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Clinical Trial Results:
A PHASE 1A/1B, MULTICENTER, OPEN LABEL, DOSE-FINDING STUDY TO ASSESS THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PRELIMINARY EFFICACY OF THE DUAL DNA-PK AND TOR KINASE INHIBITOR, CC-115, ADMINISTERED ORALLY TO SUBJECTS WITH ADVANCED SOLID TUMORS AND HEMATOLOGIC MALIGNANCIES

Summary
EudraCT number	2011-004558-24
Trial protocol	ES FR
Global end of trial date	12 Mar 2021

Results information
Results version number	v1(current)
This version publication date	20 Mar 2022
First version publication date	20 Mar 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CC-115-ST-001

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

25 Jun 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

12 Mar 2021

Was the trial ended prematurely?

Main objective of the trial

To determine the safety and tolerability of CC-115 when administered orally and to determine the pharmacokinetics (PK) of CC-115.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

25 Apr 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 6

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Spain: 15

Country: Number of subjects enrolled

United States: 94

Worldwide total number of subjects

118

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

118 participants were treated. 44 participants were treated in Part A, 74 participants were treated in Part B

Period 1 title

Dose Escalation + Dose Expansion (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

QD 0.5 mg

Arm description

CC-115 administered once a day at a dose of 0.5 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg QD (once a day)

QD 1 mg

Arm description

CC-115 administered once a day at a dose of 1 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1 mg QD (once a day)

QD 2 mg

Arm description

CC-115 administered once a day at a dose of 2 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 mg QD (once a day)

QD 4 mg

Arm description

CC-115 administered once a day at a dose of 4 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

4 mg QD (once a day)

QD 8 mg

Arm description

CC-115 administered once a day at a dose of 8 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

8 mg QD (once a day)

QD 16 mg

Arm description

CC-115 administered once a day at a dose of 16 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

16 mg QD (once a day)

QD 25 mg

Arm description

CC-115 administered once a day at a dose of 25 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

25 mg QD (once a day)

QD 40 mg

Arm description

CC-115 administered once a day at a dose of 40 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

40 mg QD (once a day)

BID 10 mg

Arm description

CC-115 administered twice a day at a dose of 10 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg BID (twice a day)

BID 15 mg

Arm description

CC-115 administered twice a day at a dose of 15 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

15 mg BID (twice a day)

Dose Expansion cohort - HNSCC

Arm description

Participants diagnosed with Head and Neck Squamous Cell Carcinoma (HNSCC). CC-115 administered twice a day at a dose of 10 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg BID (twice a day)

Dose Expansion cohort - GBM

Arm description

Participants diagnosed with Glioblastoma Multiforme (GBM). CC-115 administered twice a day at a dose of 10 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg BID (twice a day)

Dose Expansion cohort - CLL/SLL

Arm description

Participants diagnosed with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). CC-115 administered twice a day at a dose of 10 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg BID (twice a day)

Dose Expansion cohort - CRPC

Arm description

Participants diagnosed with Castration-Resistant Prostate Cancer (CRPC). CC-115 administered twice a day at a dose of 10 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg BID (twice a day)

Dose Expansion cohort - ES

Arm description

Participants diagnosed with Ewing's sarcoma (ES). CC-115 administered twice a day at a dose of 10 mg

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg BID (twice a day)

Dose Expansion cohort - BA/Food Effect

Arm description

Participants diagnosed with any tumor type and who were treated in the bioavailability(BA)/food effect substudy. CC-115 administered under fasted or fed conditions at 10 mg dose

Arm type

Experimental

Investigational medicinal product name

CC-115

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg under fasted or fed conditions

Number of subjects in period 1	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg	Dose Expansion cohort - HNSCC	Dose Expansion cohort - GBM	Dose Expansion cohort - CLL/SLL	Dose Expansion cohort - CRPC	Dose Expansion cohort - ES	Dose Expansion cohort - BA/Food Effect
Started	1	1	1	4	6	6	7	6	6	6	18	14	8	12	10	12
Completed	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Not completed	1	1	1	4	6	6	7	6	6	6	18	14	8	12	10	12
Adverse event, serious fatal	-	-	-	-	-	-	1	-	-	-	1	-	-	-	-	1
Physician decision	-	-	-	-	-	1	-	-	-	-	-	-	-	-	-	-
Consent withdrawn by subject	-	-	-	-	-	-	1	1	1	2	3	2	-	1	1	2
Disease progression	1	1	1	3	6	5	4	2	4	3	10	8	4	5	9	6
Adverse event, non-fatal	-	-	-	1	-	-	1	-	-	1	-	3	2	5	-	-
Other reasons	-	-	-	-	-	-	-	3	1	-	4	1	2	1	-	3

Baseline characteristics

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Reporting group title

QD 0.5 mg

Reporting group description

CC-115 administered once a day at a dose of 0.5 mg

Reporting group title

QD 1 mg

Reporting group description

CC-115 administered once a day at a dose of 1 mg

Reporting group title

QD 2 mg

Reporting group description

CC-115 administered once a day at a dose of 2 mg

Reporting group title

QD 4 mg

Reporting group description

CC-115 administered once a day at a dose of 4 mg

Reporting group title

QD 8 mg

Reporting group description

CC-115 administered once a day at a dose of 8 mg

Reporting group title

QD 16 mg

Reporting group description

CC-115 administered once a day at a dose of 16 mg

Reporting group title

QD 25 mg

Reporting group description

CC-115 administered once a day at a dose of 25 mg

Reporting group title

QD 40 mg

Reporting group description

CC-115 administered once a day at a dose of 40 mg

Reporting group title

BID 10 mg

Reporting group description

CC-115 administered twice a day at a dose of 10 mg

Reporting group title

BID 15 mg

Reporting group description

CC-115 administered twice a day at a dose of 15 mg

Reporting group title

Dose Expansion cohort - HNSCC

Reporting group description

Participants diagnosed with Head and Neck Squamous Cell Carcinoma (HNSCC). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - GBM

Reporting group description

Participants diagnosed with Glioblastoma Multiforme (GBM). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - CLL/SLL

Reporting group description

Participants diagnosed with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - CRPC

Reporting group description

Participants diagnosed with Castration-Resistant Prostate Cancer (CRPC). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - ES

Reporting group description

Participants diagnosed with Ewing's sarcoma (ES). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - BA/Food Effect

Reporting group description

Participants diagnosed with any tumor type and who were treated in the bioavailability(BA)/food effect substudy. CC-115 administered under fasted or fed conditions at 10 mg dose

Reporting group values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg	Dose Expansion cohort - HNSCC	Dose Expansion cohort - GBM	Dose Expansion cohort - CLL/SLL	Dose Expansion cohort - CRPC	Dose Expansion cohort - ES	Dose Expansion cohort - BA/Food Effect	Total
Number of subjects	1	1	1	4	6	6	7	6	6	6	18	14	8	12	10	12	118
Age Categorical
Units: Subjects
Adults (18-64 years)	0	1	1	3	6	5	7	4	4	3	15	13	7	3	10	6	88
From 65-84 years	1	0	0	1	0	1	0	2	2	3	3	1	1	9	0	6	30
85 years and over	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	73.0 ( 99999 )	58.0 ( 99999 )	57.0 ( 99999 )	49.8 ( 15.76 )	49.5 ( 18.92 )	47.0 ( 18.69 )	47.3 ( 15.27 )	60.3 ( 8.73 )	59.3 ( 10.60 )	62.2 ( 8.91 )	56.0 ( 10.47 )	53.0 ( 10.04 )	58.4 ( 7.69 )	67.8 ( 5.89 )	36.6 ( 12.86 )	60.8 ( 11.53 )	-
Gender Categorical
Units: Subjects
Female	1	0	0	3	2	4	4	3	3	5	5	4	3	0	2	8	47
Male	0	1	1	1	4	2	3	3	3	1	13	10	5	12	8	4	71
Race
Units: Subjects
Asian	0	0	1	1	1	3	1	0	0	0	0	0	0	0	0	0	7
Black or African American	0	0	0	0	0	1	0	1	0	0	0	1	0	0	0	1	4
White	1	1	0	3	5	2	5	5	6	6	18	12	8	12	10	10	104
Other	0	0	0	0	0	0	1	0	0	0	0	1	0	0	0	1	3
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	0	1	0	0	0	0	0	0	3	3	0	0	0	0	7
Not Hispanic or Latino	1	1	1	3	6	6	7	6	6	6	15	11	8	12	10	12	111

End points

Top of page

Reporting group title

QD 0.5 mg

Reporting group description

CC-115 administered once a day at a dose of 0.5 mg

Reporting group title

QD 1 mg

Reporting group description

CC-115 administered once a day at a dose of 1 mg

Reporting group title

QD 2 mg

Reporting group description

CC-115 administered once a day at a dose of 2 mg

Reporting group title

QD 4 mg

Reporting group description

CC-115 administered once a day at a dose of 4 mg

Reporting group title

QD 8 mg

Reporting group description

CC-115 administered once a day at a dose of 8 mg

Reporting group title

QD 16 mg

Reporting group description

CC-115 administered once a day at a dose of 16 mg

Reporting group title

QD 25 mg

Reporting group description

CC-115 administered once a day at a dose of 25 mg

Reporting group title

QD 40 mg

Reporting group description

CC-115 administered once a day at a dose of 40 mg

Reporting group title

BID 10 mg

Reporting group description

CC-115 administered twice a day at a dose of 10 mg

Reporting group title

BID 15 mg

Reporting group description

CC-115 administered twice a day at a dose of 15 mg

Reporting group title

Dose Expansion cohort - HNSCC

Reporting group description

Participants diagnosed with Head and Neck Squamous Cell Carcinoma (HNSCC). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - GBM

Reporting group description

Participants diagnosed with Glioblastoma Multiforme (GBM). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - CLL/SLL

Reporting group description

Participants diagnosed with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - CRPC

Reporting group description

Participants diagnosed with Castration-Resistant Prostate Cancer (CRPC). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - ES

Reporting group description

Participants diagnosed with Ewing's sarcoma (ES). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - BA/Food Effect

Reporting group description

Participants diagnosed with any tumor type and who were treated in the bioavailability(BA)/food effect substudy. CC-115 administered under fasted or fed conditions at 10 mg dose

Subject analysis set title

Bioavailability/Food Effect Cohort - fasting - capsule

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants in the Dose expansion cohort - BA/Food Effect under fasted conditions - capsule formulation

Subject analysis set title

Bioavailability/Food Effect Cohort - fasting - tablet

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants in the Dose expansion cohort - BA/Food Effect under fasted conditions - tablet formulation

Subject analysis set title

Bioavailability/Food Effect Cohort - fed

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants in the Dose expansion cohort - BA/Food Effect under fed conditions - tablet formulation

Primary: Number of Participants Experiencing Dose-Limiting Toxicity (DLT)

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End point title

Number of Participants Experiencing Dose-Limiting Toxicity (DLT) ^[1] ^[2]

End point description

Dose-Limiting Toxicity is defined according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4. Briefly, a DLT is any: - clinically relevant AE ≥ grade 3 that is suspected to be related to CC-115 and that commences within 28 days of first dose (with some exceptions). - Clinically relevant laboratory abnormality that is suspected to be related to CC-115 and that commences within 28 days of first dose (Cycle 1) and is ≥ grade 3, or any grade 4 laboratory abnormality that is suspected to be related to CC-115 regardless of clinical relevance. - Hyperglycemia meeting specific criteria. - Hematological toxicities meeting specific criteria. - Any AE suspected to be CC-115 related and necessitating dose reduction during Cycle 1.

End point type

Primary

End point timeframe

From first dose up to 28 days after first dose

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated in all the cohorts

End point values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg
Number of subjects analysed	1	1	1	3	6	6	6	5	6	6
Units: Participants	0	0	0	0	0	1	1	2	0	2

No statistical analyses for this end point

Primary: Maximum Observed Concentration (Cmax)

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End point title

Maximum Observed Concentration (Cmax) ^[3] ^[4]

End point description

End point type

Primary

End point timeframe

Cycle 1 Day 1 and Cycle 1 Day 15

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated in all the cohorts

End point values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg	Dose Expansion cohort - HNSCC	Dose Expansion cohort - CRPC
Number of subjects analysed	1	1	1	4	6	6	7	6	6	6	8	7
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	8.70 ( 99999 )	9.32 ( 99999 )	10.41 ( 99999 )	28.49 ( 19.3 )	36.07 ( 29.4 )	88.68 ( 72.6 )	173.45 ( 27.9 )	167.42 ( 53.3 )	51.80 ( 22.8 )	133.98 ( 43.5 )	42.39 ( 69.75 )	66.17 ( 33.10 )
Cycle 1 Day 15	8.65 ( 99999 )	8.11 ( 99999 )	13.16 ( 99999 )	30.51 ( 81.4 )	40.93 ( 25.6 )	118.22 ( 87.0 )	197.87 ( 40.4 )	243.64 ( 49.1 )	75.24 ( 45.2 )	161.99 ( 42.8 )	68.66 ( 43.17 )	112.41 ( 45.70 )

No statistical analyses for this end point

Primary: Maximum Observed Concentration (Cmax) - BA/Food Effect Cohort

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End point title

Maximum Observed Concentration (Cmax) - BA/Food Effect Cohort ^[5]

End point description

End point type

Primary

End point timeframe

Period 1 Day 1, Period 2 Day 1, Period 3 Day 1

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint

End point values	Bioavailability/Food Effect Cohort - fasting - capsule	Bioavailability/Food Effect Cohort - fasting - tablet	Bioavailability/Food Effect Cohort - fed
Number of subjects analysed	4	4	4
Units: ug/L
geometric mean (geometric coefficient of variation)
Period 1 Day 1	91.12 ( 61.59 )	50.12 ( 75.90 )	55.82 ( 39.55 )
Period 2 Day 1	84.48 ( 68.17 )	75.33 ( 69.94 )	35.90 ( 49.39 )
Period 3 Day 1	73.73 ( 92.36 )	122.49 ( 26.22 )	49.15 ( 31.25 )

No statistical analyses for this end point

Primary: Area Under the Concentration-Time Curve (AUC)

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End point title

Area Under the Concentration-Time Curve (AUC) ^[6] ^[7]

End point description

Multiple AUC (0 to X hours) were determined and are presented here. Results reported represent data collection at Cycle 1 Day 15 for AUC8, AUC12, AUC24 and AUCt. Results reported represent data collection at Cycle 1 Day 1 for AUC-inf.

End point type

Primary

End point timeframe

Cycle 1 Day 1 and Cycle 1 Day 15

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated in all the cohorts

End point values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg	Dose Expansion cohort - HNSCC	Dose Expansion cohort - CRPC
Number of subjects analysed	1	1	1	4	6	6	7	6	6	6	8	6
Units: ng*h/mL
geometric mean (geometric coefficient of variation)
AUC8	42.18 ( 99999 )	47.39 ( 99999 )	60.03 ( 99999 )	169.13 ( 70.2 )	181.82 ( 47.6 )	588.01 ( 115.0 )	943.05 ( 52.8 )	1285.54 ( 42.6 )	304.37 ( 35.8 )	802.75 ( 53.7 )	337.52 ( 62.17 )	547.19 ( 62.77 )
AUC12	53.21 ( 99999 )	65.79 ( 99999 )	72.95 ( 99999 )	234.18 ( 62.8 )	220.74 ( 57.1 )	757.98 ( 129.7 )	1180.32 ( 57.8 )	1732.76 ( 40.3 )	383.04 ( 43.4 )	1027.96 ( 55.7 )	374.29 ( 32.71 )	780.04 ( 65.58 )
AUC24	72.31 ( 99999 )	108.37 ( 99999 )	94.28 ( 99999 )	350.11 ( 62.9 )	285.56 ( 73.6 )	1094.97 ( 149.0 )	1573.20 ( 67.0 )	2650.16 ( 36.9 )	766.07 ( 43.4 )	2055.93 ( 55.7 )	99999 ( 99999 )	99999 ( 99999 )
AUC-inf	76.15 ( 99999 )	93.07 ( 99999 )	57.45 ( 99999 )	236.90 ( 48.4 )	237.47 ( 64.1 )	624.86 ( 81.7 )	1912.20 ( 92.1 )	2129.67 ( 45.3 )	605.32 ( 60.7 )	1306.58 ( 48.4 )	99999 ( 99999 )	99999 ( 99999 )
AUCt	72.31 ( 99999 )	108.37 ( 99999 )	94.28 ( 99999 )	350.11 ( 62.9 )	285.56 ( 73.6 )	1094.97 ( 149.0 )	1573.20 ( 67.0 )	2650.16 ( 36.9 )	506.67 ( 53.2 )	1657.68 ( 64.8 )	374.29 ( 32.71 )	780.04 ( 65.58 )

No statistical analyses for this end point

Primary: Area Under the Concentration-Time Curve (AUCinf) - BA/Food Effect Cohort

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End point title

Area Under the Concentration-Time Curve (AUCinf) - BA/Food Effect Cohort ^[8]

End point description

End point type

Primary

End point timeframe

Period 1 Day 1, Period 2 Day 1, Period 3 Day 1

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint

End point values	Bioavailability/Food Effect Cohort - fasting - capsule	Bioavailability/Food Effect Cohort - fasting - tablet	Bioavailability/Food Effect Cohort - fed
Number of subjects analysed	4	4	4
Units: h*ug/L
geometric mean (geometric coefficient of variation)
Period 1 Day 1	870.20 ( 79.06 )	505.24 ( 155.44 )	585.96 ( 96.77 )
Period 2 Day 1	621.70 ( 115.72 )	832.46 ( 75.74 )	720.13 ( 3.87 )
Period 3 Day 1	1023.01 ( 65.26 )	725.24 ( 79.47 )	666.99 ( 99999 )

No statistical analyses for this end point

Primary: Time to Maximum Concentration (Tmax)

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End point title

Time to Maximum Concentration (Tmax) ^[9] ^[10]

End point description

End point type

Primary

End point timeframe

Cycle 1 Day 1 and Cycle 1 Day 15

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated in all the cohorts

End point values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg	Dose Expansion cohort - HNSCC	Dose Expansion cohort - CRPC
Number of subjects analysed	1	1	1	4	6	6	7	6	6	6	8	7
Units: hr
arithmetic mean (standard deviation)
Cycle 1 Day 1	0.52 ( 99999 )	3.00 ( 99999 )	1.50 ( 99999 )	1.76 ( 0.876 )	1.92 ( 1.530 )	2.44 ( 0.940 )	2.67 ( 1.258 )	2.50 ( 1.478 )	2.11 ( 0.998 )	4.88 ( 9.215 )	1.714 ( 0.9512 )	1.571 ( 0.6726 )
Cycle 1 Day 15	1.50 ( 99999 )	1.67 ( 99999 )	2.13 ( 99999 )	3.36 ( 3.165 )	1.92 ( 1.004 )	2.04 ( 0.826 )	1.61 ( 0.829 )	3.02 ( 0.044 )	1.55 ( 0.677 )	1.83 ( 0.684 )	2.250 ( 1.3363 )	2.000 ( 1.5000 )

No statistical analyses for this end point

Primary: Time to Maximum Concentration (Tmax) - BA/Food Effect Cohort

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End point title

Time to Maximum Concentration (Tmax) - BA/Food Effect Cohort ^[11]

End point description

End point type

Primary

End point timeframe

Period 1 Day 1, Period 2 Day 1, Period 3 Day 1

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint

End point values	Bioavailability/Food Effect Cohort - fasting - capsule	Bioavailability/Food Effect Cohort - fasting - tablet	Bioavailability/Food Effect Cohort - fed
Number of subjects analysed	4	4	4
Units: hr
arithmetic mean (standard deviation)
Period 1 Day 1	1.875 ( 0.2500 )	2.375 ( 0.7500 )	3.000 ( 1.4142 )
Period 2 Day 1	1.875 ( 0.8539 )	1.500 ( 0.4082 )	9.000 ( 10.0995 )
Period 3 Day 1	2.250 ( 0.8660 )	0.875 ( 0.4787 )	6.500 ( 3.0000 )

No statistical analyses for this end point

Primary: Terminal Half-Life (t1/2)

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End point title

Terminal Half-Life (t1/2) ^[12] ^[13]

End point description

End point type

Primary

End point timeframe

Cycle 1 Day 1

Notes
[12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated in all the cohorts

End point values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg	Dose Expansion cohort - HNSCC	Dose Expansion cohort - CRPC
Number of subjects analysed	1	1	1	4	5	6	6	5	3	5	5	6
Units: hr
arithmetic mean (standard deviation)	11.93 ( 99999 )	10.60 ( 99999 )	6.17 ( 99999 )	6.61 ( 1.145 )	6.33 ( 2.098 )	7.63 ( 2.718 )	8.55 ( 4.264 )	7.96 ( 3.509 )	4.04 ( 0.827 )	5.68 ( 2.748 )	3.478 ( 2.0857 )	4.426 ( 1.6685 )

No statistical analyses for this end point

Primary: Terminal Half-Life (t1/2) - BA/Food Effect Cohort

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End point title

Terminal Half-Life (t1/2) - BA/Food Effect Cohort ^[14]

End point description

End point type

Primary

End point timeframe

Period 1 Day 1, Period 2 Day 1, Period 3 Day 1

Notes
[14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint

End point values	Bioavailability/Food Effect Cohort - fasting - capsule	Bioavailability/Food Effect Cohort - fasting - tablet	Bioavailability/Food Effect Cohort - fed
Number of subjects analysed	4	4	4
Units: hr
arithmetic mean (standard deviation)
Period 1 Day 1	14.350 ( 8.2051 )	9.686 ( 5.2947 )	8.793 ( 4.2063 )
Period 2 Day 1	8.569 ( 4.0371 )	13.261 ( 5.2962 )	11.286 ( 4.9139 )
Period 3 Day 1	13.301 ( 3.4328 )	7.856 ( 3.8410 )	11.896 ( 99999 )

No statistical analyses for this end point

Primary: Apparent Total Body Clearance (CL/F)

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End point title

Apparent Total Body Clearance (CL/F) ^[15] ^[16]

End point description

End point type

Primary

End point timeframe

Cycle 1 Day 1

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated in all the cohorts

End point values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg	Dose Expansion cohort - HNSCC	Dose Expansion cohort - CRPC
Number of subjects analysed	1	1	1	4	5	6	6	5	3	5	5	6
Units: mL/hr
geometric mean (geometric coefficient of variation)	6565.92 ( 99999 )	10744.76 ( 99999 )	34811.99 ( 99999 )	16884.66 ( 48.4 )	33687.82 ( 64.1 )	25605.72 ( 81.7 )	13073.92 ( 92.1 )	18782.26 ( 45.3 )	33040.44 ( 60.7 )	22960.71 ( 48.4 )	45310 ( 154.48 )	22940 ( 53.42 )

No statistical analyses for this end point

Primary: Apparent Total Body Clearance (CL/F) - BA/Food Effect Cohort

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End point title

Apparent Total Body Clearance (CL/F) - BA/Food Effect Cohort ^[17]

End point description

End point type

Primary

End point timeframe

Period 1 Day 1, Period 2 Day 1, Period 3 Day 1

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint

End point values	Bioavailability/Food Effect Cohort - fasting - capsule	Bioavailability/Food Effect Cohort - fasting - tablet	Bioavailability/Food Effect Cohort - fed
Number of subjects analysed	4	4	4
Units: L/hr
geometric mean (geometric coefficient of variation)
Period 1 Day 1	11.49 ( 79.06 )	19.79 ( 155.44 )	17.07 ( 96.77 )
Period 2 Day 1	16.08 ( 115.72 )	12.01 ( 75.74 )	13.89 ( 3.87 )
Period 3 Day 1	9.78 ( 65.26 )	13.79 ( 79.47 )	14.99 ( 99999 )

No statistical analyses for this end point

Primary: Apparent Volume of Distribution (Vz/F)

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End point title

Apparent Volume of Distribution (Vz/F) ^[18] ^[19]

End point description

End point type

Primary

End point timeframe

Cycle 1 Day 1

Notes
[18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated in all the cohorts

End point values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg	Dose Expansion cohort - HNSCC	Dose Expansion cohort - CRPC
Number of subjects analysed	1	1	1	4	5	6	6	5	3	5	5	6
Units: mL
geometric mean (geometric coefficient of variation)	113002.05 ( 99999 )	164320.03 ( 99999 )	310044.82 ( 99999 )	159056.04 ( 33.0 )	293636.64 ( 57.1 )	263877.04 ( 103.5 )	149036.99 ( 42.4 )	200931.87 ( 28.9 )	189478.26 ( 35.9 )	172900.26 ( 36.3 )	200450 ( 63.45 )	136170 ( 25.44 )

No statistical analyses for this end point

Primary: Apparent Volume of Distribution (Vz/F) - BA/Food Effect Cohort

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End point title

Apparent Volume of Distribution (Vz/F) - BA/Food Effect Cohort ^[20]

End point description

End point type

Primary

End point timeframe

Period 1 Day1, Period 2 Day 1, Period 3 Day 1

Notes
[20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint

End point values	Bioavailability/Food Effect Cohort - fasting - capsule	Bioavailability/Food Effect Cohort - fasting - tablet	Bioavailability/Food Effect Cohort - fed
Number of subjects analysed	4	4	4
Units: Liters
geometric mean (geometric coefficient of variation)
Period 1 Day 1	213.60 ( 179.03 )	229.85 ( 42.80 )	201.49 ( 58.84 )
Period 2 Day 1	185.77 ( 61.82 )	217.90 ( 121.48 )	215.12 ( 42.93 )
Period 3 Day 1	183.06 ( 56.26 )	145.21 ( 37.93 )	257.31 ( 99999 )

No statistical analyses for this end point

Primary: Drug Accumulation Ratio (Rac)

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End point title

Drug Accumulation Ratio (Rac) ^[21] ^[22]

End point description

End point type

Primary

End point timeframe

Cycle 1 Day 15

Notes
[21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were performed for this endpoint
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated in all the cohorts

End point values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg	Dose Expansion cohort - HNSCC	Dose Expansion cohort - CRPC
Number of subjects analysed	1	1	1	3	6	6	5	4	6	5	4	3
Units: Ratio
arithmetic mean (standard deviation)	1.18 ( 99999 )	1.63 ( 99999 )	1.12 ( 99999 )	1.33 ( 0.250 )	1.15 ( 0.183 )	1.36 ( 0.280 )	1.15 ( 0.075 )	2.94 ( 3.485 )	2.35 ( 0.599 )	4.33 ( 2.716 )	3.115 ( 2.8558 )	1.667 ( 0.3008 )

No statistical analyses for this end point

Secondary: Change from Baseline in Blood Levels of Phosphorylated 4E-Binding Protein 1 (pE4-BP1)

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End point title

Change from Baseline in Blood Levels of Phosphorylated 4E-Binding Protein 1 (pE4-BP1) ^[23]

End point description

Changes in pE4-BP1 (CD91+) are presented here

End point type

Secondary

End point timeframe

From baseline to Cycle 1 Day 2 (pre-dose)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated in all the cohorts

End point values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg
Number of subjects analysed	0 ^[24]	1	1	4	4	6	5	4	0 ^[25]	0 ^[26]
Units: Percent change from baseline
arithmetic mean (standard deviation)	( )	21.6 ( 99999 )	-8.9 ( 99999 )	10.7 ( 26.31 )	-3.4 ( 15.87 )	-33.8 ( 21.03 )	-14.4 ( 20.43 )	6.9 ( 34.94 )	( )	( )

Notes
[24] - No subjects analyzed in this cohort
[25] - No subjects analyzed in this cohort
[26] - No subjects analyzed in this cohort

No statistical analyses for this end point

Secondary: Change from Baseline in the Percent Ratio of Phosphorylated AKT (p-AKT)/ Total AKT

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End point title

Change from Baseline in the Percent Ratio of Phosphorylated AKT (p-AKT)/ Total AKT ^[27]

End point description

End point type

Secondary

End point timeframe

From baseline to Cycle 1 Day 2 (pre-dose)

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated in all the cohorts

End point values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg
Number of subjects analysed	0 ^[28]	0 ^[29]	1	4	4	6	6	6	0 ^[30]	0 ^[31]
Units: Percent change from baseline
arithmetic mean (standard deviation)	( )	( )	-40.8 ( 99999 )	23.7 ( 96.75 )	-47.6 ( 14.18 )	7.2 ( 70.69 )	-25.8 ( 40.05 )	-57.1 ( 27.51 )	( )	( )

Notes
[28] - No subjects analyzed in this cohort
[29] - No subjects analyzed in this cohort
[30] - No subjects analyzed in this cohort
[31] - No subjects analyzed in this cohort

No statistical analyses for this end point

Secondary: Change from Baseline in the Levels of UV-Stimulated phosphorylated DNA-dependent Protein Kinase (pDNA-PK)

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End point title

Change from Baseline in the Levels of UV-Stimulated phosphorylated DNA-dependent Protein Kinase (pDNA-PK) ^[32]

End point description

From baseline to Cycle 1 Day 15

End point type

Secondary

End point timeframe

pDNA-PK measured as H-score

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated in all the cohorts

End point values	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	BID 10 mg	BID 15 mg
Number of subjects analysed	1	1	1	3	6	5	6	4	0 ^[33]	0 ^[34]
Units: Percent change from baseline
arithmetic mean (standard deviation)	-16.7 ( 99999 )	14.9 ( 99999 )	1.5 ( 99999 )	2.2 ( 19.30 )	-3.1 ( 12.58 )	2.7 ( 21.20 )	1.9 ( 24.68 )	17.9 ( 24.88 )	( )	( )

Notes
[33] - No subjects analyzed in this cohort
[34] - No subjects analyzed in this cohort

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR)

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End point title

Objective Response Rate (ORR)

End point description

ORR is defined as the percentage of participants achieving a Complete Response (CR) or Partial Response (PR). Results are presented separately for Confirmed and Unconfirmed Responses. Unconfirmed Responses are based on investigator assessment using tumor-appropriate evaluation criteria.

End point type

Secondary

End point timeframe

From first dose to end of study, assessed every 2 cycles for the first 6 cycles, then every 3 cycles through the end of first year on study and then every 6 cycles thereafter

QD 0.5 mg

QD 1 mg

QD 2 mg

QD 4 mg

QD 8 mg

QD 16 mg

QD 25 mg

QD 40 mg

BID 10 mg

BID 15 mg

Dose Expansion cohort - HNSCC

Dose Expansion cohort - GBM

Dose Expansion cohort - CLL/SLL

Dose Expansion cohort - CRPC

Dose Expansion cohort - ES

Dose Expansion cohort - BA/Food Effect

Number of subjects analysed

0 ^[35]

Units: Percent of Participants

number (confidence interval 95%)

Unconfirmed responses

0 (-99999 to 99999)

16.7 (0.4 to 64.1)

0 (-99999 to 99999)

16.7 (0.4 to 64.1)

0 (-99999 to 99999)

0 (0 to 19.5)

( to )

12.5 (0.3 to 52.7)

0 (0 to 28.5)

0 (0 to 33.6)

18.2 (2.3 to 51.8)

Confirmed responses

0 (-99999 to 99999)

16.7 (0.4 to 64.1)

0 (-99999 to 99999)

0 (0 to 19.5)

( to )

99999 (99999 to 99999)

0 (0 to 33.6)

0 (0 to 28.5)

Notes
[35] - No measurements available for this cohort

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose to 100 days following last dose

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

QD 0.5 mg

Reporting group description

CC-115 administered once a day at a dose of 0.5 mg

Reporting group title

QD 1 mg

Reporting group description

CC-115 administered once a day at a dose of 1 mg

Reporting group title

QD 2 mg

Reporting group description

CC-115 administered once a day at a dose of 2 mg

Reporting group title

QD 4 mg

Reporting group description

CC-115 administered once a day at a dose of 4 mg

Reporting group title

QD 8 mg

Reporting group description

CC-115 administered once a day at a dose of 8 mg

Reporting group title

QD 16 mg

Reporting group description

CC-115 administered once a day at a dose of 16 mg

Reporting group title

QD 25 mg

Reporting group description

CC-115 administered once a day at a dose of 25 mg

Reporting group title

QD 40 mg

Reporting group description

CC-115 administered once a day at a dose of 40 mg

Reporting group title

Dose Expansion cohort - HNSCC

Reporting group description

Participants diagnosed with Head and Neck Squamous Cell Carcinoma (HNSCC). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

BID 15 mg

Reporting group description

CC-115 administered twice a day at a dose of 15 mg

Reporting group title

BID 10 mg

Reporting group description

CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - GBM

Reporting group description

Participants diagnosed with Glioblastoma Multiforme (GBM). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - ES

Reporting group description

Participants diagnosed with Ewing's sarcoma (ES). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - CRPC

Reporting group description

Participants diagnosed with Castration-Resistant Prostate Cancer (CRPC). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - CLL/SLL

Reporting group description

Participants diagnosed with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). CC-115 administered twice a day at a dose of 10 mg

Reporting group title

Dose Expansion cohort - BA/Food Effect

Reporting group description

Participants diagnosed with any tumor type and who were treated in the bioavailability(BA)/food effect substudy. CC-115 administered under fasted or fed conditions at 10 mg dose

QD 0.5 mg

QD 1 mg

QD 2 mg

QD 4 mg

QD 8 mg

QD 16 mg

QD 25 mg

QD 40 mg

Dose Expansion cohort - HNSCC

BID 15 mg

BID 10 mg

Dose Expansion cohort - GBM

Dose Expansion cohort - ES

Dose Expansion cohort - CRPC

Dose Expansion cohort - CLL/SLL

Dose Expansion cohort - BA/Food Effect

Total subjects affected by serious adverse events

subjects affected / exposed

0 / 1 (0.00%)

1 / 1 (100.00%)

0 / 1 (0.00%)

3 / 4 (75.00%)

2 / 6 (33.33%)

3 / 6 (50.00%)

2 / 7 (28.57%)

2 / 6 (33.33%)

8 / 18 (44.44%)

2 / 6 (33.33%)

3 / 6 (50.00%)

5 / 14 (35.71%)

4 / 10 (40.00%)

4 / 12 (33.33%)

5 / 8 (62.50%)

7 / 12 (58.33%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Adenocarcinoma gastric

subjects affected / exposed

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Alveolar soft part sarcoma metastatic

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Cancer pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Cholangiocarcinoma

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 6 (16.67%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Ewing's sarcoma metastatic

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Leiomyosarcoma

subjects affected / exposed

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Richter's syndrome

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Synovial sarcoma

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

occurrences causally related to treatment / all

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

Tumour pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 18 (5.56%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Deep vein thrombosis

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypotension

subjects affected / exposed

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Asthenia

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 6 (16.67%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fatigue

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

General physical health deterioration

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 18 (5.56%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 8 (12.50%)

2 / 12 (16.67%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

Non-cardiac chest pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pain

subjects affected / exposed

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Acute respiratory failure

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 18 (5.56%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Chronic obstructive pulmonary disease

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 18 (5.56%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

deaths causally related to treatment / all

0 / 0

Dyspnoea

subjects affected / exposed

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 18 (5.56%)

2 / 6 (33.33%)

0 / 6 (0.00%)

0 / 14 (0.00%)

1 / 10 (10.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypoxia

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pleural effusion

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonitis

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 18 (5.56%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary venous thrombosis

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

1 / 10 (10.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory failure

subjects affected / exposed

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

2 / 10 (20.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 2

0 / 0

Psychiatric disorders

Homicidal ideation

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Aspartate aminotransferase increased

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood alkaline phosphatase increased

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Femoral neck fracture

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Muscle strain

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Subdural haemorrhage

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Wound dehiscence

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 7 (14.29%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Aortic valve disease

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Headache

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

1 / 14 (7.14%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Seizure

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Thrombocytopenia

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Abdominal pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal wall haematoma

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

1 / 10 (10.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Constipation

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastric perforation

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

1 / 10 (10.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pancreatitis

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Small intestinal obstruction

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Acute hepatic failure

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Bile duct obstruction

subjects affected / exposed

0 / 1 (0.00%)

1 / 1 (100.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatic failure

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 7 (14.29%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Renal and urinary disorders

Acute kidney injury

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hydronephrosis

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Back pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Flank pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Acute sinusitis

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 18 (5.56%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bacteraemia

subjects affected / exposed

0 / 1 (0.00%)

1 / 1 (100.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 6 (16.67%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Device related infection

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Escherichia bacteraemia

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infection

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Meningitis

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 18 (5.56%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

1 / 8 (12.50%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyelonephritis

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyelonephritis acute

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 18 (5.56%)

0 / 6 (0.00%)

0 / 14 (0.00%)

1 / 10 (10.00%)

1 / 12 (8.33%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Septic shock

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

1 / 12 (8.33%)

occurrences causally related to treatment / all

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

Urinary tract infection

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

1 / 12 (8.33%)

1 / 8 (12.50%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Hypercalcaemia

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 18 (5.56%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

deaths causally related to treatment / all

0 / 0

Hyperglycaemia

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 6 (16.67%)

0 / 18 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 18 (5.56%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 10 (0.00%)

0 / 12 (0.00%)

0 / 8 (0.00%)

0 / 12 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	QD 0.5 mg	QD 1 mg	QD 2 mg	QD 4 mg	QD 8 mg	QD 16 mg	QD 25 mg	QD 40 mg	Dose Expansion cohort - HNSCC	BID 15 mg	BID 10 mg	Dose Expansion cohort - GBM	Dose Expansion cohort - ES	Dose Expansion cohort - CRPC	Dose Expansion cohort - CLL/SLL	Dose Expansion cohort - BA/Food Effect
Total subjects affected by non serious adverse events
subjects affected / exposed	1 / 1 (100.00%)	1 / 1 (100.00%)	1 / 1 (100.00%)	3 / 4 (75.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	7 / 7 (100.00%)	6 / 6 (100.00%)	18 / 18 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	14 / 14 (100.00%)	10 / 10 (100.00%)	12 / 12 (100.00%)	8 / 8 (100.00%)	12 / 12 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	2
Melanocytic naevus
subjects affected / exposed	0 / 1 (0.00%)	1 / 1 (100.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Tumour haemorrhage
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 18 (11.11%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0	0	0	0	0	0
Tumour necrosis
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Tumour pain
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 18 (11.11%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Vascular disorders
Arterial disorder
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Deep vein thrombosis
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	2 / 18 (11.11%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	0	0	0	1	2	0	0	1	0	0	0	1
Flushing
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1	0
Haematoma
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Hot flush
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Hypertension
subjects affected / exposed	0 / 1 (0.00%)	1 / 1 (100.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Hypotension
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	0 / 8 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	1	0	2
Orthostatic hypotension
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Pallor
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2
Peripheral coldness
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	3 / 18 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	4 / 10 (40.00%)	3 / 12 (25.00%)	2 / 8 (25.00%)	4 / 12 (33.33%)
occurrences all number	0	0	0	1	0	0	0	1	9	0	1	2	8	4	2	7
Chest discomfort
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	2
Chills
subjects affected / exposed	0 / 1 (0.00%)	1 / 1 (100.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	3	0	0	0	2	0	0	2	0	2	1	0	0	0	0
Cyst
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Discomfort
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Early satiety
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Face oedema
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	1	0
Facial pain
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Fatigue
subjects affected / exposed	0 / 1 (0.00%)	1 / 1 (100.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	6 / 7 (85.71%)	5 / 6 (83.33%)	11 / 18 (61.11%)	4 / 6 (66.67%)	3 / 6 (50.00%)	10 / 14 (71.43%)	4 / 10 (40.00%)	10 / 12 (83.33%)	1 / 8 (12.50%)	7 / 12 (58.33%)
occurrences all number	0	5	0	2	1	3	9	9	18	5	3	12	3	16	1	10
Gait disturbance
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 14 (14.29%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	0	0	0	1
General physical health deterioration
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Influenza like illness
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Malaise
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Mucosal inflammation
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	2 / 6 (33.33%)	3 / 18 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)	2 / 8 (25.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	2	6	1	0	0	0	1	3	1
Non-cardiac chest pain
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	2 / 10 (20.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	2	0	1	2
Oedema peripheral
subjects affected / exposed	1 / 1 (100.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 7 (28.57%)	1 / 6 (16.67%)	2 / 18 (11.11%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 10 (0.00%)	5 / 12 (41.67%)	2 / 8 (25.00%)	2 / 12 (16.67%)
occurrences all number	1	0	0	0	1	1	2	1	4	0	3	1	0	4	2	2
Pain
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0	0	0	1	0
Peripheral swelling
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	2
Pyrexia
subjects affected / exposed	0 / 1 (0.00%)	1 / 1 (100.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 7 (14.29%)	0 / 6 (0.00%)	5 / 18 (27.78%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 14 (14.29%)	1 / 10 (10.00%)	2 / 12 (16.67%)	5 / 8 (62.50%)	2 / 12 (16.67%)
occurrences all number	0	6	0	1	1	1	1	0	5	0	5	2	1	2	9	2
Swelling
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Temperature intolerance
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Tenderness
subjects affected / exposed	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Social circumstances

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants Experiencing Dose-Limiting Toxicity (DLT)

Primary: Number of Participants Experiencing Dose-Limiting Toxicity (DLT)

Primary: Maximum Observed Concentration (Cmax)

Primary: Maximum Observed Concentration (Cmax)

Primary: Maximum Observed Concentration (Cmax) - BA/Food Effect Cohort

Primary: Maximum Observed Concentration (Cmax) - BA/Food Effect Cohort

Primary: Area Under the Concentration-Time Curve (AUC)

Primary: Area Under the Concentration-Time Curve (AUC)

Primary: Area Under the Concentration-Time Curve (AUCinf) - BA/Food Effect Cohort

Primary: Area Under the Concentration-Time Curve (AUCinf) - BA/Food Effect Cohort

Primary: Time to Maximum Concentration (Tmax)

Primary: Time to Maximum Concentration (Tmax)

Primary: Time to Maximum Concentration (Tmax) - BA/Food Effect Cohort

Primary: Time to Maximum Concentration (Tmax) - BA/Food Effect Cohort

Primary: Terminal Half-Life (t1/2)

Primary: Terminal Half-Life (t1/2)

Primary: Terminal Half-Life (t1/2) - BA/Food Effect Cohort

Primary: Terminal Half-Life (t1/2) - BA/Food Effect Cohort

Primary: Apparent Total Body Clearance (CL/F)

Primary: Apparent Total Body Clearance (CL/F)

Primary: Apparent Total Body Clearance (CL/F) - BA/Food Effect Cohort

Primary: Apparent Total Body Clearance (CL/F) - BA/Food Effect Cohort

Primary: Apparent Volume of Distribution (Vz/F)

Primary: Apparent Volume of Distribution (Vz/F)

Primary: Apparent Volume of Distribution (Vz/F) - BA/Food Effect Cohort

Primary: Apparent Volume of Distribution (Vz/F) - BA/Food Effect Cohort

Primary: Drug Accumulation Ratio (Rac)

Primary: Drug Accumulation Ratio (Rac)

Secondary: Change from Baseline in Blood Levels of Phosphorylated 4E-Binding Protein 1 (pE4-BP1)

Secondary: Change from Baseline in Blood Levels of Phosphorylated 4E-Binding Protein 1 (pE4-BP1)

Secondary: Change from Baseline in the Percent Ratio of Phosphorylated AKT (p-AKT)/ Total AKT

Secondary: Change from Baseline in the Percent Ratio of Phosphorylated AKT (p-AKT)/ Total AKT

Secondary: Change from Baseline in the Levels of UV-Stimulated phosphorylated DNA-dependent Protein Kinase (pDNA-PK)

Secondary: Change from Baseline in the Levels of UV-Stimulated phosphorylated DNA-dependent Protein Kinase (pDNA-PK)

Secondary: Objective Response Rate (ORR)

Secondary: Objective Response Rate (ORR)

Adverse events