Phase 2 Study of Durvalumab (MEDI4736) in Patients With Glioblastoma

• Sponsor: Ludwig Institute for Cancer Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT02336165
• Collaborator: MedImmune LLC (Industry), Cancer Research Institute, New York City (Other), Cure Brain Cancer Foundation, Australia (Other)
• Enrollment: 159
• Locations: 8
• Arms: 5
• Actual Duration (Months): 76.3
• Patients Per Site: 19.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is an ongoing Phase 2, open-label, multicenter, non-randomized study of MEDI4736 (durvalumab) in subjects with glioblastoma (GBM) enrolled into 5 non-comparative cohorts. Primary study objectives, which vary by cohort due to differences in subject populations, include evaluation of the clinical efficacy as measured by the overall survival (OS) rate at 12 months (Cohort A), progression-free survival (PFS) at 6 months (Cohorts B, B2, and B3), and OS at 6 months (Cohort C). For all cohorts, secondary objectives include evaluation of the safety/tolerability and clinical efficacy of study treatment, and exploratory objectives include evaluation of the neurologic function and correlative biomarkers.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma	Drug: Durvalumab; Radiation: Standard radiotherapy; Biological: Bevacizumab	Phase 2

Detailed Description

Eligible subjects are enrolled in parallel into one of the following 5 cohorts as described below. In each cohort, the first study drug administration for the first subject and the second subject are separated by at least 1 week.

• Cohort A: Subjects with newly diagnosed unmethylated O^6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) GBM receive durvalumab (10 mg/kg every 2 weeks [Q2W]) + standard radiotherapy. The first 6 subjects are evaluated for dose-limiting toxicity (DLT) for 10 weeks to determine whether the durvalumab dose should be lowered to 3 or 1 mg/kg.

• Cohort B: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) as monotherapy.

• Cohort B2: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W).

• Cohort B3: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W).

• Cohort C: Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + continued bevacizumab (10 mg/kg Q2W). The first 6 subjects are evaluated for DLTs for 6 weeks to determine whether the durvalumab dose should be lowered to 3 or 1 mg/kg.

The Core Study lasts for up to 12 months; optional extension treatment may be offered to subjects who complete 51 weeks of treatment on the Core Study with stable disease or better and upon agreement between the subject, Investigator, and Sponsor.

Subjects are followed on study for 90 days after the last drug administration and off study every 6 months for 3 years from the date of the first dose of study treatment.

The primary study endpoints have been met, although some subjects remain in treatment and/or follow-up and data collection is ongoing.

Study Design

• Study Type: Interventional
• Actual Enrollment: 159 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study to Evaluate the Clinical Efficacy and Safety of MEDI4736 in Patients With Glioblastoma (GBM)
• Actual Study Start Date: Feb 26, 2015
• Actual Primary Completion Date: Nov 1, 2018
• Actual Study Completion Date: Jul 6, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A Subjects with newly diagnosed unmethylated MGMT GBM receive durvalumab (10 mg/kg Q2W) + standard radiotherapy.	Drug: Durvalumab; Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W.; Other Names: MEDI4736 ; Radiation: Standard radiotherapy; Focal radiotherapy is administered at 2 Gy given daily 5 days per week for a total of 60 Gy over 30 fractions per local institutional guidelines or local prescribing information. On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.
Experimental: Cohort B Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) as monotherapy.	Drug: Durvalumab; Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W.; Other Names: MEDI4736
Experimental: Cohort B2 Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (10 mg/kg Q2W).	Drug: Durvalumab; Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W.; Other Names: MEDI4736 ; Biological: Bevacizumab; Bevacizumab is administered as an IV infusion (per local prescribing information) Q2W. When durvalumab and bevacizumab are administered together (i.e., Cohorts B2, B3, and C), durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.; Other Names: Avastin
Experimental: Cohort B3 Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + bevacizumab (3 mg/kg Q2W).	Drug: Durvalumab; Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W.; Other Names: MEDI4736 ; Biological: Bevacizumab; Bevacizumab is administered as an IV infusion (per local prescribing information) Q2W. When durvalumab and bevacizumab are administered together (i.e., Cohorts B2, B3, and C), durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.; Other Names: Avastin
Experimental: Cohort C Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg Q2W) + continued bevacizumab (10 mg/kg Q2W).	Drug: Durvalumab; Durvalumab is administered as an IV infusion over 60 ± 5 minutes Q2W.; Other Names: MEDI4736 ; Biological: Bevacizumab; Bevacizumab is administered as an IV infusion (per local prescribing information) Q2W. When durvalumab and bevacizumab are administered together (i.e., Cohorts B2, B3, and C), durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.; Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. Overall Survival Rate at 12 Months (OS-12) as Estimated Using the Kaplan-Meier Method (Cohort A) [Up to 12 months]

   OS-12 with 90% confidence interval (CI) is the primary endpoint of Cohort A and is the percentage of subjects who remain alive at 12 months, where OS is measured from the time of diagnosis until the recorded date of death or last follow-up. Subjects who are lost to follow-up at the time of the analysis will be censored on the date of last follow-up.

2. Progression-free Survival Rate at 6 Months (PFS-6) as Estimated Using the Kaplan-Meier Method (Cohorts B, B2, and B3) [Up to 6 months]

   PFS-6 is the primary endpoint of Cohorts B, B2, and B3, and is the percentage of subjects who have not progressed at 6 months, with PFS measured from the date of the first dose of study treatment to the date of earliest disease progression (PD) based on modified Response Assessment in Neuro-Oncology (RANO) criteria or to the date of death, if PD does not occur. Per the RANO criteria, PD indicates any new lesion or a 25% increase in sum of the products of perpendicular diameters of enhancing lesions, or clear clinical deterioration per the Investigator (Wen et al. J Clin Oncol 2010; 28(11):1963-72).

3. Overall Survival Rate at 6 Months (OS-6) as Estimated Using the Kaplan-Meier Method (Cohort C) [Up to 6 months]

   OS-6 is the primary endpoint of Cohort C and is the percentage of subjects who remain alive at 6 months, where OS is measured from the date of the first dose of study treatment until the recorded date of death or last follow-up. Subjects who are lost to follow-up at the time of the analysis will be censored on the date of last follow-up.

Secondary Outcome Measures

1. Number of Participants With Treatment-emergent Adverse Events [Up to 15 months]

   Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) are reported based on clinical laboratory tests, vital sign and weight measurements, physical examinations, performance status evaluations, magnetic resonance imaging, and any other medically indicated assessments, including subject interviews, from the time informed consent is signed through 90 days after the last dose of durvalumab. AEs are considered to be treatment emergent if they occur or worsen in severity after the first dose of study treatment.

2. Median PFS as Estimated Using the Kaplan-Meier Method [Up to 15 months]

   PFS is measured from the date of the first dose of study treatment to the date of earliest PD based on modified RANO criteria or to the date of death, if PD does not occur. Per the RANO criteria, PD indicates any new lesion or a 25% increase in sum of the products of perpendicular diameters of enhancing lesions, or clear clinical deterioration per the Investigator (Wen et al. J Clin Oncol 2010; 28(11):1963-72).

3. Median OS as Estimated Using the Kaplan-Meier Method [Up to 36 months]

   All subjects are followed for survival at least every 6 months for up to 3 years following initiation of study treatment. In Cohort A, OS is measured from the date of diagnosis until the recorded date of death or last follow-up. In Cohorts B, B2, B3, and C, OS is measured from the date of the first dose of study treatment until the recorded date of death or last follow-up. Subjects who remain alive or are lost to follow-up at the time of the analysis are censored on the date of last follow-up.

4. Number of Subjects With Best Overall Response [Up to 15 months]

   Radiographic response is assessed by consistent imaging methods every (q) 8 to 9 weeks during study treatment administration. Response is categorized per the modified RANO criteria: complete response (CR) indicates no new lesions and disappearance of all disease sustained for ≥ 4 weeks; partial response (PR) indicates no new lesions, no progression of non-measureable disease, and ≥ 50% decrease from baseline in sum of products of perpendicular diameters of measurable lesions sustained for ≥ 4 weeks; stable disease (SD) indicates non-qualification for CR, PR, or progressive disease (PD); PD indicates any new lesion or a 25% increase in sum of the products of perpendicular diameters of enhancing lesions, or clear clinical deterioration per the Investigator (Wen et al. J Clin Oncol 2010; 28(11):1963-72).

5. Mean Changes From Baseline in the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) [Up to 12 months]

   Health-related quality of life was measured using the validated EORTC-QLQ-C30. Questionnaires may be completed by the subject or with the assistance of the examiner at baseline prior to initiation of study therapy, and then approximately every 8 weeks while on study treatment (prior to discussing treatment response at each visit, whenever possible). All questions are answered using a categorical scale (1 = not at all; 2 = a little; 3 = quite a bit; 4 = very much for symptoms and 1= very poor; 7= excellent for global heath questions). Scores were linearly transformed to 0 to 100 scales so that higher scores represented a higher level of functioning. Overall scores were calculated for each patient for each timepoint (Giesinger J et al Journal of Clinical Epidemiology. 2016 Jan;69:79-88). Mean change from baseline where baseline is the last non-missing value before the administration of MEDI4736 was reported.

6. Mean Changes From Baseline in the EORTC Brain Cancer Quality of Life Questionnaire (EORTC-QLQ-BN-20) [Up to 12 months]

   Health-related quality of life was measured using an EORTC quality of life questionnaire designed specifically for subjects with brain tumors (BN-20). Questionnaires may be completed by the subject or with the assistance of the examiner at baseline prior to initiation of study therapy, and then approximately every 8 weeks while on study treatment (prior to discussing treatment response at each visit, whenever possible). All single questions are answered using a categorical scale (e.g., 1 = not at all; 2 = a little; 3 = quite a bit; 4 = very much) and linearly transformed to 0 to 100 scales with higher scores for a symptom scale representing higher level of symptoms. The evaluation of HRQoL at each timepoint was measured by mean changes from baseline where baseline is the last non-missing value before the administration of MEDI4736 was reported.

Eligibility Criteria

Criteria

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

Inclusion Criteria [criteria apply to all cohorts unless otherwise specified]:

1. Cohort A: Subjects with newly diagnosed, untreated, unmethylated MGMT GBM who are eligible for standard radiation therapy.

2. Cohorts B, B2, B3 and C: First or second recurrence of GBM by diagnostic biopsy or contrast enhanced magnetic resonance imaging (MRI) per modified Response Assessment in Neuro-oncology (RANO) criteria, with last baseline MRI confirmation within 14 days prior to Study Day 1. Note: Recurrence is defined as progression following therapy (i.e., chemotherapy; radiation). If the subject had a surgical resection for relapsed disease and no anti-tumor therapy was administered for up to 12 weeks, and the subject has further evidence of tumor growth or undergoes another resection, this will be considered as one episode of recurrence.

3. Cohorts B, B2, B3 and C: On Study Day 1, at least 12 weeks from prior radiotherapy (unless progressive disease outside of the radiation field or histopathologic confirmation of unequivocal tumor).

4. Cohorts B, B2, B3: No prior vascular endothelial growth factor (VEGF)/VEGF receptor targeted therapy; Cohort C: No more than one prior bevacizumab regimen.

5. Cohorts B, B2, B3 and C: Recovery from any prior treatment clinically significant, related adverse events to grade ≤ 1 or pretreatment baseline with the exception of alopecia and laboratory values listed per inclusion criteria.

6. Subjects with measurable or non-measurable disease.

7. Histopathologic confirmation of glioblastoma.

8. At the time of Study Day 1, subjects must be at least 4 weeks since major surgical procedure, open biopsy, or significant traumatic injury; there should be no anticipation of need for major surgical procedure during the course of the study. There should be no core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Study Day 1.

9. Subjects who have previously been treated with the Optune™ device are eligible for the study as long as toxicity related to the treatment has resolved to ≤ grade 1 or baseline.

10. Eastern Cooperative Oncology Group (ECOG) ≤ 1 or Karnofsky performance status of ≥ 70.

11. Adequate hematologic, renal and hepatic function, as defined below:

• Absolute neutrophil count ≥ 1000/mm^3;

• Platelet count ≥ 100,000/mm^3;

• Total bilirubin ≤ 1.5 x upper limit of normal (ULN); or if subject has Gilbert syndrome, then total bilirubin ≤ 3 x ULN;

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0 x ULN;

• Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 50 mL/min (using the

Cockcroft-Gault formula):

• Female CrCl = (140 - age in years) x weight in kg x 0.85/72 x serum creatinine in mg/dL;

• Male CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum creatinine in mg/dL;

• Cohorts B2, B3 and C: Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or ≤1+ on dipstick, unless quantitative protein is < 1000 mg in a 24-hour urine sample.

1. Age must be greater than or equal to 18 years at date of consent.

2. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the United States) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations.

Exclusion Criteria [criteria apply to all cohorts unless otherwise specified]:

1. Primary tumors localized to the brain stem or spinal cord.

2. Locally directed therapies including but not limited to stereotactic radiosurgery, re-irradiation, Gliadel®, and therapeutics administered by direct injection or convection-enhanced delivery within 6 months of start of study treatment.

3. Prior exposure to durvalumab or other programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies.

4. Presence of diffuse leptomeningeal disease or extracranial disease.

5. Active, suspected or prior documented autoimmune disease (including inflammatory bowel disease, celiac disease, irritable bowel syndrome, Wegner's granulomatosis and Hashimoto's thyroiditis). Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

6. Known primary immunodeficiency or active human immunodeficiency virus.

7. Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months indicated by positive test for hepatitis B virus surface antigen or hepatitis C virus ribonucleic acid (hepatitis C virus antibody).

8. History of organ transplant requiring use of immunosuppressive medication.

9. History of active tuberculosis.

10. Significant active systemic illness including infections requiring intravenous antibiotics.

11. Current pneumonitis or interstitial lung disease.

12. Other invasive malignancy within 2 years prior to entry into the study, except for those treated with surgical therapy only.

13. History of severe allergic reactions to any unknown allergens or any components of the study drugs.

14. Any prior grade ≥ 3 immune-related adverse event (irAE) or any prior corticosteroid-refractory irAE.

15. Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study.

16. Lack of availability for follow-up assessments.

17. Lack of availability for Post Study Follow-up contacts to determine relapse and survival.

18. Women who are breast-feeding or pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin).

19. Women of childbearing potential not using a medically acceptable means of contraception for the duration of the study and unsterilized males not willing to abide by protocol-specified requirements for contraception.

20. If a subject previously received another investigational treatment, the last dose of investigational treatment was administered within 4 weeks of Day 1 of the study.

21. Any condition that, in the clinical judgment of the treating physician, is likely to prevent the subject from complying with any aspect of the protocol or that may put the subject at unacceptable risk.

22. Cohorts B2, B3, and C:

• Evidence of hemorrhage on the baseline MRI or computed tomography (CT) scan other than those that are ≤ grade 1 and either post-operative or stable on at least two consecutive scans;

• Current use of warfarin sodium or any other Coumadin®-derivative anticoagulant. Participant must be off Coumadin-derivative anticoagulants for at least 7 days prior to starting study drug. Low molecular weight heparin and Factor Xa antagonists are allowed;

• History of clinically significant bleeding within 6 months of enrollment;

• History of arterial thromboembolism within 12 months prior to enrollment;

• Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 90 mmHg on antihypertensive medications);

• Any prior history of hypertensive crisis or hypertensive encephalopathy;

• Clinically significant cardiovascular disease within 12 months prior to enrollment (or randomization), including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent;

• Evidence of bleeding diathesis or coagulopathy;

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment;

• Serious, non-healing wound, ulcer, or bone fracture.

1. Subjects must not donate blood while on study and for at least 90 days following the last durvalumab treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Facility	Los Angeles	California	United States	90095
2	Research Facility	San Francisco	California	United States	94143
3	Research Facility	Baltimore	Maryland	United States	21287
4	Research Facility	Boston	Massachusetts	United States	02114
5	Research Facility	Boston	Massachusetts	United States	02215
6	Research Facility	Saint Louis	Missouri	United States	63110
7	Research Facility	New York	New York	United States	10065
8	Research Facility	Melbourne		Australia

Sponsors and Collaborators

• Ludwig Institute for Cancer Research
• MedImmune LLC
• Cancer Research Institute, New York City
• Cure Brain Cancer Foundation, Australia

Investigators

• Study Chair: David A. Reardon, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 14, 2017

More Information

Publications

• Giesinger JM, Kieffer JM, Fayers PM, Groenvold M, Petersen MA, Scott NW, Sprangers MA, Velikova G, Aaronson NK; EORTC Quality of Life Group. Replication and validation of higher order models demonstrated that a summary score for the EORTC QLQ-C30 is robust. J Clin Epidemiol. 2016 Jan;69:79-88. doi: 10.1016/j.jclinepi.2015.08.007. Epub 2015 Sep 28.

• Responsible Party: Ludwig Institute for Cancer Research
• ClinicalTrials.gov Identifier: NCT02336165
• Other Study ID Numbers: LUD2013-006
• First Posted: Jan 12, 2015
• Last Update Posted: Jul 15, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ludwig Institute for Cancer Research: Glioblastoma; Immunotherapy; T Cell; PD-L1; MEDI4736; Radiation; Radiotherapy; GBM
• Additional relevant MeSH terms: Glioblastoma; Bevacizumab; Durvalumab

Study Results

Participant Flow

Arm/Group Title	Cohort A	Cohort B	Cohort B2	Cohort B3	Cohort C
Arm/Group Description	Subjects with newly diagnosed unmethlyated O^6-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) glioblastoma (GBM) receive durvalumab (10 mg/kg IV Q2W) + standard radiotherapy (2 Gy/day x 5 days per week, for a total of 60 Gy over 30 fractions per local guidelines). On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) as monotherapy.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (3 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + continued bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.
Period Title: Overall Study
STARTED	40	31	33	33	22
COMPLETED	6	6	2	2	0
NOT COMPLETED	34	25	31	31	22

Baseline Characteristics

Arm/Group Title	Cohort A	Cohort B	Cohort B2	Cohort B3	Cohort C	Total
Arm/Group Description	Subjects with newly diagnosed unmethlyated MGMT GBM receive durvalumab (10 mg/kg IV Q2W) + standard radiotherapy (2 Gy/day x 5 days per week, for a total of 60 Gy over 30 fractions per local guidelines). On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) as monotherapy.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (3 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + continued bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Total of all reporting groups
Overall Participants	40	31	33	33	22	159
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57.0	54.0	57.0	54.0	56.5	56.0
Sex: Female, Male (Count of Participants)
Female	12 30%	5 16.1%	15 45.5%	13 39.4%	8 36.4%	53 33.3%
Male	28 70%	26 83.9%	18 54.5%	20 60.6%	14 63.6%	106 66.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 3%	0 0%	1 4.5%	2 1.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	1 3%	1 4.5%	2 1.3%
White	38 95%	27 87.1%	28 84.8%	30 90.9%	19 86.4%	142 89.3%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	2 5%	4 12.9%	4 12.1%	2 6.1%	1 4.5%	13 8.2%
Region of Enrollment (participants) [Number]
United States	38 95%	30 96.8%	33 100%	33 100%	21 95.5%	155 97.5%
Australia	2 5%	1 3.2%	0 0%	0 0%	1 4.5%	4 2.5%
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (Count of Participants)
ECOG PS 0	24 60%	16 51.6%	9 27.3%	10 30.3%	6 27.3%	65 40.9%
ECOG PS 1	16 40%	15 48.4%	24 72.7%	23 69.7%	16 72.7%	94 59.1%
O^6-Methylguanine Deoxyribonucleic Acid Methyltransferase (MGMT) Methylation Status (Count of Participants)
Methylated	0 0%	9 29%	12 36.4%	12 36.4%	9 40.9%	42 26.4%
Unmethylated	40 100%	15 48.4%	18 54.5%	18 54.5%	11 50%	102 64.2%
Unknown	0 0%	7 22.6%	3 9.1%	3 9.1%	2 9.1%	15 9.4%
Isocitrate dehydrogenase (IDH) Mutation Status (Count of Participants)
IDH Mutant	5 12.5%	4 12.9%	4 12.1%	2 6.1%	1 4.5%	16 10.1%
Wild Type	35 87.5%	22 71%	28 84.8%	30 90.9%	19 86.4%	134 84.3%
Unknown	0 0%	5 16.1%	1 3%	1 3%	2 9.1%	9 5.7%

Outcome Measures

1. Primary Outcome

Title	Overall Survival Rate at 12 Months (OS-12) as Estimated Using the Kaplan-Meier Method (Cohort A)
Description	OS-12 with 90% confidence interval (CI) is the primary endpoint of Cohort A and is the percentage of subjects who remain alive at 12 months, where OS is measured from the time of diagnosis until the recorded date of death or last follow-up. Subjects who are lost to follow-up at the time of the analysis will be censored on the date of last follow-up.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

The population comprises all subjects who received any dose of durvalumab.

Arm/Group Title	Cohort A
Arm/Group Description	Subjects with newly diagnosed unmethlyated MGMT GBM receive durvalumab (10 mg/kg IV Q2W) + standard radiotherapy (2 Gy/day x 5 days per week, for a total of 60 Gy over 30 fractions per local guidelines). On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.
Measure Participants	40
Number (90% Confidence Interval) [percent of subjects alive]	60.0

2. Primary Outcome

Title	Progression-free Survival Rate at 6 Months (PFS-6) as Estimated Using the Kaplan-Meier Method (Cohorts B, B2, and B3)
Description	PFS-6 is the primary endpoint of Cohorts B, B2, and B3, and is the percentage of subjects who have not progressed at 6 months, with PFS measured from the date of the first dose of study treatment to the date of earliest disease progression (PD) based on modified Response Assessment in Neuro-Oncology (RANO) criteria or to the date of death, if PD does not occur. Per the RANO criteria, PD indicates any new lesion or a 25% increase in sum of the products of perpendicular diameters of enhancing lesions, or clear clinical deterioration per the Investigator (Wen et al. J Clin Oncol 2010; 28(11):1963-72).
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

The population comprises all subjects who received any dose of durvalumab.

Arm/Group Title	Cohort B	Cohort B2	Cohort B3
Arm/Group Description	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) as monotherapy.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (3 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.
Measure Participants	31	33	33
Number (90% Confidence Interval) [percentage of participants]	19.4 48.5%	15.2 49%	17.2 52.1%

3. Primary Outcome

Title	Overall Survival Rate at 6 Months (OS-6) as Estimated Using the Kaplan-Meier Method (Cohort C)
Description	OS-6 is the primary endpoint of Cohort C and is the percentage of subjects who remain alive at 6 months, where OS is measured from the date of the first dose of study treatment until the recorded date of death or last follow-up. Subjects who are lost to follow-up at the time of the analysis will be censored on the date of last follow-up.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

The population comprises all subjects who received any dose of durvalumab.

Arm/Group Title	Cohort C
Arm/Group Description	Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + continued bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.
Measure Participants	22
Number (80% Confidence Interval) [percentage of participants]	36.4 91%

4. Secondary Outcome

Title	Number of Participants With Treatment-emergent Adverse Events
Description	Toxicity is graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Adverse events (AEs) are reported based on clinical laboratory tests, vital sign and weight measurements, physical examinations, performance status evaluations, magnetic resonance imaging, and any other medically indicated assessments, including subject interviews, from the time informed consent is signed through 90 days after the last dose of durvalumab. AEs are considered to be treatment emergent if they occur or worsen in severity after the first dose of study treatment.
Time Frame	Up to 15 months

Outcome Measure Data

Analysis Population Description

The population comprises all subjects who received any dose of durvalumab.

Arm/Group Title	Cohort A	Cohort B	Cohort B2	Cohort B3	Cohort C
Arm/Group Description	Subjects with newly diagnosed unmethlyated MGMT GBM receive durvalumab (10 mg/kg IV Q2W) + standard radiotherapy (2 Gy/day x 5 days per week, for a total of 60 Gy over 30 fractions per local guidelines). On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) as monotherapy.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (3 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + continued bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.
Measure Participants	40	31	33	33	22
Any TEAE	40 100%	31 100%	33 100%	33 100%	22 100%
Serious TEAE	26 65%	18 58.1%	11 33.3%	15 45.5%	14 63.6%
Treatment-related TEAE	37 92.5%	26 83.9%	30 90.9%	31 93.9%	17 77.3%

5. Secondary Outcome

Title	Median PFS as Estimated Using the Kaplan-Meier Method
Description	PFS is measured from the date of the first dose of study treatment to the date of earliest PD based on modified RANO criteria or to the date of death, if PD does not occur. Per the RANO criteria, PD indicates any new lesion or a 25% increase in sum of the products of perpendicular diameters of enhancing lesions, or clear clinical deterioration per the Investigator (Wen et al. J Clin Oncol 2010; 28(11):1963-72).
Time Frame	Up to 15 months

Outcome Measure Data

Analysis Population Description

The population comprises all subjects who received any dose of durvalumab.

Arm/Group Title	Cohort A	Cohort B	Cohort B2	Cohort B3	Cohort C
Arm/Group Description	Subjects with newly diagnosed unmethlyated MGMT GBM receive durvalumab (10 mg/kg IV Q2W) + standard radiotherapy (2 Gy/day x 5 days per week, for a total of 60 Gy over 30 fractions per local guidelines). On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) as monotherapy.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (3 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + continued bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.
Measure Participants	40	31	33	33	22
Median (95% Confidence Interval) [weeks]	19.9	13.0	16.0	15.7	7.9

6. Secondary Outcome

Title	Median OS as Estimated Using the Kaplan-Meier Method
Description	All subjects are followed for survival at least every 6 months for up to 3 years following initiation of study treatment. In Cohort A, OS is measured from the date of diagnosis until the recorded date of death or last follow-up. In Cohorts B, B2, B3, and C, OS is measured from the date of the first dose of study treatment until the recorded date of death or last follow-up. Subjects who remain alive or are lost to follow-up at the time of the analysis are censored on the date of last follow-up.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

The population comprises all subjects who received any dose of durvalumab.

Arm/Group Title	Cohort A	Cohort B	Cohort B2	Cohort B3	Cohort C
Arm/Group Description	Subjects with newly diagnosed unmethlyated MGMT GBM receive durvalumab (10 mg/kg IV Q2W) + standard radiotherapy (2 Gy/day x 5 days per week, for a total of 60 Gy over 30 fractions per local guidelines). On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) as monotherapy.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (3 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + continued bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.
Measure Participants	40	31	33	33	22
Median (95% Confidence Interval) [weeks]	64.8	39.4	37.3	39.7	19.3

7. Secondary Outcome

Title	Number of Subjects With Best Overall Response
Description	Radiographic response is assessed by consistent imaging methods every (q) 8 to 9 weeks during study treatment administration. Response is categorized per the modified RANO criteria: complete response (CR) indicates no new lesions and disappearance of all disease sustained for ≥ 4 weeks; partial response (PR) indicates no new lesions, no progression of non-measureable disease, and ≥ 50% decrease from baseline in sum of products of perpendicular diameters of measurable lesions sustained for ≥ 4 weeks; stable disease (SD) indicates non-qualification for CR, PR, or progressive disease (PD); PD indicates any new lesion or a 25% increase in sum of the products of perpendicular diameters of enhancing lesions, or clear clinical deterioration per the Investigator (Wen et al. J Clin Oncol 2010; 28(11):1963-72).
Time Frame	Up to 15 months

Outcome Measure Data

Analysis Population Description

The population comprises all subjects who received any dose of durvalumab.

Arm/Group Title	Cohort A	Cohort B	Cohort B2	Cohort B3	Cohort C
Arm/Group Description	Subjects with newly diagnosed unmethlyated MGMT GBM receive durvalumab (10 mg/kg IV Q2W) + standard radiotherapy (2 Gy/day x 5 days per week, for a total of 60 Gy over 30 fractions per local guidelines). On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) as monotherapy.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (3 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + continued bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.
Measure Participants	40	31	33	33	22
CR	1 2.5%	0 0%	0 0%	0 0%	0 0%
PR	4 10%	4 12.9%	3 9.1%	3 9.1%	0 0%
SD	26 65%	12 38.7%	20 60.6%	18 54.5%	6 27.3%
PD	9 22.5%	15 48.4%	10 30.3%	11 33.3%	14 63.6%
Unknown Response	0 0%	0 0%	0 0%	1 3%	2 9.1%

8. Secondary Outcome

Title	Mean Changes From Baseline in the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30)
Description	Health-related quality of life was measured using the validated EORTC-QLQ-C30. Questionnaires may be completed by the subject or with the assistance of the examiner at baseline prior to initiation of study therapy, and then approximately every 8 weeks while on study treatment (prior to discussing treatment response at each visit, whenever possible). All questions are answered using a categorical scale (1 = not at all; 2 = a little; 3 = quite a bit; 4 = very much for symptoms and 1= very poor; 7= excellent for global heath questions). Scores were linearly transformed to 0 to 100 scales so that higher scores represented a higher level of functioning. Overall scores were calculated for each patient for each timepoint (Giesinger J et al Journal of Clinical Epidemiology. 2016 Jan;69:79-88). Mean change from baseline where baseline is the last non-missing value before the administration of MEDI4736 was reported.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Number of subjects who completed European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30) at baseline and each visit.

Arm/Group Title	Cohort A	Cohort B	Cohort B2	Cohort B3	Cohort C
Arm/Group Description	Subjects with newly diagnosed unmethlyated MGMT GBM receive durvalumab (10 mg/kg IV Q2W) + standard radiotherapy (2 Gy/day x 5 days per week, for a total of 60 Gy over 30 fractions per local guidelines). On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) as monotherapy.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (3 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + continued bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.
Measure Participants	40	31	33	33	22
Week 9	-6.03 (19.53)	-8.33 (26.16)	-5.56 (21.80)	-7.05 (20.78)	-12.50 (24.30)
Week 17	-2.0 (18.05)	4.17 (27.46)	-7.14 (26.53)	-7.74 (18.62)	-16.67 (6.80)
Week 25	0.42 (15.64)	10.42 (17.18)	-3.70 (31.49)	-8.33 (19.54)
Week 33	-6.25 (15.27)	30.56 (20.97)	2.08 (34.94)	11.11 (12.73)
Week 41	0.0 (11.79)	19.44 (12.73)	16.67	-2.08 (31.46)
Week 49	3.57 (13.49)	16.67 (16.67)	4.17 (17.68)	8.33

9. Secondary Outcome

Title	Mean Changes From Baseline in the EORTC Brain Cancer Quality of Life Questionnaire (EORTC-QLQ-BN-20)
Description	Health-related quality of life was measured using an EORTC quality of life questionnaire designed specifically for subjects with brain tumors (BN-20). Questionnaires may be completed by the subject or with the assistance of the examiner at baseline prior to initiation of study therapy, and then approximately every 8 weeks while on study treatment (prior to discussing treatment response at each visit, whenever possible). All single questions are answered using a categorical scale (e.g., 1 = not at all; 2 = a little; 3 = quite a bit; 4 = very much) and linearly transformed to 0 to 100 scales with higher scores for a symptom scale representing higher level of symptoms. The evaluation of HRQoL at each timepoint was measured by mean changes from baseline where baseline is the last non-missing value before the administration of MEDI4736 was reported.
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

Number of subjects who completed EORTC Brain Cancer Quality of Life Questionnaire (EORTC-QLQ-BN-20) at baseline and each visit.

Arm/Group Title	Cohort A	Cohort B	Cohort B2	Cohort B3	Cohort C
Arm/Group Description	Subjects with newly diagnosed unmethlyated MGMT GBM receive durvalumab (10 mg/kg IV Q2W) + standard radiotherapy (2 Gy/day x 5 days per week, for a total of 60 Gy over 30 fractions per local guidelines). On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) as monotherapy.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (3 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.	Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + continued bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.
Measure Participants	40	31	33	33	22
Week 9	3.63 (8.28)	5.62 (16.46)	4.26 (15.95)	3.50 (15.99)	-2.17 (17.14)
Week 17	0.85 (11.71)	0.21 (8.93)	-2.55 (18.17)	-4.06 (14.33)	9.17 (3.54)
Week 25	-0.82 (11.12)	-3.33 (8.66)	3.27 (18.46)	-1.37 (11.80)
Week 33	6.46 (16.94)	-4.44 (10.05)	-9.39 (16.32)	-17.28 (10.64)
Week 41	1.94 (18.72)	-5.83 (15.32)	5.00	-3.60 (10.38)
Week 49	5.56 (22.08)	-1.11 (5.36)	5.83 (5.89)	2.46

Adverse Events

Time Frame	All adverse events (AEs) occurring between the signing of informed consent and the off-study date (i.e., up to 15 months after the first dose of study treatment) are documented, regardless of the causal relationship to study drug. AEs that occur or worsen in severity after the first dose of study treatment are considered treatment emergent (i.e., TEAEs).
Adverse Event Reporting Description	AE documentation includes onset/resolution dates, severity using the NCI CTCAE (version 4.03), seriousness, relationship to study drug, study drug action taken, treatment, and outcome. In summaries, preferred terms are counted only once per subject at the maximum reported grade.
Arm/Group Title	Cohort A		Cohort B		Cohort B2		Cohort B3		Cohort C
Arm/Group Description	Subjects with newly diagnosed unmethlyated MGMT GBM receive durvalumab (10 mg/kg IV Q2W) + standard radiotherapy (2 Gy/day x 5 days per week, for a total of 60 Gy over 30 fractions per local guidelines). On days when radiotherapy and durvalumab overlap, radiotherapy is administered first followed by durvalumab.		Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) as monotherapy.		Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.		Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + bevacizumab (3 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.		Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10 mg/kg IV Q2W) + continued bevacizumab (10 mg/kg IV Q2W). Durvalumab is administered first followed by a 1-hour observation period, after which, bevacizumab is infused.
All Cause Mortality
	Cohort A		Cohort B		Cohort B2		Cohort B3		Cohort C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/40 (25%)		4/31 (12.9%)		6/33 (18.2%)		3/33 (9.1%)		7/22 (31.8%)
Serious Adverse Events
	Cohort A		Cohort B		Cohort B2		Cohort B3		Cohort C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/40 (65%)		18/31 (58.1%)		11/33 (33.3%)		15/33 (45.5%)		14/22 (63.6%)
Cardiac disorders
Atrial flutter	0/40 (0%)		0/31 (0%)		0/33 (0%)		1/33 (3%)		0/22 (0%)
Cardiac arrest	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Eye disorders
Blindness	0/40 (0%)		0/31 (0%)		1/33 (3%)		0/33 (0%)		0/22 (0%)
Gastrointestinal disorders
Colitis	0/40 (0%)		2/31 (6.5%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Dyspepsia	0/40 (0%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Nausea	1/40 (2.5%)		2/31 (6.5%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Vomiting	0/40 (0%)		3/31 (9.7%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Dysphagia	0/40 (0%)		0/31 (0%)		1/33 (3%)		1/33 (3%)		0/22 (0%)
Abdominal pain	0/40 (0%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Diarrhoea	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Faecal incontinence	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Small intestinal obstruction	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
General disorders
Gait disturbance	1/40 (2.5%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Asthenia	0/40 (0%)		1/31 (3.2%)		1/33 (3%)		1/33 (3%)		0/22 (0%)
Fatigue	0/40 (0%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Pyrexia	0/40 (0%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Drowning	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Mass	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Generalised oedema	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Infections and infestations
Lung infection	0/40 (0%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Pneumonia	0/40 (0%)		0/31 (0%)		0/33 (0%)		1/33 (3%)		1/22 (4.5%)
Wound infection	0/40 (0%)		0/31 (0%)		0/33 (0%)		2/33 (6.1%)		0/22 (0%)
Influenza	0/40 (0%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Infection	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Urinary tract infection	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Injury, poisoning and procedural complications
Overdose	0/40 (0%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Fall	1/40 (2.5%)		1/31 (3.2%)		0/33 (0%)		1/33 (3%)		2/22 (9.1%)
Rib fracture	0/40 (0%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Investigations
Biopsy brain	0/40 (0%)		0/31 (0%)		0/33 (0%)		1/33 (3%)		0/22 (0%)
Metabolism and nutrition disorders
Dehydration	0/40 (0%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Hyperglycaemia	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Hyperkalaemia	0/40 (0%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Hyponatraemia	2/40 (5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/40 (0%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant Neoplasm progression	7/40 (17.5%)		4/31 (12.9%)		6/33 (18.2%)		3/33 (9.1%)		6/22 (27.3%)
Nervous system disorders
Headache	2/40 (5%)		2/31 (6.5%)		1/33 (3%)		1/33 (3%)		0/22 (0%)
Haemorrhage intracranial	0/40 (0%)		2/31 (6.5%)		0/33 (0%)		1/33 (3%)		1/22 (4.5%)
Cognitive disorder	0/40 (0%)		1/31 (3.2%)		1/33 (3%)		2/33 (6.1%)		0/22 (0%)
Hemiparesis	2/40 (5%)		5/31 (16.1%)		0/33 (0%)		2/33 (6.1%)		0/22 (0%)
Hydrocephalus	0/40 (0%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Convulsion	9/40 (22.5%)		4/31 (12.9%)		2/33 (6.1%)		3/33 (9.1%)		5/22 (22.7%)
Somnolence	0/40 (0%)		2/31 (6.5%)		0/33 (0%)		1/33 (3%)		0/22 (0%)
Aphasia	1/40 (2.5%)		1/31 (3.2%)		0/33 (0%)		1/33 (3%)		0/22 (0%)
Brain oedema	2/40 (5%)		2/31 (6.5%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Encephalopathy	1/40 (2.5%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Cerebrovascular accident	0/40 (0%)		0/31 (0%)		2/33 (6.1%)		0/33 (0%)		0/22 (0%)
Neurological decompensation	0/40 (0%)		0/31 (0%)		1/33 (3%)		0/33 (0%)		0/22 (0%)
Dysarthria	0/40 (0%)		0/31 (0%)		0/33 (0%)		1/33 (3%)		0/22 (0%)
Neurologic neglect syndrome	0/40 (0%)		0/31 (0%)		0/33 (0%)		1/33 (3%)		0/22 (0%)
Partial seizures	0/40 (0%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Syncope	0/40 (0%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Lethargy	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Central nervous system lesion	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Psychiatric disorders
Confusional state	2/40 (5%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Mental status changes	2/40 (5%)		0/31 (0%)		1/33 (3%)		1/33 (3%)		0/22 (0%)
Irritability	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Pyschotic disorder	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Suicidal ideation	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Hallucination, olfactory	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Renal and urinary disorders
Urinary incontinence	0/40 (0%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Tubulointerstitial nephritis	0/40 (0%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Urinary retention	0/40 (0%)		0/31 (0%)		0/33 (0%)		1/33 (3%)		0/22 (0%)
Nephritis	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional	0/40 (0%)		0/31 (0%)		1/33 (3%)		0/33 (0%)		0/22 (0%)
Pneumonitis	0/40 (0%)		0/31 (0%)		1/33 (3%)		0/33 (0%)		0/22 (0%)
Sinus disorder	0/40 (0%)		0/31 (0%)		1/33 (3%)		0/33 (0%)		0/22 (0%)
Epistaxis	0/40 (0%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Hypoxia	0/40 (0%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Pneumonia aspiration	0/40 (0%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Skin and subcutaneous tissue disorders
Rash	0/40 (0%)		0/31 (0%)		0/33 (0%)		1/33 (3%)		0/22 (0%)
Surgical and medical procedures
Craniotomy	2/40 (5%)		3/31 (9.7%)		0/33 (0%)		1/33 (3%)		0/22 (0%)
Tumour excision	4/40 (10%)		0/31 (0%)		1/33 (3%)		2/33 (6.1%)		0/22 (0%)
Ventriculo-peritoneal shunt	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Other (Not Including Serious) Adverse Events
	Cohort A		Cohort B		Cohort B2		Cohort B3		Cohort C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/40 (100%)		31/31 (100%)		33/33 (100%)		33/33 (100%)		22/22 (100%)
Blood and lymphatic system disorders
Anaemia	4/40 (10%)		2/31 (6.5%)		3/33 (9.1%)		5/33 (15.2%)		2/22 (9.1%)
Thrombocytopenia	2/40 (5%)		2/31 (6.5%)		1/33 (3%)		4/33 (12.1%)		1/22 (4.5%)
Leukopenia	0/40 (0%)		0/31 (0%)		2/33 (6.1%)		4/33 (12.1%)		1/22 (4.5%)
Lymphopenia	0/40 (0%)		0/31 (0%)		6/33 (18.2%)		7/33 (21.2%)		2/22 (9.1%)
Neutropenia	0/40 (0%)		0/31 (0%)		1/33 (3%)		2/33 (6.1%)		0/22 (0%)
Cardiac disorders
Bradycardia	2/40 (5%)		0/31 (0%)		1/33 (3%)		2/33 (6.1%)		2/22 (9.1%)
Ear and labyrinth disorders
Tinnitus	4/40 (10%)		1/31 (3.2%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Endocrine disorders
Hyperthyroidism	4/40 (10%)		2/31 (6.5%)		1/33 (3%)		1/33 (3%)		0/22 (0%)
Hypothyroidism	3/40 (7.5%)		3/31 (9.7%)		2/33 (6.1%)		3/33 (9.1%)		1/22 (4.5%)
Cushingoid	0/40 (0%)		1/31 (3.2%)		1/33 (3%)		2/33 (6.1%)		0/22 (0%)
Endocrine disorder	0/40 (0%)		0/31 (0%)		0/33 (0%)		2/33 (6.1%)		1/22 (4.5%)
Eye disorders
Dry eye	2/40 (5%)		0/31 (0%)		2/33 (6.1%)		1/33 (3%)		0/22 (0%)
Lacrimation increased	1/40 (2.5%)		0/31 (0%)		2/33 (6.1%)		1/33 (3%)		1/22 (4.5%)
Vision blurred	5/40 (12.5%)		1/31 (3.2%)		3/33 (9.1%)		2/33 (6.1%)		1/22 (4.5%)
Eye pain	3/40 (7.5%)		1/31 (3.2%)		1/33 (3%)		0/33 (0%)		0/22 (0%)
Gastrointestinal disorders
Abdominal pain	0/40 (0%)		3/31 (9.7%)		2/33 (6.1%)		1/33 (3%)		0/22 (0%)
Constipation	10/40 (25%)		6/31 (19.4%)		4/33 (12.1%)		7/33 (21.2%)		3/22 (13.6%)
Diarrhoea	10/40 (25%)		3/31 (9.7%)		6/33 (18.2%)		8/33 (24.2%)		1/22 (4.5%)
Dyspepsia	3/40 (7.5%)		2/31 (6.5%)		2/33 (6.1%)		3/33 (9.1%)		0/22 (0%)
Nausea	12/40 (30%)		6/31 (19.4%)		5/33 (15.2%)		4/33 (12.1%)		2/22 (9.1%)
Vomiting	4/40 (10%)		1/31 (3.2%)		2/33 (6.1%)		1/33 (3%)		1/22 (4.5%)
Faecal incontinence	0/40 (0%)		0/31 (0%)		2/33 (6.1%)		0/33 (0%)		0/22 (0%)
Haemorrhoidal haemorrhage	0/40 (0%)		0/31 (0%)		2/33 (6.1%)		1/33 (3%)		0/22 (0%)
Dysphagia	3/40 (7.5%)		1/31 (3.2%)		0/33 (0%)		2/33 (6.1%)		4/22 (18.2%)
Gastrooesophageal reflux disease	1/40 (2.5%)		1/31 (3.2%)		0/33 (0%)		4/33 (12.1%)		0/22 (0%)
Stomatitis	1/40 (2.5%)		1/31 (3.2%)		0/33 (0%)		2/33 (6.1%)		0/22 (0%)
Dry mouth	3/40 (7.5%)		0/31 (0%)		1/33 (3%)		0/33 (0%)		0/22 (0%)
General disorders
Asthenia	2/40 (5%)		2/31 (6.5%)		3/33 (9.1%)		0/33 (0%)		1/22 (4.5%)
Fatigue	29/40 (72.5%)		10/31 (32.3%)		13/33 (39.4%)		18/33 (54.5%)		7/22 (31.8%)
Gait disturbance	13/40 (32.5%)		10/31 (32.3%)		11/33 (33.3%)		5/33 (15.2%)		5/22 (22.7%)
Non-cardiac chest pain	0/40 (0%)		2/31 (6.5%)		1/33 (3%)		1/33 (3%)		0/22 (0%)
Oedema peripheral	4/40 (10%)		2/31 (6.5%)		2/33 (6.1%)		1/33 (3%)		1/22 (4.5%)
Chills	2/40 (5%)		0/31 (0%)		2/33 (6.1%)		3/33 (9.1%)		0/22 (0%)
Catheter site pain	2/40 (5%)		0/31 (0%)		0/33 (0%)		2/33 (6.1%)		0/22 (0%)
Injection site bruising	1/40 (2.5%)		0/31 (0%)		1/33 (3%)		2/33 (6.1%)		0/22 (0%)
Pyrexia	4/40 (10%)		2/31 (6.5%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Face oedema	6/40 (15%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Infections and infestations
Upper respiratory tract infection	3/40 (7.5%)		4/31 (12.9%)		0/33 (0%)		1/33 (3%)		0/22 (0%)
Nasopharyngitis	1/40 (2.5%)		0/31 (0%)		2/33 (6.1%)		2/33 (6.1%)		0/22 (0%)
Skin infection	2/40 (5%)		0/31 (0%)		2/33 (6.1%)		0/33 (0%)		0/22 (0%)
Urinary tract infection	3/40 (7.5%)		0/31 (0%)		5/33 (15.2%)		4/33 (12.1%)		1/22 (4.5%)
Sinusitis	3/40 (7.5%)		0/31 (0%)		1/33 (3%)		1/33 (3%)		1/22 (4.5%)
Oral candidiasis	4/40 (10%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Injury, poisoning and procedural complications
Fall	0/40 (0%)		5/31 (16.1%)		9/33 (27.3%)		4/33 (12.1%)		3/22 (13.6%)
Contusion	1/40 (2.5%)		1/31 (3.2%)		3/33 (9.1%)		5/33 (15.2%)		1/22 (4.5%)
Joint dislocation	0/40 (0%)		0/31 (0%)		2/33 (6.1%)		0/33 (0%)		0/22 (0%)
Investigations
Alanine aminotransferase increased	8/40 (20%)		4/31 (12.9%)		6/33 (18.2%)		9/33 (27.3%)		4/22 (18.2%)
Aspartate aminotransferase increased	11/40 (27.5%)		4/31 (12.9%)		4/33 (12.1%)		8/33 (24.2%)		1/22 (4.5%)
Blood alkaline phosphatase increased	0/40 (0%)		2/31 (6.5%)		1/33 (3%)		2/33 (6.1%)		1/22 (4.5%)
Blood thyroid stimulating hormone decreased	2/40 (5%)		3/31 (9.7%)		2/33 (6.1%)		0/33 (0%)		0/22 (0%)
Lymphocyte count decreased	3/40 (7.5%)		5/31 (16.1%)		0/33 (0%)		0/33 (0%)		4/22 (18.2%)
Platelet count decreased	2/40 (5%)		4/31 (12.9%)		4/33 (12.1%)		2/33 (6.1%)		1/22 (4.5%)
Weight decreased	5/40 (12.5%)		2/31 (6.5%)		2/33 (6.1%)		2/33 (6.1%)		1/22 (4.5%)
Amylase increased	7/40 (17.5%)		1/31 (3.2%)		6/33 (18.2%)		6/33 (18.2%)		0/22 (0%)
Blood bilirubin increased	1/40 (2.5%)		0/31 (0%)		3/33 (9.1%)		2/33 (6.1%)		1/22 (4.5%)
Blood lactate dehydrogenase increased	3/40 (7.5%)		1/31 (3.2%)		3/33 (9.1%)		1/33 (3%)		0/22 (0%)
Lipase increased	11/40 (27.5%)		1/31 (3.2%)		6/33 (18.2%)		5/33 (15.2%)		0/22 (0%)
Neutrophil count decreased	2/40 (5%)		0/31 (0%)		2/33 (6.1%)		4/33 (12.1%)		1/22 (4.5%)
Thyroxine free decreased	1/40 (2.5%)		1/31 (3.2%)		2/33 (6.1%)		0/33 (0%)		0/22 (0%)
White blood cell count decreased	3/40 (7.5%)		1/31 (3.2%)		2/33 (6.1%)		4/33 (12.1%)		1/22 (4.5%)
Blood thyroid stimulating hormone increased	0/40 (0%)		1/31 (3.2%)		1/33 (3%)		2/33 (6.1%)		0/22 (0%)
Weight increased	1/40 (2.5%)		0/31 (0%)		0/33 (0%)		4/33 (12.1%)		0/22 (0%)
White blood cell count increased	0/40 (0%)		0/31 (0%)		1/33 (3%)		2/33 (6.1%)		0/22 (0%)
Haematocrit decreased	3/40 (7.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Transaminases increased	3/40 (7.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	9/40 (22.5%)		6/31 (19.4%)		8/33 (24.2%)		5/33 (15.2%)		5/22 (22.7%)
Hypokalaemia	3/40 (7.5%)		2/31 (6.5%)		5/33 (15.2%)		3/33 (9.1%)		2/22 (9.1%)
Hyponatraemia	3/40 (7.5%)		3/31 (9.7%)		5/33 (15.2%)		5/33 (15.2%)		5/22 (22.7%)
Decreased appetite	8/40 (20%)		1/31 (3.2%)		5/33 (15.2%)		4/33 (12.1%)		1/22 (4.5%)
Hypoalbuminaemia	2/40 (5%)		0/31 (0%)		4/33 (12.1%)		4/33 (12.1%)		0/22 (0%)
Hypocalcaemia	2/40 (5%)		0/31 (0%)		4/33 (12.1%)		1/33 (3%)		1/22 (4.5%)
Hypoglycaemia	2/40 (5%)		0/31 (0%)		2/33 (6.1%)		2/33 (6.1%)		1/22 (4.5%)
Hypernatraemia	0/40 (0%)		1/31 (3.2%)		0/33 (0%)		4/33 (12.1%)		0/22 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/40 (12.5%)		2/31 (6.5%)		8/33 (24.2%)		7/33 (21.2%)		2/22 (9.1%)
Back pain	5/40 (12.5%)		1/31 (3.2%)		1/33 (3%)		3/33 (9.1%)		0/22 (0%)
Flank pain	0/40 (0%)		2/31 (6.5%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Muscular weakness	5/40 (12.5%)		2/31 (6.5%)		3/33 (9.1%)		5/33 (15.2%)		0/22 (0%)
Myalgia	6/40 (15%)		3/31 (9.7%)		4/33 (12.1%)		2/33 (6.1%)		0/22 (0%)
Musculoskeletal pain	1/40 (2.5%)		1/31 (3.2%)		0/33 (0%)		2/33 (6.1%)		1/22 (4.5%)
Neck pain	7/40 (17.5%)		0/31 (0%)		0/33 (0%)		3/33 (9.1%)		0/22 (0%)
Pain in extremity	2/40 (5%)		0/31 (0%)		1/33 (3%)		3/33 (9.1%)		1/22 (4.5%)
Muscle spasms	3/40 (7.5%)		0/31 (0%)		1/33 (3%)		1/33 (3%)		0/22 (0%)
Nervous system disorders
Aphasia	11/40 (27.5%)		3/31 (9.7%)		6/33 (18.2%)		7/33 (21.2%)		6/22 (27.3%)
Ataxia	2/40 (5%)		3/31 (9.7%)		1/33 (3%)		0/33 (0%)		2/22 (9.1%)
Balance disorder	1/40 (2.5%)		2/31 (6.5%)		1/33 (3%)		1/33 (3%)		0/22 (0%)
Cognitive disorder	6/40 (15%)		2/31 (6.5%)		1/33 (3%)		1/33 (3%)		4/22 (18.2%)
Convulsion	5/40 (12.5%)		1/31 (3.2%)		6/33 (18.2%)		2/33 (6.1%)		2/22 (9.1%)
Dizziness	10/40 (25%)		7/31 (22.6%)		6/33 (18.2%)		5/33 (15.2%)		0/22 (0%)
Dysarthria	2/40 (5%)		2/31 (6.5%)		2/33 (6.1%)		1/33 (3%)		0/22 (0%)
Headache	19/40 (47.5%)		12/31 (38.7%)		9/33 (27.3%)		9/33 (27.3%)		8/22 (36.4%)
Hemiparesis	4/40 (10%)		3/31 (9.7%)		12/33 (36.4%)		3/33 (9.1%)		4/22 (18.2%)
Memory impairment	2/40 (5%)		7/31 (22.6%)		2/33 (6.1%)		2/33 (6.1%)		2/22 (9.1%)
Paraesthesia	3/40 (7.5%)		4/31 (12.9%)		5/33 (15.2%)		5/33 (15.2%)		2/22 (9.1%)
Somnolence	2/40 (5%)		1/31 (3.2%)		2/33 (6.1%)		1/33 (3%)		1/22 (4.5%)
Visual field defect	2/40 (5%)		3/31 (9.7%)		3/33 (9.1%)		2/33 (6.1%)		0/22 (0%)
Facial paresis	2/40 (5%)		0/31 (0%)		2/33 (6.1%)		2/33 (6.1%)		1/22 (4.5%)
Hypoaesthesia	2/40 (5%)		1/31 (3.2%)		0/33 (0%)		2/33 (6.1%)		0/22 (0%)
Lethargy	0/40 (0%)		1/31 (3.2%)		1/33 (3%)		2/33 (6.1%)		1/22 (4.5%)
Peripheral motor neuropathy	1/40 (2.5%)		0/31 (0%)		1/33 (3%)		2/33 (6.1%)		0/22 (0%)
Tremor	6/40 (15%)		0/31 (0%)		1/33 (3%)		2/33 (6.1%)		1/22 (4.5%)
Amnesia	4/40 (10%)		1/31 (3.2%)		1/33 (3%)		1/33 (3%)		1/22 (4.5%)
Disturbance in attention	3/40 (7.5%)		0/31 (0%)		1/33 (3%)		1/33 (3%)		1/22 (4.5%)
Peripheral sensory neuropathy	3/40 (7.5%)		1/31 (3.2%)		1/33 (3%)		0/33 (0%)		0/22 (0%)
Dysgeusia	3/40 (7.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		1/22 (4.5%)
Psychiatric disorders
Confusional state	6/40 (15%)		5/31 (16.1%)		2/33 (6.1%)		2/33 (6.1%)		6/22 (27.3%)
Depression	8/40 (20%)		2/31 (6.5%)		1/33 (3%)		6/33 (18.2%)		0/22 (0%)
Agitation	3/40 (7.5%)		0/31 (0%)		2/33 (6.1%)		3/33 (9.1%)		0/22 (0%)
Anxiety	7/40 (17.5%)		0/31 (0%)		4/33 (12.1%)		2/33 (6.1%)		1/22 (4.5%)
Insomnia	11/40 (27.5%)		1/31 (3.2%)		5/33 (15.2%)		4/33 (12.1%)		2/22 (9.1%)
Irritability	3/40 (7.5%)		0/31 (0%)		0/33 (0%)		2/33 (6.1%)		0/22 (0%)
Renal and urinary disorders
Micturition urgency	3/40 (7.5%)		2/31 (6.5%)		0/33 (0%)		1/33 (3%)		0/22 (0%)
Nephrolithiasis	0/40 (0%)		2/31 (6.5%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Urinary incontinence	3/40 (7.5%)		2/31 (6.5%)		1/33 (3%)		2/33 (6.1%)		2/22 (9.1%)
Haematuria	2/40 (5%)		0/31 (0%)		3/33 (9.1%)		0/33 (0%)		0/22 (0%)
Proteinuria	0/40 (0%)		0/31 (0%)		4/33 (12.1%)		1/33 (3%)		1/22 (4.5%)
Incontinence	3/40 (7.5%)		0/31 (0%)		0/33 (0%)		2/33 (6.1%)		1/22 (4.5%)
Pollakiuria	0/40 (0%)		1/31 (3.2%)		1/33 (3%)		2/33 (6.1%)		0/22 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	8/40 (20%)		5/31 (16.1%)		6/33 (18.2%)		6/33 (18.2%)		5/22 (22.7%)
Dyspnoea	4/40 (10%)		2/31 (6.5%)		3/33 (9.1%)		5/33 (15.2%)		0/22 (0%)
Dysphonia	4/40 (10%)		1/31 (3.2%)		12/33 (36.4%)		9/33 (27.3%)		2/22 (9.1%)
Epistaxis	0/40 (0%)		0/31 (0%)		2/33 (6.1%)		2/33 (6.1%)		2/22 (9.1%)
Hiccups	0/40 (0%)		0/31 (0%)		2/33 (6.1%)		0/33 (0%)		1/22 (4.5%)
Sneezing	2/40 (5%)		0/31 (0%)		2/33 (6.1%)		2/33 (6.1%)		0/22 (0%)
Nasal congestion	1/40 (2.5%)		1/31 (3.2%)		1/33 (3%)		3/33 (9.1%)		0/22 (0%)
Oropharyngeal pain	2/40 (5%)		1/31 (3.2%)		0/33 (0%)		2/33 (6.1%)		1/22 (4.5%)
Rhinorrhoea	1/40 (2.5%)		0/31 (0%)		1/33 (3%)		2/33 (6.1%)		0/22 (0%)
Skin and subcutaneous tissue disorders
Dry skin	5/40 (12.5%)		2/31 (6.5%)		4/33 (12.1%)		1/33 (3%)		0/22 (0%)
Rash maculo-papular	3/40 (7.5%)		2/31 (6.5%)		1/33 (3%)		0/33 (0%)		1/22 (4.5%)
Alopecia	20/40 (50%)		1/31 (3.2%)		2/33 (6.1%)		0/33 (0%)		0/22 (0%)
Pruritus	4/40 (10%)		1/31 (3.2%)		4/33 (12.1%)		1/33 (3%)		1/22 (4.5%)
Rash	9/40 (22.5%)		1/31 (3.2%)		5/33 (15.2%)		3/33 (9.1%)		1/22 (4.5%)
Dermatitis acneiform	3/40 (7.5%)		0/31 (0%)		1/33 (3%)		0/33 (0%)		0/22 (0%)
Pain of skin	3/40 (7.5%)		0/31 (0%)		0/33 (0%)		0/33 (0%)		0/22 (0%)
Vascular disorders
Hot flush	2/40 (5%)		2/31 (6.5%)		1/33 (3%)		3/33 (9.1%)		1/22 (4.5%)
Hypertension	6/40 (15%)		1/31 (3.2%)		8/33 (24.2%)		5/33 (15.2%)		2/22 (9.1%)

Limitations/Caveats

The primary study endpoints have been met; final data will be incorporated upon study completion and availability of the data.

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.