Manchester | United Kingdom | M20 4BX | |
| 4 | Research Site | Newcastle upon Tyne | United Kingdom | NE7 7DN |
Sponsors and Collaborators
- AstraZeneca
Investigators
- Study Director: Gabriella Mariani, MD, AstraZeneca UK, MSD
- Principal Investigator: Emma Dean, BMEDSCI, BM, BS, PHD, The Christie NHS Foundation Trust, UK
- Principal Investigator: Fiona Blackhall, PhD, FRCP, The Christie NHS Foundation Trust Clinical Trials Unit; UK
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01809210
Other Study ID Numbers:
- D1532C00070
- EudraCT number: 2012-005202-22
First Posted:
Mar 12, 2013
Last Update Posted:
Mar 13, 2018
Last Verified:
Mar 1, 2018
Keywords provided by AstraZeneca
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | Patients were enrolled into dose-finding cohorts to evaluate escalating doses of selumetinib (AZD6244; ARRY-142886) to determine the maximum tolerated dose in combination with standard first-line chemotherapy regimens. Chemotherapy was administered on Day 1 (and Day 8 for gemcitabine) of each 3-week cycle. |
|---|---|
| Pre-assignment Detail | Data cut off (DCO) was 7 Jan 16. DCO was defined as the earliest of 12 (±1) weeks after last patient started, or 28 days after final patient discontinued, selumetinib or chemotherapy doublet regimen. |
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units |
| Period Title: Overall Study | |||||||
| STARTED | 3 | 9 | 7 | 3 | 6 | 15 | 12 |
| COMPLETED | 2 | 8 | 4 | 2 | 4 | 12 | 7 |
| NOT COMPLETED | 1 | 1 | 3 | 1 | 2 | 3 | 5 |
Baseline Characteristics
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb | Total |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | Total of all reporting groups |
| Overall Participants | 3 | 9 | 7 | 3 | 6 | 15 | 12 | 55 |
| Age (Years) [Mean (Standard Deviation) ] | ||||||||
| Mean (Standard Deviation) [Years] |
58.7
(3.79)
|
69.2
(3.53)
|
55.1
(8.65)
|
64.7
(7.23)
|
59.5
(5.28)
|
61.8
(5.86)
|
60.2
(8.39)
|
61.5
(7.45)
|
| Sex: Female, Male (Count of Participants) | ||||||||
| Female |
1
33.3%
|
5
55.6%
|
3
42.9%
|
1
33.3%
|
4
66.7%
|
5
33.3%
|
7
58.3%
|
26
47.3%
|
| Male |
2
66.7%
|
4
44.4%
|
4
57.1%
|
2
66.7%
|
2
33.3%
|
10
66.7%
|
5
41.7%
|
29
52.7%
|
| Race/Ethnicity, Customized (Count of Participants) | ||||||||
| Black Or African American |
1
33.3%
|
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
1
6.7%
|
0
0%
|
3
5.5%
|
| Other |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
6.7%
|
1
8.3%
|
2
3.6%
|
| White |
2
66.7%
|
9
100%
|
7
100%
|
3
100%
|
5
83.3%
|
13
86.7%
|
11
91.7%
|
50
90.9%
|
Outcome Measures
| Title | Dose Limiting Toxicity (DLT) Events in Chemotherapy in Combination With Selumetinib |
|---|---|
| Description | Any toxicity not attributable to the disease or disease-related processess under investigation, considered related to the combination of chemotherapy plus selumetinib, which occurs within the timeframe and is dose limiting |
| Time Frame | The first dose on Cycle 1 Day 1 up to the time before dosing on Cycle 2 Day 1, assessed up to 3 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set - all patients who received at least 1 dose of selumetinib. |
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units |
| Measure Participants | 3 | 9 | 7 | 3 | 6 | 15 | 12 |
| Evaluable patients |
3
100%
|
7
77.8%
|
4
57.1%
|
3
100%
|
6
100%
|
12
80%
|
6
50%
|
| Evaluable patients with a DLT Event |
0
0%
|
2
22.2%
|
1
14.3%
|
0
0%
|
0
0%
|
1
6.7%
|
1
8.3%
|
| Title | Best Objective Response |
|---|---|
| Description | The best response a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); Progressive Disease (PD), >=20% increase in the sum of the longest diameter of target lesions, the sum must also demonstrate an absolute increase of >=5mm; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm |
| Time Frame | Screening, week 6 and week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Tumour response analysis set - dosed patients with a baseline tumour assessment. |
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units |
| Measure Participants | 3 | 9 | 7 | 3 | 6 | 15 | 12 |
| Complete response |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Partial response |
1
33.3%
|
2
22.2%
|
2
28.6%
|
1
33.3%
|
1
16.7%
|
2
13.3%
|
2
16.7%
|
| Unconfirmed complete or partial response |
0
0%
|
3
33.3%
|
0
0%
|
0
0%
|
2
33.3%
|
2
13.3%
|
2
16.7%
|
| Stable disease |
0
0%
|
1
11.1%
|
2
28.6%
|
2
66.7%
|
3
50%
|
7
46.7%
|
6
50%
|
| RECIST progression |
2
66.7%
|
0
0%
|
1
14.3%
|
0
0%
|
0
0%
|
1
6.7%
|
1
8.3%
|
| Death |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
6.7%
|
0
0%
|
| Incomplete post-baseline assessments |
0
0%
|
3
33.3%
|
2
28.6%
|
0
0%
|
0
0%
|
2
13.3%
|
1
8.3%
|
| Title | Percentage Change From Baseline at 6 Weeks in Target Lesion Size |
|---|---|
| Description | The percentage change in the sum of the diameters of target lesions |
| Time Frame | Week 6 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Tumour response analysis set - dosed patients with a baseline tumour assessment. |
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units |
| Measure Participants | 3 | 9 | 7 | 3 | 6 | 15 | 12 |
| Mean (Standard Deviation) [% change] |
-7.5
(19.79)
|
-29.3
(11.15)
|
-10.4
(24.45)
|
-14.7
(1.91)
|
-24.4
(32.60)
|
-18.9
(10.55)
|
-18.4
(19.58)
|
| Title | Best Percentage Change From Baseline in Target Lesion Size |
|---|---|
| Description | The best percentage change in tumour size a patient has had during their time in the study up until RECIST progression or last valuable assessment in the absence of RECIST progression. Percentage change was derived at each visit by the percentage change in the sum of the diameters of target lesions |
| Time Frame | Screening, week 6 and week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Tumour response analysis set - dosed patients with a baseline tumour assessment. |
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units |
| Measure Participants | 3 | 9 | 7 | 3 | 6 | 15 | 12 |
| Mean (Standard Deviation) [% change] |
-11.9
(26.52)
|
-34.6
(8.11)
|
-41.3
(21.25)
|
-28.3
(15.25)
|
-34.7
(33.30)
|
-24.4
(14.71)
|
-25.4
(20.51)
|
| Title | Objective Response Rate (ORR) |
|---|---|
| Description | The number of patients who had at least 1 confirmed visit response of Complete Response (CR) or Partial Response (PR) prior to any evidence of progression. Per Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm; Objective Response Rate (ORR) = CR + PR |
| Time Frame | Up until progression or last evaluable assessment in the absence of progression, up to 9 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| Tumour response analysis set - dosed patients with a baseline tumour assessment. |
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units |
| Measure Participants | 3 | 9 | 7 | 3 | 6 | 15 | 12 |
| Number [participants] |
1
(26.52)
33.3%
|
2
(8.11)
22.2%
|
2
(21.25)
28.6%
|
1
(15.25)
33.3%
|
1
(33.30)
16.7%
|
2
(14.71)
13.3%
|
2
(20.51)
16.7%
|
| Title | AUC (0-tau) |
|---|---|
| Description | Area under the concentration time curve (AUC) over a dosing interval at steady state (0-tau) |
| Time Frame | Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set - patients with sufficient samples to provide an adequate PK profile for determination of PK parameters with no important adverse events or protocol deviations that may have impacted PK |
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units |
| Measure Participants | 3 | 9 | 7 | 3 | 6 | 15 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL] |
NA
(NA)
|
3571
(42.13)
|
3339
(15.08)
|
4813
(30.93)
|
4366
(48.14)
|
4116
(33.92)
|
5202
(52.94)
|
| Title | Cmax,ss |
|---|---|
| Description | Maximum plasma concentration at steady state |
| Time Frame | Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set - patients with sufficient samples to provide an adequate PK profile for determination of PK parameters with no important adverse events or protocol deviations that may have impacted PK |
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units |
| Measure Participants | 3 | 9 | 7 | 3 | 6 | 15 | 12 |
| Geometric Mean (Geometric Coefficient of Variation) [ng/mL] |
476.7
(51.12)
|
1222
(59.86)
|
1487
(23.09)
|
1615
(27.71)
|
1375
(40.21)
|
1364
(57.78)
|
2309
(35.99)
|
| Title | Tmax,ss |
|---|---|
| Description | Time to reach maximum plasma concentration at steady state |
| Time Frame | Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set - patients with sufficient samples to provide an adequate PK profile for determination of PK parameters with no important adverse events or protocol deviations that may have impacted PK |
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units |
| Measure Participants | 3 | 9 | 7 | 3 | 6 | 15 | 12 |
| Median (Full Range) [h] |
1.00
(51.12)
|
1.25
(23.09)
|
1.00
(57.78)
|
1.00
(59.86)
|
1.75
(27.71)
|
1.48
(40.21)
|
1.50
(35.99)
|
| Title | CL/F |
|---|---|
| Description | Apparent oral plasma clearance |
| Time Frame | Cycle 2 Day1, pre-dose, 0.5, 1, 1.5, 2, 4, 8, 10 hours post dose |
Outcome Measure Data
| Analysis Population Description |
|---|
| Pharmacokinetic analysis set - patients with sufficient samples to provide an adequate PK profile for determination of PK parameters with no important adverse events or protocol deviations that may have impacted PK |
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units |
| Measure Participants | 3 | 9 | 7 | 3 | 6 | 15 | 12 |
| Mean (Standard Deviation) [L/h] |
NA
(NA)
|
14.72
(5.156)
|
22.64
(3.521)
|
10.72
(3.328)
|
18.82
(9.777)
|
19.08
(5.881)
|
21.02
(9.857)
|
Adverse Events
| Time Frame | Adverse Events are collected throughout the study, from informed consent until the end of follow-up, which is defined as 28 +/- 7 days after selumetinib is discontinued. Patients were expected to receive up to 6 cycles (18 wks) of chemotherapy. | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||||||||
| Arm/Group Title | Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb | |||||||
| Arm/Group Description | selumetinib 50mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, gemcitabine 1250mg/m2 , carboplatin 5 units | selumetinib 75mg bd, gemcitabine 1250mg/m2 , cisplatin 75mg/m2 | selumetinib 50mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | selumetinib 75mg bd, pemetrexed 500 mg/m2, cisplatin 75mg/m2 | selumetinib 100mg bd, pemetrexed 500 mg/m2, carboplatin 5 units | |||||||
All Cause Mortality |
||||||||||||||
| Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | / (NaN) | |||||||
Serious Adverse Events |
||||||||||||||
| Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/3 (33.3%) | 6/9 (66.7%) | 3/7 (42.9%) | 2/3 (66.7%) | 3/6 (50%) | 9/15 (60%) | 9/12 (75%) | |||||||
| Blood and lymphatic system disorders | ||||||||||||||
| Anaemia | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 2/12 (16.7%) | 2 |
| Febrile neutropenia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Neutropenia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 1/12 (8.3%) | 1 |
| Thrombocytopenia | 0/3 (0%) | 0 | 4/9 (44.4%) | 4 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 4/12 (33.3%) | 4 |
| Cardiac disorders | ||||||||||||||
| Myocardial infarction | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Tachycardia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Eye disorders | ||||||||||||||
| Chorioretinopathy | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Retinal vein occlusion | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Gastrointestinal disorders | ||||||||||||||
| Duodenal ulcer | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Large intestine perforation | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Nausea | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 2/7 (28.6%) | 2 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Stomatitis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Vomiting | 0/3 (0%) | 0 | 1/9 (11.1%) | 3 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| General disorders | ||||||||||||||
| Pyrexia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Infections and infestations | ||||||||||||||
| Cellulitis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Lower respiratory tract infection | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Mediastinitis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Neutropenic sepsis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Pneumonia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Upper respiratory tract infection | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Investigations | ||||||||||||||
| Transaminases increased | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Metabolism and nutrition disorders | ||||||||||||||
| Dehydration | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 2 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Fluid overload | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Hypoglycaemia | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Musculoskeletal and connective tissue disorders | ||||||||||||||
| Musculoskeletal chest pain | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Pain in extremity | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Nervous system disorders | ||||||||||||||
| Syncope | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 1/12 (8.3%) | 1 |
| Renal and urinary disorders | ||||||||||||||
| Acute kidney injury | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 1/12 (8.3%) | 1 |
| Urinary retention | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||
| Dyspnoea | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Epistaxis | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Haemoptysis | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Pleural effusion | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Pulmonary embolism | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||||||||||
| Cohort 1 sel50, Gem, Cis | Cohort 2 sel50, Gem, Carb | Cohort 3 sel75, Gem, Cis | Cohort 4 sel150, Pem, Carb | Cohort 5 sel75, Pem, Carb | Cohort 6 sel75, Pem, Cis | Cohort 7 sel100, Pem, Carb | ||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/3 (100%) | 9/9 (100%) | 7/7 (100%) | 3/3 (100%) | 6/6 (100%) | 15/15 (100%) | 12/12 (100%) | |||||||
| Blood and lymphatic system disorders | ||||||||||||||
| Anaemia | 1/3 (33.3%) | 1 | 5/9 (55.6%) | 7 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 4/12 (33.3%) | 4 |
| Leukopenia | 0/3 (0%) | 0 | 3/9 (33.3%) | 5 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Neutropenia | 0/3 (0%) | 0 | 5/9 (55.6%) | 9 | 2/7 (28.6%) | 2 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 6/12 (50%) | 6 |
| Thrombocytopenia | 0/3 (0%) | 0 | 3/9 (33.3%) | 5 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 4/12 (33.3%) | 4 |
| Cardiac disorders | ||||||||||||||
| Atrial fibrillation | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Palpitations | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Sinus tachycardia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Ear and labyrinth disorders | ||||||||||||||
| Tinnitus | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 2/15 (13.3%) | 2 | 0/12 (0%) | 0 |
| Eye disorders | ||||||||||||||
| Conjunctival oedema | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Dry eye | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 1/12 (8.3%) | 1 |
| Eyelid oedema | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Foreign body sensation in eyes | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Lacrimation increased | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Periorbital oedema | 0/3 (0%) | 0 | 3/9 (33.3%) | 3 | 2/7 (28.6%) | 2 | 2/3 (66.7%) | 2 | 1/6 (16.7%) | 1 | 2/15 (13.3%) | 2 | 6/12 (50%) | 6 |
| Retinopathy | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Vision blurred | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 2/15 (13.3%) | 2 | 1/12 (8.3%) | 1 |
| Visual acuity reduced | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Gastrointestinal disorders | ||||||||||||||
| Abdominal distension | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Abdominal pain | 0/3 (0%) | 0 | 1/9 (11.1%) | 3 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Abdominal tenderness | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Chapped lips | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Constipation | 1/3 (33.3%) | 1 | 5/9 (55.6%) | 6 | 4/7 (57.1%) | 5 | 2/3 (66.7%) | 2 | 2/6 (33.3%) | 2 | 6/15 (40%) | 7 | 9/12 (75%) | 13 |
| Diarrhoea | 2/3 (66.7%) | 4 | 5/9 (55.6%) | 21 | 4/7 (57.1%) | 7 | 1/3 (33.3%) | 2 | 3/6 (50%) | 8 | 9/15 (60%) | 16 | 6/12 (50%) | 8 |
| Dry mouth | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Dyspepsia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 3/15 (20%) | 3 | 3/12 (25%) | 5 |
| Faeces discoloured | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Flatulence | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Gastritis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Gastrooesophageal reflux disease | 0/3 (0%) | 0 | 2/9 (22.2%) | 2 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Gingival bleeding | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Haematemesis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Haemorrhoids | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Mouth ulceration | 0/3 (0%) | 0 | 1/9 (11.1%) | 3 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 4/15 (26.7%) | 4 | 3/12 (25%) | 3 |
| Nausea | 3/3 (100%) | 9 | 5/9 (55.6%) | 13 | 5/7 (71.4%) | 22 | 3/3 (100%) | 4 | 5/6 (83.3%) | 8 | 8/15 (53.3%) | 15 | 10/12 (83.3%) | 14 |
| Oesophagitis | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Oral pain | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 2/12 (16.7%) | 2 |
| Rectal haemorrhage | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Retching | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Salivary hypersecretion | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Stomatitis | 0/3 (0%) | 0 | 1/9 (11.1%) | 2 | 3/7 (42.9%) | 5 | 1/3 (33.3%) | 1 | 1/6 (16.7%) | 1 | 3/15 (20%) | 4 | 2/12 (16.7%) | 3 |
| Tongue ulceration | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Vomiting | 3/3 (100%) | 8 | 4/9 (44.4%) | 8 | 4/7 (57.1%) | 19 | 1/3 (33.3%) | 1 | 4/6 (66.7%) | 9 | 6/15 (40%) | 12 | 7/12 (58.3%) | 13 |
| General disorders | ||||||||||||||
| Chills | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Face oedema | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Fat tissue increased | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Fatigue | 2/3 (66.7%) | 3 | 6/9 (66.7%) | 8 | 3/7 (42.9%) | 4 | 1/3 (33.3%) | 1 | 2/6 (33.3%) | 2 | 9/15 (60%) | 13 | 7/12 (58.3%) | 11 |
| Feeling cold | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Gait disturbance | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Malaise | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Mucosal inflammation | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Non-cardiac chest pain | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Oedema peripheral | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 2/6 (33.3%) | 2 | 4/15 (26.7%) | 5 | 4/12 (33.3%) | 5 |
| Peripheral swelling | 0/3 (0%) | 0 | 1/9 (11.1%) | 2 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 2/6 (33.3%) | 4 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Pyrexia | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 2/7 (28.6%) | 2 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 2/15 (13.3%) | 2 | 0/12 (0%) | 0 |
| Immune system disorders | ||||||||||||||
| Hypersensitivity | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Infections and infestations | ||||||||||||||
| Anal abscess | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Angular cheilitis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 1/12 (8.3%) | 1 |
| Cellulitis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 2/15 (13.3%) | 3 | 0/12 (0%) | 0 |
| Clostridium difficile colitis | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Conjunctivitis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 2/15 (13.3%) | 2 | 2/12 (16.7%) | 3 |
| Cystitis | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Folliculitis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Herpes zoster | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Localised infection | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Lower respiratory tract infection | 0/3 (0%) | 0 | 4/9 (44.4%) | 4 | 1/7 (14.3%) | 1 | 2/3 (66.7%) | 3 | 0/6 (0%) | 0 | 2/15 (13.3%) | 2 | 0/12 (0%) | 0 |
| Lower respiratory tract infection bacterial | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Lung infection | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Mastitis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Oral candidiasis | 0/3 (0%) | 0 | 4/9 (44.4%) | 4 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 3/15 (20%) | 3 | 3/12 (25%) | 4 |
| Oral herpes | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 1/15 (6.7%) | 1 | 1/12 (8.3%) | 1 |
| Paronychia | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Periorbital cellulitis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Pneumonia | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 2 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Rash pustular | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 1/12 (8.3%) | 1 |
| Skin infection | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Upper respiratory tract infection | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 2/7 (28.6%) | 2 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 2/15 (13.3%) | 2 | 0/12 (0%) | 0 |
| Urinary tract infection | 1/3 (33.3%) | 1 | 1/9 (11.1%) | 2 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 2/12 (16.7%) | 2 |
| Vaginal infection | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Vulvovaginal candidiasis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||||||
| Arthropod bite | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Contusion | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Humerus fracture | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Investigations | ||||||||||||||
| Alanine aminotransferase increased | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Aspartate aminotransferase increased | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Breath sounds abnormal | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Ejection fraction decreased | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Troponin I increased | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||||||||||
| Abnormal loss of weight | 1/3 (33.3%) | 1 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Abnormal weight gain | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Decreased appetite | 1/3 (33.3%) | 2 | 4/9 (44.4%) | 4 | 2/7 (28.6%) | 5 | 0/3 (0%) | 0 | 3/6 (50%) | 3 | 4/15 (26.7%) | 4 | 2/12 (16.7%) | 2 |
| Dehydration | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 2/15 (13.3%) | 2 | 1/12 (8.3%) | 1 |
| Fluid overload | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Fluid retention | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Hyperuricaemia | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Hypokalaemia | 0/3 (0%) | 0 | 1/9 (11.1%) | 3 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Hypomagnesaemia | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 2/3 (66.7%) | 2 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Hyponatraemia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Ketosis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||||||||
| Arthralgia | 0/3 (0%) | 0 | 2/9 (22.2%) | 2 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Back pain | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 2/6 (33.3%) | 2 | 1/15 (6.7%) | 1 | 1/12 (8.3%) | 1 |
| Bone pain | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Joint swelling | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Muscle spasms | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Muscular weakness | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Musculoskeletal chest pain | 1/3 (33.3%) | 1 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 2 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Myalgia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Pain in extremity | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 2 | 2/6 (33.3%) | 2 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||||||||||
| Lipoma | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Tumour pain | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Nervous system disorders | ||||||||||||||
| Ageusia | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Aphonia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Dizziness | 0/3 (0%) | 0 | 2/9 (22.2%) | 5 | 2/7 (28.6%) | 2 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Dysarthria | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Dysgeusia | 1/3 (33.3%) | 1 | 2/9 (22.2%) | 2 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 2/12 (16.7%) | 2 |
| Headache | 0/3 (0%) | 0 | 2/9 (22.2%) | 2 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 2/15 (13.3%) | 2 | 5/12 (41.7%) | 5 |
| Hemiparesis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Hypoaesthesia | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Lethargy | 0/3 (0%) | 0 | 2/9 (22.2%) | 2 | 3/7 (42.9%) | 6 | 1/3 (33.3%) | 3 | 2/6 (33.3%) | 2 | 5/15 (33.3%) | 6 | 1/12 (8.3%) | 1 |
| Migraine | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Neuropathy peripheral | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Neurotoxicity | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Paraesthesia | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 2/12 (16.7%) | 2 |
| Presyncope | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Seizure | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Syncope | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Tremor | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Psychiatric disorders | ||||||||||||||
| Depressed mood | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 1/12 (8.3%) | 1 |
| Depression | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 3/12 (25%) | 3 |
| Insomnia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Renal and urinary disorders | ||||||||||||||
| Dysuria | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Pollakiuria | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 2 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Stress urinary incontinence | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Urinary incontinence | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Reproductive system and breast disorders | ||||||||||||||
| Perineal fistula | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Perineal ulceration | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Vaginal haemorrhage | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Vulvovaginal discomfort | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||
| Cough | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 2/6 (33.3%) | 2 | 4/15 (26.7%) | 4 | 0/12 (0%) | 0 |
| Dysphonia | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Dyspnoea | 1/3 (33.3%) | 1 | 1/9 (11.1%) | 1 | 1/7 (14.3%) | 1 | 1/3 (33.3%) | 1 | 3/6 (50%) | 3 | 2/15 (13.3%) | 2 | 2/12 (16.7%) | 2 |
| Dyspnoea exertional | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Epistaxis | 1/3 (33.3%) | 1 | 4/9 (44.4%) | 5 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 3/6 (50%) | 4 | 1/15 (6.7%) | 2 | 1/12 (8.3%) | 1 |
| Haemoptysis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 2/7 (28.6%) | 2 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 2/15 (13.3%) | 2 | 0/12 (0%) | 0 |
| Hiccups | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Oropharyngeal pain | 0/3 (0%) | 0 | 2/9 (22.2%) | 2 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Pneumothorax | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Productive cough | 1/3 (33.3%) | 1 | 1/9 (11.1%) | 1 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Pulmonary embolism | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 2/6 (33.3%) | 2 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Pulmonary oedema | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Respiratory failure | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Rhinorrhoea | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Wheezing | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||||||||||
| Acne | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Alopecia | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 1/12 (8.3%) | 1 |
| Dermatitis acneiform | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 2/15 (13.3%) | 2 | 2/12 (16.7%) | 2 |
| Dry skin | 0/3 (0%) | 0 | 2/9 (22.2%) | 2 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 3/12 (25%) | 3 |
| Erythema | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Hyperhidrosis | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Nail disorder | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Pain of skin | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Plantar erythema | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Pruritus | 1/3 (33.3%) | 1 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 1/12 (8.3%) | 1 |
| Rash | 0/3 (0%) | 0 | 3/9 (33.3%) | 4 | 5/7 (71.4%) | 5 | 2/3 (66.7%) | 2 | 1/6 (16.7%) | 2 | 8/15 (53.3%) | 10 | 6/12 (50%) | 6 |
| Rash generalised | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 1/15 (6.7%) | 1 | 1/12 (8.3%) | 1 |
| Rash maculo-papular | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 1/6 (16.7%) | 1 | 1/15 (6.7%) | 1 | 2/12 (16.7%) | 4 |
| Rash papular | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 2/15 (13.3%) | 2 | 0/12 (0%) | 0 |
| Skin fissures | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 2 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Skin lesion | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Skin ulcer | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Vascular disorders | ||||||||||||||
| Deep vein thrombosis | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 1/15 (6.7%) | 1 | 0/12 (0%) | 0 |
| Flushing | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Hot flush | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
| Hypertension | 0/3 (0%) | 0 | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/3 (0%) | 0 | 1/6 (16.7%) | 1 | 3/15 (20%) | 4 | 1/12 (8.3%) | 1 |
| Peripheral coldness | 0/3 (0%) | 0 | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/3 (33.3%) | 1 | 0/6 (0%) | 0 | 0/15 (0%) | 0 | 0/12 (0%) | 0 |
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.
Results Point of Contact
| Name/Title | Dr Gabriella Mariani , MD |
|---|---|
| Organization | AstraZeneca |
| Phone | +44 (0)207 6048000 |
| ClinicalTrialTransparency@astrazeneca.com |
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01809210
Other Study ID Numbers:
- D1532C00070
- EudraCT number: 2012-005202-22
First Posted:
Mar 12, 2013
Last Update Posted:
Mar 13, 2018
Last Verified:
Mar 1, 2018