A Phase I Trial of AZD3965 in Patients With Advanced Cancer

• ClinicalTrials.gov Identifier: NCT01791595
• Recruitment Status: Completed
• First Posted: February 15, 2013
• Results First Posted: April 11, 2022
• Last Update Posted: April 11, 2022
• Sponsor: Cancer Research UK
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Cancer Research UK

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Adult Solid Tumor; Diffuse Large B Cell Lymphoma; Burkitt Lymphoma
• Intervention: Drug: AZD3965
• Enrollment: 53

Participant Flow

Recruitment Details	Trial participants were enrolled at seven trial sites between 23 April 2013 and 24 July 2019. Two additional patients were recruited to the trial but were withdrawn prior to receiving AZD3965.
Pre-assignment Details

Arm/Group Title	AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)	AZD3965 Expansion Cohort (10 mg BD)
Arm/Group Description	AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment (first 3 trial participants in the Expansion Cohort only; subsequent patients started treatment at Cycle 1, Day 1). Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Period Title: Part 1 AZD3965 Cohort 1 (5 mg OD)
Started	3	0	0	0	0	0	0
Completed	0	0	0	0	0	0	0
Not Completed	3	0	0	0	0	0	0
Reason Not Completed
Death	1	0	0	0	0	0	0
Evidence of disease progression	2	0	0	0	0	0	0
Period Title: Part 1 AZD3965 Cohort 2 (10 mg OD)
Started	0	5	0	0	0	0	0
Completed	0	0	0	0	0	0	0
Not Completed	0	5	0	0	0	0	0
Reason Not Completed
Evidence of disease progression	0	5	0	0	0	0	0
Period Title: Part 1 AZD3965 Cohort 3 (20 mg OD)
Started	0	0	8	0	0	0	0
Completed	0	0	0	0	0	0	0
Not Completed	0	0	8	0	0	0	0
Reason Not Completed
Adverse Event	0	0	1	0	0	0	0
Evidence of disease progression	0	0	6	0	0	0	0
Physician Decision	0	0	1	0	0	0	0
Period Title: Part 1 AZD3965 Cohort 4 (30 mg OD)
Started	0	0	0	5	0	0	0
Completed	0	0	0	1	0	0	0
Not Completed	0	0	0	4	0	0	0
Reason Not Completed
Adverse Event	0	0	0	2	0	0	0
Evidence of disease progression	0	0	0	2	0	0	0
Period Title: Part 1 AZD3965 Cohort 5 (15 mg BD)
Started	0	0	0	0	11	0	0
Completed	0	0	0	0	0	0	0
Not Completed	0	0	0	0	11	0	0
Reason Not Completed
Adverse Event	0	0	0	0	4	0	0
Evidence of disease progression	0	0	0	0	5	0	0
Withdrawal by Subject	0	0	0	0	1	0	0
Physician Decision	0	0	0	0	1	0	0
Period Title: Part 1 AZD3965 Cohort 6 (10 mg BD)
Started	0	0	0	0	0	8	0
Completed	0	0	0	0	0	0	0
Not Completed	0	0	0	0	0	8	0
Reason Not Completed
Adverse Event	0	0	0	0	0	5	0
Evidence of disease progression	0	0	0	0	0	3	0
Period Title: Part 2 AZD3965 Expansion (10 mg BD)
Started	0	0	0	0	0	0	11
Completed	0	0	0	0	0	0	1
Not Completed	0	0	0	0	0	0	10
Reason Not Completed
Adverse Event	0	0	0	0	0	0	1
Evidence of disease progression	0	0	0	0	0	0	6
Withdrawal by Subject	0	0	0	0	0	0	2
Physician Decision	0	0	0	0	0	0	1

Baseline Characteristics

Arm/Group Title		AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)	AZD3965 Expansion Cohort (10 mg BD)	Total
Arm/Group Description		AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment (first 3 trial participants in the Expansion Cohort only; subsequent patients started treatment at Cycle 1, Day 1). Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	Total of all reporting groups
Overall Number of Baseline Participants		3	5	8	5	11	8	11	51
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	3 participants	5 participants	8 participants	5 participants	11 participants	8 participants	11 participants	51 participants
		62; (18 to 75)	66; (62 to 76)	64.5; (26 to 77)	72; (45 to 79)	63; (22 to 73)	63.5; (47 to 75)	70; (48 to 82)	65; (18 to 82)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants	5 participants	8 participants	5 participants	11 participants	8 participants	11 participants	51 participants
	Female	1 33.3%	3 60.0%	3 37.5%	2 40.0%	5 45.5%	1 12.5%	4 36.4%	19 37.3%
	Male	2 66.7%	2 40.0%	5 62.5%	3 60.0%	6 54.5%	7 87.5%	7 63.6%	32 62.7%
Race and Ethnicity Not Collected [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants
									0
		[1] Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United Kingdom	Number Analyzed	3 participants	5 participants	8 participants	5 participants	11 participants	8 participants	11 participants	51 participants
		3	5	8	5	11	8	11	51

Outcome Measures

1. Primary Outcome

Title	MTD of AZD3965
Description	MTD was determined by testing increasing AZD3965 doses in Part 1 dose escalation cohorts (Cohorts 1-6) and defined as the total daily dose level below that at which ≥2 out of ≤6 evaluable patients had a dose-limiting toxicity (DLT) during Cycle 1 (including Day -7). DLTs were defined as highly probably/probably AZD3965 related haematological, cardiac, ophthalmic, other Grade 3/4 toxicity, death or drug-related toxicity causing AZD3965 interruption >2 weeks (see protocol for specific criteria)
Time Frame	Day -7 to Day 28

Outcome Measure Data

Analysis Population Description

All patients recruited to dose escalation cohorts 1 to 6 who received at least one dose of AZD3965 (n=40)

Arm/Group Title	Part 1 Dose Escalation (Cohorts 1-6)
Arm/Group Description:	All eligible participants recruited to dose escalation cohorts 1 to 6 who received at least one dose of AZD3965.
Overall Number of Participants Analyzed	40
Measure Type: Number; Unit of Measure: mg (twice daily)
	10

2. Primary Outcome

Title	Number of Patients Who Experienced DLTs
Description	Number of patients who experienced protocol-defined DLTs (defined according to NCI CTCAE version 4.02). DLTs were defined as highly probably/probably AZD3965 related haematological, cardiac, ophthalmic, other Grade 3/4 toxicity, death or drug-related toxicity causing AZD3965 interruption >2 weeks (see protocol for specific criteria)
Time Frame	Day -7 to Day 28

Outcome Measure Data

Analysis Population Description

All recruited patients who received at least one dose of AZD3965 (N=51)

Arm/Group Title	AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)	AZD3965 Expansion Cohort (10 mg BD)
Arm/Group Description:	AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment (first 3 trial participants in the Expansion Cohort only; subsequent patients started treatment at Cycle 1, Day 1). Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed	3	5	8	5	11	8	11
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%	1 12.5%	1 20.0%	3 27.3%	2 25.0%	1 9.1%

3. Primary Outcome

Title	Number of Patients Who Experienced Serious AEs
Description	A serious adverse event (SAE) is any AE, regardless of dose, causality or expectedness, that results in death, is life-threatening, requires in-patient hospitalisation or prolongs existing in-patient hospitalisation, results in persistent or significant incapacity or disability, is a congenital anomaly or birth defect or is any other medically important event. Any ophthalmic and/or cardiac DLT is considered a medically important event and therefore an SAE in this trial. Specific AE terms are provided in the Adverse Events section
Time Frame	From the date of written informed consent and until 28 days after the last dose of AZD3965; an average (median) of 80 days (range: 36 to 517 days)

Outcome Measure Data

Analysis Population Description

All recruited patients who received at least one dose of AZD3965 (N=51)

Arm/Group Title	AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)	AZD3965 Expansion Cohort (10 mg BD)
Arm/Group Description:	AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment (first 3 trial participants in the Expansion Cohort only; subsequent patients started treatment at Cycle 1, Day 1). Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed	3	5	8	5	11	8	11
Measure Type: Count of Participants; Unit of Measure: Participants
	1 33.3%	1 20.0%	3 37.5%	2 40.0%	8 72.7%	4 50.0%	8 72.7%

4. Primary Outcome

Title	Number of Patients Who Experienced Non-Serious AEs
Description	A non-serious AE is any untoward medical occurrence that does not meet the serious criteria described for outcome measure 3 above. Specific AE terms are provided in the Adverse Events section
Time Frame	From the date of written informed consent and until 28 days after the last dose of AZD3965; an average (median) of 80 days (range: 36 to 517 days)

Outcome Measure Data

Analysis Population Description

All recruited patients who received at least one dose of AZD3965 (N=51)

Arm/Group Title	AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)	AZD3965 Expansion Cohort (10 mg BD)
Arm/Group Description:	AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment (first 3 trial participants in the Expansion Cohort only; subsequent patients started treatment at Cycle 1, Day 1). Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed	3	5	8	5	11	8	11
Measure Type: Count of Participants; Unit of Measure: Participants
	3 100.0%	5 100.0%	7 87.5%	5 100.0%	11 100.0%	7 87.5%	11 100.0%

5. Secondary Outcome

Title	Area Under the Concentration-Time Curve (AUC) From 0 to 24 Hours Post AZD3965 Dosing
Description	Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed liquid chromatography tandem mass spectrometry (LC-MS/MS) method. For twice daily dosing, Day -7 data reflect the full daily dose but subsequent timepoints reflect half the daily dose as PK sampling was conducted up to 12 hours following the first of the two daily doses; therefore, AUC is from 0 to 12 hours at those timepoints and is reported as a separate outcome measure.
Time Frame	Part 1 (Cohorts 1-4): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose) and Day 1 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Part 1: Eligible patients who received AZD3965 on Day -7 and had a baseline and post-dose sample analysed (N=32; could only be calculated for N=5 in Cohort 6 [N=6 for some PK parameters]); Part 2: Eligible patients who received AZD3965 on Day 1 and had a baseline and post-dose sample analysed (N=11). Only calculated for Day -7 and Day 1 in Part 1 and not calculated for other timepoints due to low number of samples or for Part 2 due to limited number of sampling timepoints.

Arm/Group Title	AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)
Arm/Group Description:	AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed	3	5	8	5	6	5
Mean (Standard Deviation); Unit of Measure: h*ng/mL
Day -7	211.7 (84.9)	730.8 (311.4)	1509.3 (384.8)	2843 (1337.4)	3984.7 (2339.9)	1540 (693.6)
Day 1	274 (1)	999 (126.3)	2123.5 (589.6)	3031 (1360.5)	NA [1] (NA)	NA [1] (NA)

[1]

For twice daily dosing, Day -7 data reflect the full daily dose but subsequent timepoints reflect half the daily dose as PK sampling was conducted up to 12 hours following the first of the two daily doses; therefore, AUC is from 0 to 12 hours at those timepoints and is reported as a separate outcome measure

6. Secondary Outcome

Title	AUC From 0 to 12 Hours Post AZD3965 Dosing
Description	Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed LC-MS/MS method. AUC from 0 to 12 hours was applicable to twice daily dosing on Day 1 only. See AUC From 0 to 24 Hours Post AZD3965 Dosing for AUC for other cohorts and timepoints.
Time Frame	Part 1 (Cohorts 5-6): Day 1 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 12 hours post-dose)

Outcome Measure Data

Analysis Population Description

Part 1: Eligible patients who received AZD3965 on Day -7 and had a baseline and post-dose sample analysed (N=32; could only be calculated for N=5 in Cohort 6 [N=6 for some PK parameters]); Part 2: Eligible patients who received AZD3965 on Day 1 and had a baseline and post-dose sample analysed (N=11). Only calculated for Day -7 and Day 1 in Part 1 and not calculated for other timepoints due to low number of samples or for Part 2 due to limited number of sampling timepoints.

Arm/Group Title	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)
Arm/Group Description:	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed	6	5
Mean (Standard Deviation); Unit of Measure: h*ng/mL
	1251.5 (654.2)	620 (272.2)

7. Secondary Outcome

Title	Maximum Observed Plasma Concentration of AZD3965
Description	Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed LC-MS/MS method. For twice daily dosing, Day -7 data reflect the full daily dose and other timepoints reflect half the daily dose.
Time Frame	Part 1 (Cohorts 1-6): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose), Day 1 & 29 (each pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24 hours post-dose [12 hours post-dose if BD]); Part 2 (Expansion): Day 1 (pre-dose; 4, 6, 12 hours post-dose)

Outcome Measure Data

Analysis Population Description

Part 1: Eligible patients who received AZD3965 on Day -7 and had a baseline and post-dose sample analysed (N=33) (Only limited samples were available at Day 29); Part 2: Eligible patients who received AZD3965 on Day 1 and had a baseline and post-dose sample analysed (in Part 2 of the trial, PK data were only collected for Day 1)

Arm/Group Title		AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)	AZD3965 Expansion Cohort (10 mg BD)
Arm/Group Description:		AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment (first 3 trial participants in the Expansion Cohort only; subsequent patients started treatment at Cycle 1, Day 1). Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed		3	5	8	5	6	6	6
Mean (Standard Deviation); Unit of Measure: ng/mL
Day -7	Number Analyzed	3 participants	5 participants	8 participants	5 participants	6 participants	6 participants	0 participants
		43.4 (22)	122 (62.7)	222.7 (95.1)	377.6 (80.2)	483.9 (205.7)	226 (85.7)
Day 1	Number Analyzed	3 participants	5 participants	8 participants	5 participants	6 participants	6 participants	6 participants
		38.4 (9.5)	135.0 (53.2)	219.9 (62.1)	458.4 (237)	213.6 (122.1)	106.2 (57.1)	78.5 (42.3)
Day 29	Number Analyzed	1 participants	2 participants	3 participants	1 participants	0 participants	5 participants	0 participants
		48.6 [1] (NA)	271.6 (123.3)	310.1 (180.6)	239.2 [1] (NA)		132.3 (38.6)

[1]

Only one patient had evaluable data at this timepoint

8. Secondary Outcome

Title	Time to Maximum Observed Concentration of AZD3965
Description	Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed LC-MS/MS method. For twice daily dosing, Day -7 data reflect the full daily dose and other timepoints reflect half the daily dose.
Time Frame	Part 1 (Cohorts 1-6): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose) and Day 1 (pre-dose, 0.25, 0.5, 1, 2, 4, 6, 24 hours post-dose [12 hours post-dose if BD])

Outcome Measure Data

Analysis Population Description

Part 1: Eligible patients who received AZD3965 on Day -7 and had a baseline and post-dose sample analysed (N=33); Part 2: Eligible patients who received AZD3965 on Day 1 and had a baseline and post-dose sample analysed (N=11). Only calculated for Day -7 and Day 1 in Part 1; not calculated for other timepoints due to low number of samples or for Part 2 due to number of sampling time points. One patient in Cohort 6 did not have Day -7 data (N=5).

Arm/Group Title		AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)
Arm/Group Description:		AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed		3	5	8	5	6	6
Median (Full Range); Unit of Measure: Hour
Day -7	Number Analyzed	3 participants	5 participants	8 participants	5 participants	6 participants	5 participants
		1.1; (1 to 2)	1.1; (1 to 4.1)	1; (0.5 to 2)	1.1; (0.5 to 2.1)	1.5; (0.9 to 4)	1.92; (0.95 to 4.02)
Day 1	Number Analyzed	3 participants	5 participants	8 participants	5 participants	6 participants	6 participants
		2; (1 to 4)	2; (1 to 4.2)	2.05; (1 to 6.1)	1.1; (1 to 3.9)	2; (1 to 4)	1.075; (0.98 to 6.08)

9. Secondary Outcome

Title	Elimination Half Life for AZD3965
Description	Plasma samples were analysed to determine the concentrations of AZD3965 using a previously developed LC-MS/MS method.
Time Frame	Part 1 (Cohorts 1-6): Day -7 (pre-dose; 0.25, 0.5, 1, 2, 4, 6, 24, 48 hours post-dose and Day 1 pre-dose (168 hours post Day -7 dose)

Outcome Measure Data

Analysis Population Description

Part 1: Eligible patients who received AZD3965 on Day -7 and had a baseline and post-dose sample analysed (N=32; one patient had a reduced dose in Cohort 6 at Day -7 so these data are not included in half life calculation). Not calculated for Part 2 due to limited number of sampling timepoints.

Arm/Group Title	AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)
Arm/Group Description:	AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed	3	5	8	5	6	5
Mean (Standard Deviation); Unit of Measure: Hour
	51.9 (4.9)	45.4 (6.4)	38.3 (5.9)	38.7 (13.3)	37.5 (8.5)	33.6 (4.3)

10. Secondary Outcome

Title	Plasma Level of Cell Death Marker M30 (Caspase-Cleaved CK18; Part 1 Only)
Description	Plasma samples were analysed to determine the level of M30 using a validated cell death ELISA in Part 1 (Cohorts 1-6). Assays not conducted for Part 2 of the trial as considered uninformative.
Time Frame	Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose)

Outcome Measure Data

Analysis Population Description

All patients in Part 1 who received AZD3965 and provided pre and post-treatment blood samples (N=37). Some patients did not have data at all timepoints

Arm/Group Title		AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)
Arm/Group Description:		AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed		3	5	8	5	11	5
Mean (Standard Deviation); Unit of Measure: U/L
Baseline	Number Analyzed	1 participants	4 participants	8 participants	5 participants	11 participants	5 participants
		383 [1] (NA)	944.8 (72.6)	392.3 (300.3)	196.0 (96.3)	464.9 (304.9)	359.6 (364)
Day -7	Number Analyzed	2 participants	5 participants	8 participants	5 participants	11 participants	5 participants
		201 (17)	865.6 (250.3)	410.1 (296.5)	225.6 (114.5)	464.8 (312.3)	342 (371.9)
Day 1	Number Analyzed	2 participants	5 participants	8 participants	5 participants	11 participants	5 participants
		174.5 (60.1)	860.6 (191.5)	428.4 (302.9)	220.6 (112.7)	487.9 (326.9)	336.6 (375.9)
Day 8	Number Analyzed	3 participants	5 participants	7 participants	5 participants	9 participants	5 participants
		226 (86.2)	959.4 (90.8)	457.1 (339.5)	206.8 (90.2)	418.6 (327.8)	343.4 (370.8)
Day 29	Number Analyzed	2 participants	3 participants	5 participants	4 participants	3 participants	5 participants
		176 (46.7)	836.7 (282.9)	428 (366.6)	267.8 (157.8)	660.3 (489.7)	344.6 (369.5)

[1]

Only one patient had evaluable data at this timepoint

11. Secondary Outcome

Title	Plasma Level of Cell Death Marker M65 (Total Plus Caspase-Cleaved CK18; Part 1 Only)
Description	Plasma samples were analysed to determine the level of M65 using a validated cell death enzyme-linked immunosorbent assay (ELISA) in Part 1 (Cohorts 1-6). Assays not conducted for Part 2 of the trial as considered uninformative.
Time Frame	Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose)

Outcome Measure Data

Analysis Population Description

All patients in Part 1 who received AZD3965 and provided pre and post-treatment blood samples (N=37). Some patients did not have data at all timepoints

Arm/Group Title		AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)
Arm/Group Description:		AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed		3	5	8	5	11	5
Mean (Standard Deviation); Unit of Measure: U/L
Baseline	Number Analyzed	1 participants	4 participants	8 participants	5 participants	11 participants	5 participants
		533.0 [1] (NA)	4496.0 (1008.0)	1602.1 (1627.4)	1046.6 (1338.7)	1344.3 (1202.5)	287.6 (192.2)
Day -7	Number Analyzed	2 participants	5 participants	8 participants	5 participants	11 participants	5 participants
		623.5 (446.2)	3846.4 (1772.5)	1796.4 (1697.6)	935.6 (1000.7)	1488.7 (1409.6)	233.2 (126.9)
Day 1	Number Analyzed	2 participants	5 participants	8 participants	5 participants	11 participants	5 participants
		469.0 (12.7)	3935.6 (1522.0)	1742.0 (1840.9)	981.0 (1054.8)	1673.0 (1450.2)	255.4 (157.3)
Day 8	Number Analyzed	3 participants	5 participants	7 participants	5 participants	9 participants	5 participants
		841.3 (651.4)	4478.4 (730.2)	1807.0 (2072.6)	474.2 (568.5)	1418.4 (1472.6)	252.0 (155.1)
Day 29	Number Analyzed	2 participants	3 participants	5 participants	4 participants	3 participants	5 participants
		801.5 (314.7)	5000.0 (0.0)	1226.8 (2123.2)	443.0 (566.5)	2609.3 (2452.2)	285.0 (172.3)

[1]

Only one patient had evaluable data at this timepoint

12. Secondary Outcome

Title	Plasma Level of Nucleosomal DNA (nDNA) as a Measure of Apoptosis (Part 1 Only)
Description	Plasma samples were analysed to determine the level of nDNA using validated methodology in Part 1 (Cohorts 1-6). Assays not conducted for Part 2 of the trial as considered uninformative.
Time Frame	Baseline (Day -14 to -8), Day -7 (pre-dose) Day 1 (24 hours post-dose), Day 8 (pre-dose), Day 29 (pre-dose)

Outcome Measure Data

Analysis Population Description

All patients in Part 1 who received AZD3965 and provided pre and post-treatment blood samples (N=37). Some patients did not have data at all timepoints

Arm/Group Title		AZD3965 Cohort 1 (5 mg OD)	AZD3965 Cohort 2 (10 mg OD)	AZD3965 Cohort 3 (20 mg OD)	AZD3965 Cohort 4 (30 mg OD)	AZD3965 Cohort 5 (15 mg BD)	AZD3965 Cohort 6 (10 mg BD)
Arm/Group Description:		AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed		3	5	8	5	11	5
Mean (Standard Deviation); Unit of Measure: Optical density
Baseline	Number Analyzed	1 participants	4 participants	8 participants	5 participants	11 participants	5 participants
		0.123 [1] (NA)	0.778 (1.144)	0.614 (0.865)	0.170 (0.138)	0.485 (0.879)	0.139 (0.134)
Day -7	Number Analyzed	2 participants	5 participants	8 participants	5 participants	11 participants	5 participants
		0.450 (0.180)	0.731 (0.860)	0.580 (0.889)	0.204 (0.187)	0.259 (0.257)	0.140 (0.158)
Day 1	Number Analyzed	2 participants	5 participants	8 participants	5 participants	11 participants	5 participants
		0.397 (0.372)	0.924 (1.114)	0.593 (0.796)	0.200 (0.186)	0.241 (0.191)	0.140 (0.146)
Day 8	Number Analyzed	3 participants	5 participants	7 participants	5 participants	9 participants	5 participants
		0.441 (0.280)	1.111 (1.059)	0.697 (1.033)	0.206 (0.135)	0.287 (0.305)	0.149 (0.136)
Day 29	Number Analyzed	2 participants	3 participants	5 participants	4 participants	3 participants	5 participants
		0.298 (0.270)	1.060 (0.538)	0.841 (1.208)	0.144 (0.116)	0.195 (0.179)	0.156 (0.144)

[1]

Only one patient had evaluable data at this timepoint

13. Secondary Outcome

Title	Number of Patients Who Experienced a Complete Response, Partial Response or Stable Disease According to RECIST 1.1 or a Complete Remission, Partial Remission or Stable Disease According to the IWG Criteria for Lymphoma (Part 2 Only)
Description	Antitumour activity measured according to RECIST version 1.1 (solid tumours)(see Eishenhauer et al; Eur J Cancer 2009, 45:228-247) or IWG criteria for Lymphoma (lymphoma)(see Cheson, Fisher et al; JCO 2014, 32:3059-3067). Complete or partial response/remission was confirmed by repeat measurements ≥4 weeks after response criteria were met; patients with stable disease met criteria at least once ≥6 weeks after first dose of AZD3965
Time Frame	Radiological disease assessment at screening/baseline and every 6 weeks to end of treatment; an average (median) of 44 days (range: 36 to 432 days)

Outcome Measure Data

Analysis Population Description

Part 2: All patients who met the eligibility criteria, received at least 75% of their first continuous treatment cycle (28 days) and had a baseline assessment of disease (N=5)

Arm/Group Title	AZD3965 Expansion Cohort (10 mg BD)
Arm/Group Description:	AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment (first 3 trial participants in the Expansion Cohort only; subsequent patients started treatment at Cycle 1, Day 1). Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
Overall Number of Participants Analyzed	5
Measure Type: Count of Participants; Unit of Measure: Participants
Stable disease	1 20.0%
Complete remission	1 20.0%

Adverse Events

Time Frame	Safety data was collected from the date of written informed consent and continued until 28 days after the last dose of AZD3965, an average (median) of 80 days (range: 36-517).
Adverse Event Reporting Description	AE terms from vocabulary, NCI CTCAE V4.02 for Part 1 (AZD3965 Cohorts 1-6) and MedDRA V23.0 for Part 2 (Expansion Cohort)
Arm/Group Title	AZD3965 Cohort 1 (5 mg OD)		AZD3965 Cohort 2 (10 mg OD)		AZD3965 Cohort 3 (20 mg OD)		AZD3965 Cohort 4 (30 mg OD)		AZD3965 Cohort 5 (15 mg BD)		AZD3965 Cohort 6 (10 mg BD)		AZD3965 Expansion Cohort (10 mg BD)
Arm/Group Description	AZD3965: Day -7: single dose of 5 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 5 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.		AZD3965: Day -7: single dose of 10 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.		AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 20 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.		AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 30 mg AZD3965 OD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.		AZD3965: Day -7: single dose of 30 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 15 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.		AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment. Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Trial participants benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.		AZD3965: Day -7: single dose of 20 mg AZD3965 orally prior to start of continuous treatment (first 3 trial participants in the Expansion Cohort only; subsequent patients started treatment at Cycle 1, Day 1). Cycle 1, Day 1: commenced dosing of 10 mg AZD3965 BD orally for up to 6 28-day cycles. Patients benefitting from treatment could continue beyond 6 cycles for as long as they continued to benefit on agreement between the Investigator and the Sponsor.
All-Cause Mortality
	AZD3965 Cohort 1 (5 mg OD)		AZD3965 Cohort 2 (10 mg OD)		AZD3965 Cohort 3 (20 mg OD)		AZD3965 Cohort 4 (30 mg OD)		AZD3965 Cohort 5 (15 mg BD)		AZD3965 Cohort 6 (10 mg BD)		AZD3965 Expansion Cohort (10 mg BD)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	1/3 (33.33%)		1/5 (20.00%)		0/8 (0.00%)		0/5 (0.00%)		0/11 (0.00%)		0/8 (0.00%)		0/11 (0.00%)
Serious Adverse Events
	AZD3965 Cohort 1 (5 mg OD)		AZD3965 Cohort 2 (10 mg OD)		AZD3965 Cohort 3 (20 mg OD)		AZD3965 Cohort 4 (30 mg OD)		AZD3965 Cohort 5 (15 mg BD)		AZD3965 Cohort 6 (10 mg BD)		AZD3965 Expansion Cohort (10 mg BD)
	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 (33.33%)		1/5 (20.00%)		3/8 (37.50%)		2/5 (40.00%)		8/11 (72.73%)		4/8 (50.00%)		8/11 (72.73%)
Blood and lymphatic system disorders
Anemia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Cardiac disorders
Pericardial effusion † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	0/11 (0.00%)	0
Eye disorders
Retinopathy † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	1/8 (12.50%)	1	0/11 (0.00%)	0
Gastrointestinal disorders
Abdominal pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	2	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Diarrhea † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Vomiting † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	1/8 (12.50%)	1	1/11 (9.09%)	1
General disorders
Chills † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	0/11 (0.00%)	0
Death NOS † 1	1/3 (33.33%)	1	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Fatigue † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Fever † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Infusion related reaction † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Oedema peripheral † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Ulcer † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Infections and infestations
Infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Infections and infestations - Other, specify † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Infective exacerbation of bronchiectasis † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Lung infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	2/8 (25.00%)	2	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	0/11 (0.00%)	0
Ophthalmic herpes zoster † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Sepsis † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	2/11 (18.18%)	2
Injury, poisoning and procedural complications
Accidental overdose † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Hip fracture † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Investigations
Blood bilirubin increased † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Cardiac troponin I increased † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Cardiac troponin T increased † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Troponin I increased † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Metabolism and nutrition disorders
Acidosis † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	0/11 (0.00%)	0
Hypercalcemia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	2	0/8 (0.00%)	0	0/11 (0.00%)	0
Pain in jaw † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplastic syndrome † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Tumor pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Nervous system disorders
Headache † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Renal and urinary disorders
Renal and urinary disorders - Other, specify † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Urinary retention † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	2/8 (25.00%)	2	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Hypoxia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Lower respiratory tract infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Pneumonitis † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	0/11 (0.00%)	0
Vascular disorders
Hypotension † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Pulmonary embolism † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
1 Term from vocabulary, CTCAE4.02/MedDRA23.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	AZD3965 Cohort 1 (5 mg OD)		AZD3965 Cohort 2 (10 mg OD)		AZD3965 Cohort 3 (20 mg OD)		AZD3965 Cohort 4 (30 mg OD)		AZD3965 Cohort 5 (15 mg BD)		AZD3965 Cohort 6 (10 mg BD)		AZD3965 Expansion Cohort (10 mg BD)
	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 (100.00%)		5/5 (100.00%)		7/8 (87.50%)		5/5 (100.00%)		11/11 (100.00%)		7/8 (87.50%)		11/11 (100.00%)
Blood and lymphatic system disorders
Anemia † 1	1/3 (33.33%)	2	3/5 (60.00%)	4	3/8 (37.50%)	3	2/5 (40.00%)	6	4/11 (36.36%)	4	0/8 (0.00%)	0	1/11 (9.09%)	1
Blood and lymphatic system disorders - Other, specify † 1	2/3 (66.67%)	2	2/5 (40.00%)	3	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Cardiac disorders
Atrial fibrillation † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Atrial flutter † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Chest pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	2/11 (18.18%)	2
Sinus tachycardia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Supraventricular tachycardia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Eye disorders
Blindness transient † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Blurred vision † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	2/5 (40.00%)	2	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Cataract † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	1/11 (9.09%)	1
Conjunctivitis † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	2/11 (18.18%)	2
Ear pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Eye disorders - Other, specify † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	2/5 (40.00%)	3	1/11 (9.09%)	1	1/8 (12.50%)	1	0/11 (0.00%)	0
Eye inflammation † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Eye pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Optic nerve disorder † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Retinal vascular disorder † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Retinopathy † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	2/8 (25.00%)	3	5/5 (100.00%)	7	4/11 (36.36%)	6	2/8 (25.00%)	3	0/11 (0.00%)	0
Vision blurred † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	2/11 (18.18%)	2
Watering eyes † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Dry eye † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Gastrointestinal disorders
Abdominal discomfort † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Abdominal pain † 1	1/3 (33.33%)	3	3/5 (60.00%)	4	1/8 (12.50%)	1	1/5 (20.00%)	1	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	2
Bloating † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Constipation † 1	3/3 (100.00%)	3	1/5 (20.00%)	1	3/8 (37.50%)	4	2/5 (40.00%)	2	4/11 (36.36%)	4	2/8 (25.00%)	2	2/11 (18.18%)	2
Diarrhea † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	4/11 (36.36%)	4
Dry mouth † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	1/8 (12.50%)	1	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	1/11 (9.09%)	1
Dyspepsia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Dysphagia † 1	1/3 (33.33%)	1	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Enterovesical fistula † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Esophagitis † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Gastroesophageal reflux disease † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Mucositis oral † 1	1/3 (33.33%)	2	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	2/11 (18.18%)	4	0/8 (0.00%)	0	0/11 (0.00%)	0
Nausea † 1	3/3 (100.00%)	3	4/5 (80.00%)	5	1/8 (12.50%)	1	2/5 (40.00%)	4	3/11 (27.27%)	3	1/8 (12.50%)	1	3/11 (27.27%)	3
Oral hemorrhage † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Oral pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Toothache † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	0/11 (0.00%)	0
Vomiting † 1	2/3 (66.67%)	2	2/5 (40.00%)	4	0/8 (0.00%)	0	1/5 (20.00%)	3	4/11 (36.36%)	4	2/8 (25.00%)	2	2/11 (18.18%)	2
General disorders
Cyst † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Edema limbs † 1	0/3 (0.00%)	0	2/5 (40.00%)	2	2/8 (25.00%)	2	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Facial pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Fatigue † 1	2/3 (66.67%)	2	4/5 (80.00%)	4	2/8 (25.00%)	2	1/5 (20.00%)	1	3/11 (27.27%)	3	5/8 (62.50%)	5	5/11 (45.45%)	5
Fever † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	1/8 (12.50%)	1	1/5 (20.00%)	1	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Flu like symptoms † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Malaise † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Non-cardiac chest pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	2/11 (18.18%)	2	0/8 (0.00%)	0	0/11 (0.00%)	0
Oedema peripheral † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	5/11 (45.45%)	6
Pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	2/11 (18.18%)	2
Performance status decreased † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Pyrexia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Infections and infestations
Candida infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	3/11 (27.27%)	3
Fungal skin infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
H3N2 influenza † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Infections and infestations - Other, specify † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	1/8 (12.50%)	1	0/5 (0.00%)	0	4/11 (36.36%)	5	0/8 (0.00%)	0	0/11 (0.00%)	0
Lip infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Localised infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Lower respiratory tract infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Moraxella infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Nasopharyngitis † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Oral herpes † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Pseudomonas infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Rhinitis † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Rhinitis infective † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Upper respiratory infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	3/8 (37.50%)	3	0/11 (0.00%)	0
Upper respiratory tract infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	2
Urinary tract infection † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	2/8 (25.00%)	2	1/5 (20.00%)	2	3/11 (27.27%)	4	1/8 (12.50%)	1	0/11 (0.00%)	0
Injury, poisoning and procedural complications
Bruising † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Hip fracture † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Injury, poisoning and procedural complications - Other, specify † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Investigations
Alanine aminotransferase increased † 1	2/3 (66.67%)	3	1/5 (20.00%)	1	2/8 (25.00%)	3	0/5 (0.00%)	0	2/11 (18.18%)	2	1/8 (12.50%)	1	0/11 (0.00%)	0
Alkaline phosphatase increased † 1	1/3 (33.33%)	1	2/5 (40.00%)	3	3/8 (37.50%)	3	0/5 (0.00%)	0	0/11 (0.00%)	0	2/8 (25.00%)	2	0/11 (0.00%)	0
Aspartate aminotransferase increased † 1	2/3 (66.67%)	4	2/5 (40.00%)	2	3/8 (37.50%)	3	0/5 (0.00%)	0	1/11 (9.09%)	1	1/8 (12.50%)	1	0/11 (0.00%)	0
Blood bilirubin increased † 1	2/3 (66.67%)	3	0/5 (0.00%)	0	1/8 (12.50%)	3	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	0/11 (0.00%)	0
Cardiac troponin I increased † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	3	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Cardiac troponin T increased † 1	1/3 (33.33%)	1	1/5 (20.00%)	1	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	0/11 (0.00%)	0
Creatinine increased † 1	1/3 (33.33%)	1	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	1/8 (12.50%)	1	0/11 (0.00%)	0
Investigations - Other, specify † 1	2/3 (66.67%)	5	2/5 (40.00%)	5	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Lymphocyte count decreased † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	0/11 (0.00%)	0
Retinogram abnormal † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Weight increased † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Weight loss † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Metabolism and nutrition disorders
Anorexia † 1	1/3 (33.33%)	1	3/5 (60.00%)	4	2/8 (25.00%)	2	2/5 (40.00%)	2	4/11 (36.36%)	4	3/8 (37.50%)	3	0/11 (0.00%)	0
Decreased appetite † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	3/11 (27.27%)	3
Dehydration † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Hypercalcemia † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Hyperkalemia † 1	1/3 (33.33%)	1	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Hypoalbuminemia † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	1/8 (12.50%)	1	0/5 (0.00%)	0	2/11 (18.18%)	2	1/8 (12.50%)	1	1/11 (9.09%)	1
Hypocalcemia † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Hypokalaemia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	3/11 (27.27%)	3
Hypomagnesaemia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Hyponatremia † 1	1/3 (33.33%)	1	3/5 (60.00%)	4	1/8 (12.50%)	1	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Hypophosphatemia † 1	0/3 (0.00%)	0	1/5 (20.00%)	3	1/8 (12.50%)	2	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	3/11 (27.27%)	4
Increased appetite † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Metabolism and nutrition disorders - Other, specify † 1	2/3 (66.67%)	2	1/5 (20.00%)	2	2/8 (25.00%)	3	1/5 (20.00%)	1	2/11 (18.18%)	3	1/8 (12.50%)	1	0/11 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	2/8 (25.00%)	2	0/5 (0.00%)	0	4/11 (36.36%)	4	1/8 (12.50%)	1	1/11 (9.09%)	1
Back pain † 1	1/3 (33.33%)	1	1/5 (20.00%)	1	0/8 (0.00%)	0	1/5 (20.00%)	1	0/11 (0.00%)	0	1/8 (12.50%)	1	1/11 (9.09%)	1
Bone pain † 1	1/3 (33.33%)	2	0/5 (0.00%)	0	1/8 (12.50%)	1	1/5 (20.00%)	1	0/11 (0.00%)	0	1/8 (12.50%)	1	0/11 (0.00%)	0
Chest wall pain † 1	1/3 (33.33%)	1	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	0/11 (0.00%)	0
Generalized muscle weakness † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Muscle spasms † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	2/11 (18.18%)	2
Musculoskeletal discomfort † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	2/11 (18.18%)	2
Musculoskeletal pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Myalgia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Neck pain † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Pain in extremity † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	2/8 (25.00%)	4	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	2/11 (18.18%)	2
Nervous system disorders
Ataxia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Balance disorder † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Concentration impairment † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Dizziness † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	3/11 (27.27%)	3	0/8 (0.00%)	0	0/11 (0.00%)	0
Dysgeusia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	2/11 (18.18%)	2	0/8 (0.00%)	0	0/11 (0.00%)	0
Dysphasia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Headache † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	2/11 (18.18%)	3	2/8 (25.00%)	2	0/11 (0.00%)	0
Movements involuntary † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	2	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Nervous system disorders - Other, specify † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Neuralgia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	3
Paresthesia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Peripheral sensory neuropathy † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Taste disorder † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Product Issues
Device occlusion † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Psychiatric disorders
Anxiety † 1	1/3 (33.33%)	1	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Depression † 1	1/3 (33.33%)	1	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Insomnia † 1	1/3 (33.33%)	1	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Renal and urinary disorders
Cystitis noninfective † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Hematuria † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Nocturia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Pollakiuria † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Proteinuria † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Urinary incontinence † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Urine discoloration † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Reproductive system and breast disorders
Genitals enlarged † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Respiratory, thoracic and mediastinal disorders
Cough † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	1/5 (20.00%)	1	1/11 (9.09%)	1	0/8 (0.00%)	0	3/11 (27.27%)	3
Dysphonia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Dyspnea † 1	1/3 (33.33%)	1	2/5 (40.00%)	2	1/8 (12.50%)	1	0/5 (0.00%)	0	1/11 (9.09%)	1	1/8 (12.50%)	1	2/11 (18.18%)	2
Epistaxis † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Hoarseness † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Hypoxia † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Pleural effusion † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Productive cough † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	1/8 (12.50%)	1	3/11 (27.27%)	5
Respiratory, thoracic and mediastinal disorders - Other, specify † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	1/11 (9.09%)	1	0/8 (0.00%)	0	0/11 (0.00%)	0
Sore throat † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Skin and subcutaneous tissue disorders
Dry skin † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Erythema † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Hyperhidrosis † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Pruritus † 1	1/3 (33.33%)	1	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Rash acneiform † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Rash maculo-papular † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	1/8 (12.50%)	1	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Skin and subcutaneous tissue disorders - Other, specify † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Skin infection † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	1/5 (20.00%)	1	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Urticaria † 1	1/3 (33.33%)	3	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Vascular disorders
Deep vein thrombosis † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Hypertension † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
Orthostatic hypotension † 1	0/3 (0.00%)	0	0/5 (0.00%)	0	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	1/11 (9.09%)	1
Thromboembolic event † 1	0/3 (0.00%)	0	1/5 (20.00%)	1	0/8 (0.00%)	0	0/5 (0.00%)	0	0/11 (0.00%)	0	0/8 (0.00%)	0	0/11 (0.00%)	0
1 Term from vocabulary, CTCAE4.02/MedDRA23.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

Lactate accumulation in peripheral blood mononuclear cells was originally a measure for assessment of the primary objective but the assay was confounded by methodological problems and high inter-patient variability. This measure was removed for Part 2 and not used for assessment of the primary objective. M30, M65 and nDNA assays are only quasi quantitative; data >upper limit substituted with upper limit and data <lower limit substituted with lower limit/2.

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: Regulatory Affairs Manager
• Organization: Cancer Research UK Centre for Drug Development
• Phone: +44 203 4696878
• EMail: regulatory@cancer.org.uk

Publications:

Noble RA, Bell N, Blair H, Sikka A, Thomas H, Phillips N, Nakjang S, Miwa S, Crossland R, Rand V, Televantou D, Long A, Keun HC, Bacon CM, Bomken S, Critchlow SE, Wedge SR. Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma. Haematologica. 2017 Jul;102(7):1247-1257. doi: 10.3324/haematol.2016.163030. Epub 2017 Apr 6.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

McNeillis R, Greystoke A, Walton J, Bacon C, Keun H, Siskos A, Petrides G, Leech N, Jenkinson F, Bowron A, Halford S, Plummer R. A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965. Br J Cancer. 2020 Apr;122(8):1141-1145. doi: 10.1038/s41416-020-0727-8. Epub 2020 Feb 20. Erratum In: Br J Cancer. 2020 Mar 12;:

Kershaw S, Cummings J, Morris K, Tugwood J, Dive C. Optimisation of immunofluorescence methods to determine MCT1 and MCT4 expression in circulating tumour cells. BMC Cancer. 2015 May 10;15:387. doi: 10.1186/s12885-015-1382-y.

Lamb R, Harrison H, Hulit J, Smith DL, Lisanti MP, Sotgia F. Mitochondria as new therapeutic targets for eradicating cancer stem cells: Quantitative proteomics and functional validation via MCT1/2 inhibition. Oncotarget. 2014 Nov 30;5(22):11029-37. doi: 10.18632/oncotarget.2789.

• Responsible Party: Cancer Research UK
• ClinicalTrials.gov Identifier: NCT01791595
• Other Study ID Numbers: CRUKD/12/004; 2010-024463-41 ( EudraCT Number )
• First Submitted: February 11, 2013
• First Posted: February 15, 2013
• Results First Submitted: November 9, 2021
• Results First Posted: April 11, 2022
• Last Update Posted: April 11, 2022